Leptin: Master Regulator of Biological Functions

that Affects Breathing

Estelle B. Gauda,*1 Silvia Conde,2 Mirian Bassi,3 Daniel B. Zoccal,3 Debora Simoes Almeida
Colombari,3 Eduardo Colombari,3 and Nikola Despotovic4

ABSTRACT
Obesity is a global epidemic in developed countries accounting for many of the metabolic and
cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep-
disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hyperten-
sion. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other
biological functions including central and peripheral circuits that control breathing. By binding
to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links
energy and metabolism to breathing. In this comprehensive article, we review the central and
peripheral locations of leptin’s actions that affect cardiorespiratory responses during health and
disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity-
induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO2
sensitivity. On the other hand, hyperleptinemia augments peripheral chemoreflexes to hypoxia and
induces sympathoexcitation. Thus, “leptin resistance” in obesity is relative. We delineate the cir-
cuits responsible for these divergent effects, including signaling pathways. We review the unique
effects of leptin during development on organogenesis, feeding behavior, and cardiorespiratory
responses, and how undernutrition and overnutrition during critical periods of development can
lead to cardiorespiratory comorbidities in adulthood. We conclude with suggestions for future
directions to improve our understanding of leptin dysregulation and associated clinical diseases
and possible therapeutic targets. Lastly, we briefly discuss the yin and the yang, specifically the
contribution of relative adiponectin deficiency in adults with hyperleptinemia to the development
of metabolic and cardiovascular disease. © 2020 American Physiological Society. Compr Physiol
10:1047-1083, 2020.

Didactic Synopsis • Leptin acts on the carotid body to modify spontaneous

Major teaching points
Leptin is a master regulator of metabolism and of many
other biological functions including breathing. Neuronal
circuits that are primarily involved in feeding behavior and
metabolism are interconnected with those in the respira-
tory network. Leptin also modifies the activity from cells
and neurons in the carotid body, which mediate changes in
ventilation and sympathetic activity in response to hypoxia.
Leptin deficiency or leptin resistance occurring at any time
during the lifespan can lead to adverse cardiorespiratory
outcomes including abnormal feeding behavior, obesity,
hypertension, metabolic dysregulation, intermittent hypoxia,
and obstructive sleep apnea.
• Breathing must match the metabolic demands of the body.
• Leptin, a hormone produced by fat tissue, is able to
stimulate breathing by acting on central POMC-MC4R
pathway.
• Leptin-signaling deficiency potentially contributes to
obesity-associated breathing disorders.
minute ventilation and hypoxic ventilatory responses.
• Leptin is involved in carotid body responses to chronic
conditions as obesity and chronic intermittent hypoxia.
• Hyperleptinemia contributes to increased carotid body
sensitization that promotes altered breathing and aug-
mented sympathetic activity.
• During early development, leptin does not decrease feed-
ing behavior or increase CO2 sensitivity.
• Leptin is key to organogenesis during early development.
*Correspondence to estelle.gauda@sickkids.ca
1 Division of Neonatology, Department of Pediatrics, The Hospital for
Sick Children, Toronto, Ontario, Canada
2 CEDOC, NOVA Medical School, Faculdade de Ciências Médicas,
Lisboa, Portugal
3 Department of Physiology and Pathology, School of Dentistry, São
Paulo State University (UNESP), Araraquara, São Paulo, Brazil
4 Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
Published online, July 2020 (comprehensivephysiology.com)
DOI:10.1002/cphy.c190031
Copyright © American Physiological Society.

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Leptin in the Control of Breathing
• Overnutrition (hyperleptinemia) and undernutrition
(hypoleptinemia) during fetal and early development lead
to leptin resistance in adulthood and cardiorespiratory
comorbidities.
• Adiponectin, another adipokine produced by adipocytes,
counterbalances the adverse effects of leptin, but circulat-
ing levels are low in individuals with obesity and sleep-
disordered breathing.
Introduction
Leptin is pleiotropic adipocyte-derived hormone that is
most notable for its role in energy homeostasis and appetite
suppression. However, it is also a master regulator of many
biological functions including organogenesis, metabolism,
learning and memory, reproduction, cardiovascular home-
ostasis, and immunity, to name a few. After describing
the journey to its discovery, characterization, and cellular
and molecular signaling, this article will largely focus on
the unique contribution of leptin to central and peripheral
systems that control breathing in health and disease.
Overview of Leptin
Discovery of leptin
In 1949 at the Jackson Laboratory, Dr. George Snell and
his colleagues noticed that one of their mouse lines devel-
oped extreme obesity. After a series of investigations, they
concluded that it was caused by a mutation in an autosomal
recessive gene for obesity (ob/ob) (161). Although they
were unable to recognize the gene or identify its product,
they were able to locate the gene to chromosome 6. In the
1960s, another new strain of obese and diabetic mice (db/db)
was discovered at the Jackson Laboratory (158). Similar
to the ob/ob mouse, the db/db mouse had hyperphagia,
extreme obesity, diabetes, neuroendocrine dysfunction, and
infertility.
A seminal parabiosis experiment performed by Coleman
(60) substantially moved the field forward. They surgically
joined the circulatory systems of ob/ob and db/db mice and
observed that the ob/ob mouse was no longer hyperphagic
and had significant weight loss and improved glucose reg-
ulation. They concluded that the circulating factor in the
db/db mouse was inducing the changes observed in the ob/ob
mouse. Thereafter, Dr. Jeffrey Friedman, a young resident
physician, directed his full attention to the discovery and
characterization of the product of the ob gene. In 1994, using
positional cloning techniques, he detected a 20-fold increase
in expression of a 4.5 kb RNA strand in the adipose tissue
of C57B1/6J ob/ob mice (401). Further studies revealed that
the increase in 4.5 kb RNA was the result of a snowball
effect: The C57B1/6J ob/ob mice had a nonsense mutation
that transcribed a detectable RNA product, but for which the
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Comprehensive Physiology
subsequent protein was nonfunctional. This nonfunctional
protein downregulated its expression leading to increased
levels of detectable mRNA. Today, we recognize the ob gene
product as a mutant form of the leptin (LEP) gene, which was
aptly leptos from the Greek root for “thin.” Predictably, the db
gene product is a mutation in the leptin receptor (LEPR) gene.
Leptin is primarily produced in white adipose tissue, although
brown adipose tissue, placental syncytiotrophoblasts, mam-
mary glands, skeletal muscle, and ovaries are amongst a
handful of other tissues capable of synthesizing this hormone
(111, 244). Its serum concentration is under diurnal regula-
tion, increasing at night to suppress hunger and decreasing
throughout the day to stimulate metabolism (81). Interest-
ingly, its serum concentration increases exponentially with
adipose tissue mass (66).
Leptin gene and protein product
LEP is located on chromosome 7q32.1 in humans, which
encodes a 16 kDa peptide hormone consisting of 146 amino
acids. Within the primary sequence is a 21 amino acid signal
peptide that is highly conserved between animal species
(172). While there are no common human variants of the
leptin gene, eight mutant forms have been discovered in
Eastern countries—all of which result in extreme infant
obesity and hyperphagia. Seven of the mutant forms impair
LEP expression, resulting in low serum leptin. Conversely,
the most recently discovered mutation (89, 274), in 2014,
identified a transversion that resulted in high serum levels of
a nonfunctioning protein (376).
Leptin receptor
Leptin exists in both a free and bound form in the cir-
culation; both forms are capable of binding to the leptin
receptor (Ob-R). Ob-R is a member of the class I cytokine
receptor family, which includes other receptors with the
gp130 subunit, such as the IL-2, 3, 4, 6, and 7 receptors
(133, 380). The six Ob-R isoforms—identified as Ob-Ra
to Ob-Rf, sequentially—are alternative splicing products
of the LEPR gene. The isoforms are subdivided into three
classes: long (Ob-Rb), short (Ob-Ra, Ob-Rc, Ob-Rd, and
Ob-Rf), and secretory (Ob-Re). All of the Ob-R isoforms
have a conserved extracellular ligand-binding domain on their
N-terminus, which consists of 816 amino acids, 4 essential
cysteine residues, a Trp-Ser-X-Trp-Ser (WSXWS) motif, and
a fibronectin III domain. Five of the isoforms—excluding
the secretory Ob-Re isoform—have a 34 amino acid trans-
membrane domain that anchors the receptor to the plasma
membrane, as well as a variable length intracellular domain.
The intracellular domain of the short isoforms ranges from
32 to 40 amino acids, while Ob-Rb has 303 (133, 244, 380).
The short isoforms contain a box 1 motif that allows for
it to activate Janus kinase (JAK) tyrosine kinases, but the
strength of the signal is much weaker than the long Ob-Rb
isoform, which contains three motifs for the binding of JAK
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Comprehensive Physiology Leptin in the Control of Breathing

tyrosine kinase and the signal transducer and activator of
transcription (STAT) transcription factor. Thus, the Ob-Rb
has been identified as the master regulator of intracellular
signaling from leptin; the short isoforms are associated
with leptin internalization and proteolysis, and the secretory
Ob-Re isoform is a serum carrier protein that transfers leptin
to the membrane proteins (111, 133). As it relates to obesity,
the Ob-Rb isoform is the most important because it predom-
inates in the hypothalamus—where the central control of
hunger takes place (266). Its role in feeding behavior, along
with the concept that Ob-Rb is the only isoform capable of
fully activating the JAK/STAT signal transduction pathway,
helps to explain why modifications to the Ob-Rb receptor are
responsible for the development of early-onset obesity.
Leptin signaling
As depicted in Figure 1 (111), leptin signaling primarily
occurs through the JAK/STAT pathway following ligand
binding to Ob-Rb. Only Ob-Rb is capable of fully activating
this transduction pathway because it contains all three of box
1, box 2, and box 3 motifs. Box 1 and box 2 motifs are required
for the binding of JAK tyrosine kinase, while box 3 allows for
the binding of the STAT transcription factor. Short isoforms
of Ob-R only contain the box 1 motif and are consequently
unable to activate all JAK kinases (133). On the intracellular
domain of the Ob-R receptors, there are four intracellular
tyrosine residues (Tyr974, Tyr985, Tyr1077, and Tyr1139)
that are involved in the activation of the JAK/STAT and other
intracellular signal transduction pathways described below.
Upon ligand binding to Ob-Rb, JAK2 binds to box 1 and
box 2 motifs and is subsequently autophosphorylated. This
phosphorylated JAK2 then activates Tyr985 and Tyr1138,
allowing for the binding of STAT proteins on the box 3 motif.
STAT proteins—most notably STAT3—are then activated
through subsequent tyrosine phosphorylations by JAK2. The
activated STAT3 protein dissociates from the receptor and
forms a homo- or heterodimer that is capable of translocating
to the nucleus, where it exerts its influence on the gene
expression of suppressor of cytokine signaling 3 (SOCS3)
and protein tyrosine phosphatase 1B (PTP1B), among other
proteins (111, 133, 244). SOCS-3 and PTP1B are notable

L Leptin

Ob-Rb
Membrane

IRS 1/2
B P Cytosol
o JAK2
x PI3K
1
ERK
P
974 P
Grb-2
SHP-2
P SOCS3 SOCS3
985
AgRP

POMC
P STAT-5 +
1077
STAT-3
P P P −
1138 ST
1/3 AT STAT-3 Nucleus
/5

Figure 1 Intracellular signaling pathways activated when leptin binds to the long form of the
leptin receptor (Ob-Rb) in cells in the arcuate nucleus that express POMC and AgRP. Janus kinase
(JAK2) associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (Ob-Rb) contains four
important tyrosine residues (Tyr974 , Tyr985 , Tyr1077 , and Tyr1138 ). These phosphorylated tyrosine residues pro-
vide docking sites for signaling proteins. Tyr1138 recruits the transcription factor STAT3, which is subsequently
phosphorylated by JAK2, dimerizes, and translocates to the nucleus, where it induces SOCS3 and POMC (pro-
opiomelanocortin) expression, while repressing AgRP (agouti-related peptide). SOCS proteins inhibit signaling by
binding to phosphorylated JAK proteins or interacting directly with tyrosine-phosphorylated receptors. The ability
of SOCS3 to inhibit leptin-stimulated phosphorylation of JAK2 and ERK provides a negative feedback mechanism
on the leptin signaling system. Grb-2, growth factor receptor binding-2; STAT3, signal transducer and activator of
transcription; SOCS, suppressor of cytokine signaling. Adapted, with permission, from Fruhbeck G, 2006 (111).

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Leptin in the Control of Breathing Comprehensive Physiology

for their ability to act as negative feedback modulators in the
JAK/STAT pathway, by inhibiting the activity of JAK2 and
dephosphorylating the JAK2 protein, respectively (111).
In the hypothalamus, the Ob-Rb receptor is located on
two distinct neuronal populations: the proopiomelanocortin
(POMC) and the neuropeptide Y/agouti-related protein
(NPY/AgRP) neurons. POMC neurons are anorexigenic;
as such, their activation through Ob-Rb ligand binding
increases POMC expression, which eventually leads to the
loss of adiposity. Contrarily, NPY/AgRP neurons—which are
orexigenic—are inhibited by Ob-Rb activity, leading to a loss
of appetite. It is through this JAK/STAT signaling pathway
for POMC, NPY, and AgRP that we as humans are able to
regulate our fat stores (374). In the case of obesity, the Ob-R
often becomes resistant to leptin, so although leptin levels
are high in serum—signaling for weight loss—appetite is not
suppressed. Physiological leptin resistance occurs during the
neonatal, prepubertal, and pregnant stages of life facilitating
rapid weight gain (134, 171, 173).
Leptin signaling can also occur through several other path-
ways including through the mitogen-activated protein kinase
(MAPK) cascade, phosphoinositide 3-kinase (PI3K) cAMP
pathway, and via 5′ -AMP-activated protein kinase (AMPK)
(111). Each of these pathways has a role in nonhypothalamic
tissues, several of which are used in cells and neurons in the
brainstem and peripheral chemoreceptors that are involved in
respiration.
Leptin and Central Control of Breathing
Overview of breathing control and chemoreception
Breathing is an automatic act generated by a complex net-
work located in the hindbrain (the pons and medulla). This
respiratory network, schematically depicted in Figure 2 (120),
rhythmically coordinates the contraction and relaxation of
thoracic and abdominal muscles to produce pressure gradients
that move the air in and out of the lungs, as well as regulate
muscles that control the upper airway patency and then the
resistance to airflow (77). The respiratory rhythm, inspiratory
and expiratory phase transition, and muscular pattern control

Orexinergic neurons
SARs Peripheral
Inspiratory neurons Laryngeal
RARs arterial
chemoreflex
Expiratory neurons C fiber chemoreceptors

CO2/H+ chemosensors

Pontine
respiratory
group Nucleus of solitary tract
Forebrain (phase switching)
(hypothalamus) Dorsal respiratory group
inspiratory neurons

Ventral respiratory column

Facial Rostral (rhythm generating) Caudal (pattern forming)

nucleus PBC
BötzC Ventral respiratory group VRG
pacemaker neurons
expiratory inspiratory and
neurons Rostral VRG Caudal VRG
expiratory
RTN/pFRG
CO2/H+

Bulbospinal
neurons

Bulbospinal neurons synapse with respiratory motoneurons

(phrenic, intercostals, upper airway, abdominals)

Figure 2 The medullary respiratory network with pulmonary and pontine feedbacks. General
schematic diagram representing the respiratory network with two interacting feedback. This schematic shows the
interactions between different populations of respiratory neurons within major brain areas involved in the control
of breathing, such as the CO2 -sensitive cells in the hypothalamus, Raphe and RTN/pFRG, the pons, the ventral
respiratory group (BötzC, PBC and VRG), the NTS and the peripheral inputs and efferents. Abbreviations: BötzC,
Bötzinger complex; PBC, pre-Bötzinger complex; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group;
SAR, slowly adapting receptors; RAR, rapidly adapting receptors. Adapted, with permission, from Gauda E and Martin
R, 2018 (120).

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Comprehensive Physiology
are determined by the intrinsic membrane properties of the
respiratory premotor and motor neurons located in the brain-
stem and spinal cord, as well as by the reciprocal excitatory
and inhibitory synaptic interactions of pontomedullary res-
piratory nuclei. Moreover, the functioning of the respiratory
central pattern and rhythm generator is continuously modified
by neuromodulators, such as peptides, amines, and hormones,
which set either the excitability of respiratory neurons or the
synaptic strength between neuronal groups.
An important characteristic of the mammalian respiratory
system is its ability to adjust breathing rhythm and pattern
according to changes in internal and external environments.
Ventilation increases and decreases proportionally to swings
in carbon dioxide production and oxygen consumption
caused by changes in metabolic rate. The respiratory system
is also capable of compensating for disturbances that affect
the mechanics of breathing, such as the airway narrowing
that occurs in asthmatic patients. Breathing also undergoes
appropriate adjustments when the mechanical advantage
of the respiratory muscles is altered by postural changes
or by movement. This flexibility of breathing arises, to a
great degree, from sensors distributed throughout the body
that send feedback and feedforward signals to the brainstem
respiratory network. Among these sensors, there are chemore-
ceptors that detect changes in levels of oxygen and acidity
in the arterial blood and in the brain; and mechanoreceptors
that monitor the expansion of the lung, the size of the airway,
the force of respiratory muscle contraction, and the extent of
muscle shortening (197).
Although the diaphragm is the major inspiratory pumping
muscle, its action is assisted and augmented by a complex
assembly of respiratory muscles. Intercostal muscles insert-
ing on the ribs, the abdominal muscles, and muscles such as
the scalene and sternocleidomastoid that attach both to the
ribs and to the cervical spine at the base of the skull also
play an important role supporting the changes in pulmonary
volume, then the generation of inspiratory and expiratory
flows. Moreover, laryngeal muscles and muscles of the oral
and nasal pharynx adjust the upper airway resistance to gas
movement during inspiration and expiration. The fact that
these muscles are engaged in other physiological functions,
such as speaking, suckling, chewing and swallowing, and
postural maintenance, highlights the complexity of their
control by the central nervous system. The nonrespiratory
actions of the respiratory muscles indicate that the function-
ing of brainstem respiratory network (responsible for the
automatic generation of breathing) is significantly influenced
by higher brain centers and even controlled voluntarily to
a substantial degree. An outstanding example of voluntary
control is the ability to suspend breathing by holding one’s
breath. Inputs from higher brain centers to the brainstem
respiratory network promote breathing adjustments that not
only support behavioral-related respiratory changes but also
satisfied metabolic demands accompanied by minimal use
of energy. This flexibility in breathing patterns in large part
arises from sensors distributed throughout the body that
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Leptin in the Control of Breathing
send signals to the respiratory neuronal networks in the
brain (197).
Respiratory movements emerge from the synchronous
interactions of respiratory neuronal groups located in the
brainstem, with distinct phenotypic and biophysical features
(307, 308, 405). The respiratory groups reside in a long
column of cells, extending from the caudal medulla along the
ventrolateral medulla to the dorsolateral pons as well as to the
nucleus of the solitary tract (NTS) (35, 242, 251). Within this
network, there is a group of inspiratory neurons, located in
the ventral surface of medulla, which are able to intrinsically
generate fictive inspiratory bursts when isolated in vitro
(346). These neurons composed the so-called pre-Bötzinger
complex (pre-BötC). Because the inhibition of the pre-BötC
neurons in vivo stops breathing, this region is suggested to be
the primary inspiratory oscillator (361). In addition to their
intrinsic properties, there is evidence indicating that breathing
generation under resting conditions also requires interactions
with other respiratory neuronal groups, especially from the
Bötzinger complex (BötC) (216)—region located in the
rostral ventral respiratory column that contains inhibitory
expiratory neurons. Connections between pre-BötC/BötC
with pontine and other medullary regions (Raphe and NTS)
are necessary for proper respiratory motor pattern formation
and phase control (67, 345), generating eupneic breathing
(Figure 2) (120).
A second respiratory oscillator has also been identified in
the rostral ventrolateral medulla (RVLM), which is condition-
ally recruited to control expiratory motor activity (167). This
oscillator, presented in the retrotrapezoid nucleus/parafacial
respiratory group (RTN/pFRG) and composed of expiratory
neurons, is responsible for providing excitatory drive to
promote abdominal expiratory contractions, hence increas-
ing minute ventilation, during situations of high metabolic
demand, such as physical exercise, or during hypoxia
(reduced PO2 ) and hypercapnia (enhanced PCO2 ) (1, 2, 405).
Experiments are still being done to determine how this
conditional expiratory oscillator interacts with other res-
piratory compartments within the brainstem to coordinate
inspiratory and expiratory outputs during the occurrence
of active expiration. More recently, the “triple oscillator
network” theory has been proposed with the identification
of a group of excitatory neurons rostral to the pre-BötC and
dorsomedial (DM) to the nucleus ambiguus, post-inspiratory
complex (PiCo), which putatively is responsible for the
rhythmical control of post-inspiratory activity (10). This third
respiratory oscillator might be responsible for generating
post-inspiratory behaviors, such as vocalization, swallowing,
and breath holding (11).
Disturbances in blood gases and arterial pH are rapidly
detected by the body, causing effects on breathing. In con-
scious animals, minor changes in brain interstitial fluid (ISF)
pH are sufficient to generate reflex response on ventilation
(101, 252, 264)—the reduction of ISF pH from 7.30 to 7.25 is
associated with a twofold increase in alveolar ventilation. The
traditional concept of the function of central chemoreception
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Leptin in the Control of Breathing
is that it, along with peripheral chemoreception at the carotid
body (CB), (i) regulates arterial PCO2 within normal limits
in response to primary changes in CO2 , and (ii) regulates
blood pH in response to acid-base disturbances (142, 252).
Eight putative groups of neurons that exhibit capacity to
intrinsically detect changes in H+ levels have been identified
(i) the RTN/pFRG (198, 199), (ii) the rostral medullary raphe
(MR) (raphe magnus) (152, 254), (iii) the caudal MR (152,
153) (raphe obscurus) indirectly via the RTN (78), (iv) the
caudal NTS (253), (v) the region just dorsal to the caudal
ventral medullary surface (70), (vi) the pre-BötC (317),
(vii) the fastigial nucleus of the cerebellum (218), and (viii)
the orexin-containing neurons of the hypothalamus (252).
Mild focal acidosis at many, but not all, these brainstem sites
can stimulate ventilation.
The hypothalamus is a key center for autonomic and neu-
roendocrine control but also influences other neurovegetative
mechanisms including respiration. Different hypothalamic
nuclei, such as the paraventricular nucleus (PVN), perifor-
nical area (PFA), dorsomedial hypothalamus (DMH), and
lateral and posterior hypothalamus, are able to generate
respiratory responses when engaged. These hypothalamic
nuclei are interconnected with respiratory nuclei located
in the midbrain, pons, medulla and spinal cord (113). For
instance, the activation of DMH neurons causes a vigorous
stimulation of respiratory activity, causing hyperventilation
(224). Moreover, projections from the PFA neurons to the
NTS, to the dorsolateral pons, including the Kölliker-Fuse
nucleus and the lateral and medial parabrachial nuclei and to
the respiratory motor neurons in the spinal cord have been
identified (49, 114, 186, 248, 267, 279, 318, 319, 400). The
PFA also receives afferent fibers from other hypothalamic
areas such as the arcuate (ARC) nucleus (127) which is a crit-
ical center for modulation of the metabolic, cardiovascular,
and respiratory functions.
The role of leptin on the central mechanisms that
control breathing
The output from the respiratory network is constantly
adjusted by the actions of neuromodulators, which changes
the excitability of respiratory neurons (modifying the conduc-
tance of ion channels or the functional voltage range of the
membrane) or the synaptic properties (86). The neuromod-
ulators, mostly amines and peptides, can be endogenously
released, or be present in challenge situations (hypoxia
or hypercapnia for example). Leptin, a peptide hormone
produced by adipose tissue, acts in brain centers to control
critical physiological functions related to metabolism and
cardiorespiratory regulation. The importance of leptin for
respiratory control is evident from studies showing that leptin-
deficient mice (ob/ob) exhibit impaired ventilatory responses
to hypercapnia (increased PCO2 in the arterial blood), which
can be corrected by exogenous leptin administered to the
central nervous system. For example, microinjections of
leptin for three consecutive days into the RVLM increased
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Comprehensive Physiology
baseline ventilation and the ventilatory response to CO2 in
leptin-deficient (ob/ob) mice (26). These results indicate that
leptin facilitates the processing of ventilatory response to
hypercapnia, possibly by acting on either chemosensitive or
respiratory neurons of the RVLM, including the neurons from
the RTN and the rostral ventral respiratory column. Inter-
estingly, leptin produced negligible acute effects on basal
activity and CO2 /H+ response of chemosensitive neurons
of the RTN (27), when administrated to brainstem slices in
vitro. One explanation for this finding is that leptin actions
on ventral chemosensitive region of the medulla require a
time to develop and may involve the synthesis of intracellular
proteins that control cellular activity and excitability. Alterna-
tively, the effects of leptin may be indirect and involve other
types of cells. These possibilities still await experimental
verification to be confirmed.
Findings from several studies in animals show that leptin
acts centrally to alter ventilation (12). In anesthetized rats, lep-
tin administration in the NTS—the primary site of peripheral
cardiorespiratory afferents in the brainstem—promotes an
increase of respiratory motor output and ventilatory response
to CO2 (58, 163). Leptin also attenuates the cardiovagal
component of the baroreceptor reflex (16) and potentiates
sympathoexcitatory responses evoked by the activation of
the chemoreflex (58). Moreover, systemic administration of
leptin enhances c-fos expression in leptin receptor-expressing
neurons of the caudal aspect of the NTS (region that receives
predominantly afferent inputs from peripheral chemorecep-
tor) (93, 135), supporting the hypotheses that leptin activates
NTS neurons involved with regulation of respiration.
In addition to the potential effects of leptin in the medulla,
leptin may also act on hypothalamic neurons and modify
breathing. Chronic administration (7 consecutive days) of
leptin in the lateral ventricle (LV) reduced daily food intake
and body weight while it enhanced baseline ventilation in rats
(Figure 3) (30). This leptin effect on basal ventilation was
principally secondary to an increase in tidal volume whereas
respiratory frequency did not change, suggesting that leptin
acts on specific targets in the respiratory network rather than
producing a generalized respiratory stimulation. Leptin given
centrally also enhanced the ventilatory response to hyper-
capnia again by increasing tidal volume but frequency was
also increased when leptin was given centrally. In agreement
with these observations, LepR/Nestin-cre mice (transgenic
model with deletion of leptin receptors in the central ner-
vous system) exhibit a diminished ventilatory response to
hypercapnia (Figure 3); thereby reinforcing the notion that
leptin acts centrally to modulate breathing and control CO2
homeostasis (30).
Leptin and control of breathing in newborns
Similar to adults and children, leptin levels are proportional
to fat mass in the fetus and newborn, but it is also produced
by the placenta (371). Although leptin levels are lowest in
the smallest and youngest premature infants, it is higher
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Comprehensive Physiology Leptin in the Control of Breathing

(a) 60
Control Daily i.c.v. microinjections

Food intake (g/day)

45
αβ

30

15 α

0
(A) C1 C2 C3 t1 t2 t3 t4 t5 t6 Control-PBS LEP
SHU SHU + Lep
2400 1500 α
α
(mL/(min kg))

(mL/(min kg))
1600 1000 β
β

ΔVE
VE

αβ β
800 α
500

0
0
(B) Room air 7% CO2

Wild-type LepR/Nestin-cre
9000 9000 MC4R–/– LepR/POMC-cre
(mL/(min kg))

(mL/(min kg))

6000 6000
VE

ΔVE

θγ
θγ
3000 θ 3000
θ
θ θ
0 0
(C) Room air 7% CO2

Figure 3 The effect of central leptin administration on food intake and breathing. (A) Daily
food intake during control period (C1–C3) and during lateral ventricle (LV) treatment (t1–t6) with PBS (control),
(LEP, 5 μg/day), MC3/4R antagonist SHU-9119 (SHU, 0.6 nmol/day), or SHU-9119 + leptin for 7 days in rats.
(B) Basal ventilation and ventilatory response to 7% CO2 after LV treatments in rats. (C) Ventilatory responses in
mice: wild-type, leptin receptor deletion in the entire brain (LepR/Nestin-cre), leptin receptor deletion in POMC
neurons (LepR/POMC-cre) and mice with MC4R deficiency (MC4R−/− ). Adapted, with permission, from Bassi
M, et al., 2015 (30).

during the first several days of life than afterward. Apnea and Knowing that leptin increases CO2 chemosensitivity in adult
periodic breathing are inversely related to gestational age, models, and CO2 sensitivity is highest during the first several
and essentially all infants born less than 28 weeks gestation days in newborn rats, then falls, before increasing again at
will need therapeutic intervention to stabilize breathing 10 days to stabilize to adult levels by postnatal day 21 (355),
and decrease the frequency prolonged apnea and associated Gauda and colleagues designed an experiment using SD rats
bradycardia and hypoxemia, for review see Ref. 80. Of note, to determine the effect of leptin on the ventilatory response to
apnea of prematurity, intermittent hypoxia (IH), and periodic hypercapnia (CO2 5%/O2 40% balanced in N2 ) in freely mov-
breathing increases in frequency after 48 h and peaks 2 to ing rats, during the first 3 to 4 weeks of postnatal development
4 weeks after birth (25, 80, 235). The increased frequency of (2–4, 7–9, and 19–21 days of age, n = 10 per age group). They
periodic breathing parallels the increased responsiveness of found that the ventilatory response to CO2 increased with
the CB (80, 91, 123). Premature infants also have reduced postnatal development; however, the animals between 19 and
sensitivity to CO2 at birth which increases within the first 21 postnatal days had the greatest change in ventilation when
several weeks of postnatal development (75, 108, 309). exposed to hypercapnia. Exogenous leptin (3 or 6 mg/kg)
Chemosensitivity to CO2 and hypoxia in Sprague Dawley given intraperitoneally augmented the ventilatory response to
(SD) rats matures within the first 3 to 4 weeks after birth, and CO2 only in the oldest animals (unpublished data).
SD rats are commonly used as a translational model to study In another series of experiments in unanesthetized and
maturation of mechanisms that control breathing (75, 121). unrestrained SD rats, at postnatal day 18 to 21, Gauda

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Leptin in the Control of Breathing Comprehensive Physiology

and colleagues determined whether exposure to high CO2 (A)

(7% CO2 balanced in 40% O2 and N2 ) for 1 h would modify
the level of protein expression of pSTAT (measured with
western blot) in tissue homogenates of the NTS, LC, and
RTN, areas that are known to contain CO2 sensitive cells.
They found that pSTAT protein expression after 60 min of
exposure was upregulated in the NTS and LC but not in
the RTN (unpublished data). Thus, these preliminary data
suggested that CO2 sensitivity in newborn rat pups prior to
3 weeks of life is not affected by leptin. Of note, 4 to 6 weeks
after birth is the age when neurons in the arcuate nucleus
of the hypothalamus (ARH) developed the mature adult
response to leptin (23), discussed below. It would be of inter-
est to determine if similar cellular mechanisms that mature
the ARH neurons are also occurring in CO2 chemosensitive
areas in the brainstem during development.
Relative leptin deficiency in newborn infants and risk
of SIDS: a translational perspective
Increased ventilatory and arousal responses to CO2 is an
important and essential defense response during airway
obstruction or rebreathing. Premature infants and those
who are small for gestational age (SGA) have a two- to
threefold increased risk of dying of sudden infant death
syndrome (SIDS) (18, 91). SIDS occurs during sleep and
frequently after infants are fed. Infants who are formula
fed have increased risk of SIDS in contrast to those who
are breastfed. In fact, exclusive breastfeeding reduces the
odds of SIDS to 0.27 (95% CI 0.44–0.69) (148). Breastmilk
is a source of leptin, and plasma leptin levels do increase
postprandial in infants (57). Savino et al. (326) measured
serum leptin levels in a cohort of term infants between 2
and 3 months of age who were exclusively breastfed (n = 25)
or formula fed (n = 26). Leptin serum levels were higher
in breastfed (7.1 ± 10.4 ng/mL) than in formula-fed infants
(3.7 ± 3.87 ng/mL) infants (P < 0.05). One could speculate
that increased leptin levels in breastfed infants may con-
fer some protection from SIDS by increasing ventilatory
responses to CO2 when the airway becomes compromised
or rebreathing occurs during sleep. Smith et al. (326, 344),
recently published, that in adult mice, dorsal raphe serotonin
neurons mediate CO2 -induced arousal from sleep without
increasing ventilation. Finn et al. used situ hybridization to
map neurons in the rostral brainstem that expressed mRNA
for the serotonin transporter and Ob-Rs in monkeys (102);
neurons in the caudal dorsal raphe and rostral median raphe
had the highest level of co-expression of mRNA for Ob-
Rs and serotonin transporter as shown in Figure 4 (102).
Dorsal raphe neurons in ob/ob mice and lean littermates
also co-express immunoreactivity for Ob-Rs and serotonin
transporter. Of interest, the leptin-deficient mice had less
neurons in the dorsal raphe that co-expressed immunoreac-
tivity for Ob-Rs and serotonin transporter (61). While the
mouse study designed by Collin et al. (61) was intended to
test hypotheses related to symptoms of depression in ob/ob
Aq
CG
C3
mlf
CLi
xscp
(B) Aq IC
CG
rDR
scp
mlf
rMR
(C) 4V
LC
CG
mlf
cDR
Ob-R mRNA
SERT mRNA cMR
SERT/Ob-R mRNA
Figure 4 Anatomical localization of serotonin (SERT) and
Ob-R mRNA expression in the rostral brainstem of the mon-
key. Plates represent sections containing five regions of Raphe nuclei
included in the analysis: CLi (A), rostral DR (rDR; B), rostral MR (rMR; B),
caudal DR (cDR; C), and caudal MR (cMR; C). Symbols represent the
locations of cells containing SERT mRNA (gray triangles), Ob-R mRNA
(empty inverted triangles), or both SERT/Ob-R mRNAs (black circles).
Aq, cerebral aqueduct; CG, central gray; C3, oculomotor nucleus; mlf,
medial longitudinal fasciculus; xscp, decussation of superior cerebellar
peduncle; IC, inferior colliculus; scp, superior cerebellar peduncle; 4V,
fourth ventricle; LC, locus coeruleus. Adapted, with permission, from
Finn PD, et al., 2001 (102).
mice, the findings could be extrapolated to models of sudden
death when reduced arousal responses are hypothesized to
be contributory (45). The developmental trajectory of CO2
chemosensitivity of these dorsal raphe neurons mediating
arousal in animals or humans during sleep is not known.
Moreover, it is not known whether leptin augments the
arousal response to CO2 during early postnatal develop-
ment and whether the insensitivity of these neurons to CO2
contributes to the pathophysiology of SIDS.
Central effects of leptin on cardiorespiratory
coupling
Cardiorespiratory disorders are commonly associated with
obesity and metabolic dysfunction (Figure 5) (107). The
obstructive sleep apnea (OSA) syndrome is the most com-
mon breathing disease related to obesity (71, 212, 214,
265). The pathological mechanisms causing hypertension,
baroreflex impairment, and hypoxia-induced activation of
chemoreflex sensors, which increase both the sympathetic

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Comprehensive Physiology Leptin in the Control of Breathing

Obesity
Type 2 diabetes

Mechanical load
Narrowed airway
Increased fat
Weight-dependent
mass

Sympathetic activity
Oxidative stress
Inflammation
Lipolysis Sleep
Intermittent hypoxia
Sleep fragmentation apnea

Sympathetic
activity Decreased
Leptin resistance chemosensitivity
Insulin resistance
Hyperglycemia Physiology-dependent
Sympathetic activity
inflammation

Figure 5 Schematic diagram depicting the interrelationship between weight-

dependent and physiological-dependent mechanisms on metabolic and cardiorespi-
ratory responses in obesity. While weight-dependent mechanisms are a function of the physical
increase in body mass or fat mass (e.g., increased mechanical load, narrowed airway), physiology-
dependent mechanisms are physiological changes coincident with obesity or diabetes which go on to
influence chemosensitivity and sleep apnea either directly or via action on sympathetic activity, inflam-
mation, or other mechanisms. Adapted, with permission, from Framnes SN and Arble DM, 2018 (107).

tone and peripheral vascular resistance (215). Emerging
hypotheses postulate that pathophysiological components of
obesity, including altered glycemic control, insulin action,
and leptin signaling, contribute to the development of OSA
(Figure 5 and Table 1) (107). It is possible that obese
physiology leads to greater reductions in pharyngeal dilator
muscle tone promoting airway obstruction during sleep or
causing central sleep apnea via decreased chemosensitivity
(Figure 5) (107).
In addition to leptin’s effects on appetite and metabolic
functions, growing evidence suggests that leptin is able to
mediate autonomic sympathetic activity (219, 295) and also
central breathing control (26, 29, 53, 164, 214). In obese
subjects, the excess leptin is associated with the percent-
age of adipose tissue, suggesting that obese people have a
selective leptin resistance, inhibiting its action on appetite
modulation (66).
Sympathetic oscillations coupled to the respiratory activity
have been proposed as an important homeostatic mechanism
optimizing tissue perfusion and blood gas uptake/delivery,
especially under conditions of blood gas challenges (hypoxia
and hypercapnia). The ventral surface of the medulla oblon-
gata has been implicated as the main site of synaptic
interactions between respiratory and sympathetic neurons
(Figure 6A) (239, 404). The ventral medulla houses the
pre-sympathetic neurons of the RVLM—the major source of
excitatory inputs to the preganglionic sympathetic neurons
of the spinal cord that maintain baseline arterial pressure
in adequate levels (138, 311). Due to their anatomical
proximity, it has been suggested that the respiratory neurons
of the ventral medulla establish synaptic connections with
the presympathetic neurons of the RVLM and generate the
respiratory oscillation in the sympathetic activity (147, 223,
231, 402, 406). Other brain areas are also critical to the
circuitry regulating the coupling of respiratory and sympa-
thetic activities. The neurons of the NTS receive afferents
from baroreceptors and chemoreceptors, for this reason, this
nucleus is considered an important integrative center to medi-
ate sympathetic and chemorespiratory response (404, 405).
Based on these pathophysiological aspects of the mecha-
nisms of respiratory-sympathetic coupling, a previous study
evaluated the possibility that changes in the strength of
interactions between respiratory and sympathetic neurons
may contribute to increasing baseline sympathetic activity in
chronic intermittent hypoxia (CIH) (Figure 6B) (239).
Systemic administration of leptin has been shown to
increase c-fos expression in neurons of the cNTS (93, 95) and
enhance phrenic burst amplitude (53). Moreover, microin-
jections of leptin in the NTS increase renal sympathetic
activity (219) and ventilation (163). Therefore, leptin can
act directly on NTS cells. There is a positive correlation
between obesity and high levels of leptin in OSA patients that
develop hypertension, which is less pronounced in nonobese
OSA patients (146, 272, 328). Therefore, it is possible that
CIH, peripheral chemoreflex activation, and leptin effects
may be correlated. This hypothesis comes from experi-
ments that evaluated the effects of leptin or l-glutamate
microinjections into the cNTS on sympathetic response

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Leptin in the Control of Breathing Comprehensive Physiology

Table 1 Summary of Presented Evidence that Obstructive Sleep

Apnea and Its Components are Associated with Decreased Glycemic
Leptin Effects on Melanocortin/POMC
Control, Insulin Resistance, Increased Leptin, and Decreased Neurons—Linking Energy to Breathing
Chemosensitivity
The involvement of the melanocortin/POMC neurons
Model Results in mediating leptin’s action on cardiorespiratory
responses
Obstructive sleep apnea ↓ Hypoxic ventilatory response Melanocortin receptors (MC3/4R) mediate most of the
(human)
↓ Hypercapnic ventilatory response metabolic and cardiovascular actions of leptin. In the CNS,
↓ Glycemic control leptin depolarizes POMC neurons in the arcuate nucleus
of the hypothalamus (ARC) inducing the release of α-
↑ Insulin resistance
melanocyte-stimulating hormone (α-MSH) which, in turn,
↑ Leptin activates the MC3/4Rs located in several hypothalamic nuclei
Type 2 diabetes + obstructive ↓ Glycemic control as well as in other regions of the brain including the brainstem
sleep apnea (68, 144, 243) (Figure 8). Deletion of Ob-Rs specifically in
↑ Apnea-hypopnea index
POMC neurons abolished the ability of leptin to raise blood
↑ Central sleep apnea
pressure and to reduce fasting glucose and insulin levels
↑ Insulin resistance (84). Moreover, pharmacological blockade of MC3/4R com-
Sleep fragmentation ↓ Glycemic control pletely prevented the anorexic and antidiabetic effects of
↑ Insulin resistance leptin (72).
Previous experiments in anesthetized rodents showed that
↑ Leptin
leptin activates neurons in brain sites essential for breathing,
Intermittent hypoxia ↓ Glycemic control including the NTS, RVLM, and possibly the RTN, key cen-
↑ Insulin resistance tral chemosensitive areas (27). The melanocortin pathway
↑ Leptin has been identified as a putative downstream mechanism
(30). To better understand how leptin modulates the central
↓ Chemosensitivity
breathing function, Yao et al. (391) investigated the effect of
Obesity + intermittent hypoxia ↑ Insulin resistance leptin on medulla versus hypothalamus in ob/ob mice. Leptin
↓ Hypoxic ventilatory response improved the upper airway obstruction during sleep when
↓ Hypercapnic ventilatory response administered into the lateral cerebral ventricle. However,
leptin administration into the fourth ventricle had no effect
Reprinted, with permission, from Framnes SN and Arble DM, 2018 on airway obstruction during sleep, suggesting that leptin
(107). is acting on the hypothalamus instead of the brainstem to
mediate airway flow (391). It appears that upper airway
motoneurons were synaptically coupled to neurons of the
during the peripheral chemoreflex activation (58). Thus leptin DMH that were immunopositive for phosphorylated STAT3
enhances the sympatho-excitatory responses to peripheral whereas the phrenic motoneurons were synaptically coupled
chemoreflex activation through its actions on cNTS neurons to the immunopositive STAT3 neurons of the NTS. Perhaps,
involved with the processing of peripheral chemoreceptor the POMC neurons of the hypothalamus are mediating
inputs. these effects of leptin; however, this hypothesis needs to be
A recent study reinforces the hypothesis that leptin can tested.
be involved in cardiorespiratory changes related to obesity. The melanocortin/POMC neurons was previously reported
Rats fed for 12 weeks with high-fat diet (HFD) had elevated as a mediator of leptin’s effects on ventilation. In accord with
mean arterial pressure (MAP), impaired reflex bradycardia, a study, chronic (6 days) intracerebroventricular microinjec-
increased respiratory frequency, and accentuated abdom- tion of MC3/4R antagonist reduced the ventilatory response
inal motor activity during activation of the chemoreflex to hypercapnia and abolished the ability of leptin to increase
with hypercapnia (Figure 7 and Table 2) (350). Once the baseline ventilation in rats (28). In addition, the ventilatory
cardiorespiratory coupling seems to be coordinated due to response to CO2 was diminished in mice with targeted dele-
the activity of dorsal and ventral nuclei of medulla, espe- tion of POMC neurons (LepR/POMC-cre transgenic mice)
cially NTS and RVLM, it is possible that rats exposed to (28). This attenuation of chemorespiratory response is similar
HFD have altered neuronal sympathetic-respiratory activ- to the response found in mice that had a targeted deletion of
ity due to high circulating leptin levels, which certainly Ob-Rs in the brain (LepR/Nestin-cre transgenic mice). Taken
contribute to cardiorespiratory changes in HFD rats. Nev- together, this information reveals that the absence of leptin
ertheless, the mechanisms by which leptin optimized the signaling pathways as well as POMC cells in the brain impair
chemoreflex-induced respiratory response and modify the the chemosensitive response. According to this data, it was
respiratory-sympathetic coupling are still to be determined. demonstrated that obese agouti yellow mice who lack MC4R,

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Comprehensive Physiology Leptin in the Control of Breathing

(A) Respiratory-sympathetic coupling (B) Control CIH

(active l/passive E) (active l/active E)
Larger Traube-Hering waves

Peripheral afferent
information PP
(e.g., pulmonary receptors,
baroreceptors, chemoreceptors)

Brainstem respiratory network Upper airways

PN
Expiratory Inspiratory Spinal cord
Motor nuclei late-E

Respiratory muscles
Sympathetic
tSN
Rostral ventrolateral medulla

late-E
Spinal cord Blood vessels no late-E
IML Heart
AbN

l E l E
2s 2s

Figure 6 (A) Schematic model of interactions between respiratory network and sympathetic nervous system. The
brain stem respiratory nuclei generate the coordinated inspiratory and expiratory motor activities responsible to control upper airway
resistance and respiratory movements. It has been suggested that the respiratory neurons interact with presympathetic neurons of rostral
ventrolateral medulla (RVLM), generating the respiratory oscillations in the sympathetic activity. In addition to these central mechanisms,
the peripheral afferent inputs, like those from pulmonary stretch receptors, arterial baroreceptors, and peripheral chemoreceptors, may
interact with respiratory and sympathetic neurons and also contribute to respiratory-sympathetic coupling. (B) Illustration shows the pattern
of raw and integrated (∫ ) activities of thoracic sympathetic (tSN), abdominal (AbN), and phrenic nerves (PN) as well as the magnitude
of perfusion pressure (PP) of control and chronic intermittent hypoxia (CIH) rats. Note that in control rats the amplitude of AbN activity is
low, indicating that the respiratory pattern is composed of active inspiration (active I) and passive expiration (passive E). On the other
hand, in CIH rats the AbN exhibits an addition burst during the late part of expiration (late-E), indicating that not only inspiration but also
expiration are active in CIH rats (active I/active E). In addition, as a consequence of the active expiratory pattern, the tSN exhibits a
correlated peak of discharge during late-E. EXP indicates expiratory neurons; INSP, inspiratory neurons; SYMP, presympathetic neurons;
IML, intermediolateral column; PMN, phrenic motor neurons; AMN, abdominal motor neurons. Adapted, with permission, from Moraes
DJ, et al., 2012 (239).

200 90

*
breaths/min

150
breaths/min

60
fR

ΔfR

100
30

50
0
Basal 7% CO2 SD HFD
300 450
Δ DIA amplitude (%)

Δ ABD amplitude (%)

200 #
# 300 *#
100
150

0
0
SD HFD
SD HFD

Figure 7 Effect of HFD on ventilation in rats. Rats fed with high-fat diet (HFD) during
12 weeks have high variation of the respiratory frequency (fR ) and abdominal expiratory
motor activity (ABD) during hypercapnia (10% of CO2 ) compared to standard diet (SD)
fed rats. The activity of the diaphragm muscle (DIA) was similar among the groups (SD
n = 14 and HFD n = 13). * Different from SD and # different from basal condition, P < 0.05.
Adapted, with permission, from Speretta GF, et al., 2018 (350)

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Table 2 Body Weight, Adiposity and Metabolic Parameters in Rats rats, whereas food restriction to prevent excess weight gain
Fed with Standard Chow Diet or High-fat Diet for 12 Weeks in MC4R deficient rats may attenuate the elevation in MAP
caused by CIH (85). The authors also found that MC4R
SD HFD deficiency was associated with impaired ventilatory response
to hypercapnia independently of obesity. More studies are
Final body weight (g) 437 ± 11 507 ± 12* needed to be understand the involvement of MC4R signaling
Epididymal adipose tissue 0.41 ± 0.08 0.82 ± 0.12* in mediating the blood pressure response to CIH, more studies
(g/100 g b. wt.) are needed.
Retroperitoneal adipose tissue 0.55 ± 0.10 1.77 ± 0.17*
The MC3/4Rs also are present on PVN, DMH and perifor-
(g/100 g b. wt.) nical (PeF) nuclei of hypothalamus (179) and these regions
are modulating the metabolism, cardiovascular, and breath-
Mesenteric adipose tissue 0.58 ± 0.06 1.24 ± 0.15*
(g/100 g b. wt.) ing function (106). The activation of PVN and DMH nuclei
promotes activation of phrenic nerve which, in turn, enhances
Total cholesterol (rag/dL) 62 ± 4.5 84 ± 5.3*
pulmonary ventilation (106, 210, 394). Indeed, the disinhibi-
HDL (mg/dL) 26 ± 3.1 27 ± 3.9 tion of PeF nuclei promotes an increase in MAP, phrenic nerve
TGL (mg/dL) 37 ± 1.0 58 ± 4.9* discharge, and firing rate of the chemosensitive RTN/pFRG
Glucose (mg/dL) 90 ± 7.6 112 ± 4.8* neurons of isoflurane-anesthetized rats (106, 200). However,
how leptin affects breathing via activation of the melanocortin
Kitt (%/min) 3.7 ± 0.1 1.7 ± 0.1*
system in DMH or PeF nuclei needs further investigation.
Leptin (ng/mL) 1.2 ± 0.5 6.4 ± 0.7*
VO2 (mL/(kg min)) 17.01 ± 1.63 14.88 ± 1.40
Leptin’s unique effects during early development
VCO2 (mL/(kg min)) 13.02 ± 0.79 11.36 ± 1.05
Leptin is a master regulator of feeding behavior and energy
RQ (VCO2 /VO2 ) 0.78 ± 0.02 0.76 ± 0.01
balance in children and adults via binding to Ob-Rs on
All values are presented as means ± SEM. Non-paired Student t-test neurons in the ARC in the hypothalamus. However, during
“*” different from SD group; P < 0.05 (n = 4–10/group). SD, standard early development, leptin does not influence feeding behav-
chow diet; HFD, high-fat diet; HDL, high-density lipoprotein; TGL, triacyl- ior or metabolism. Relevant to feeding behavior, the ARC
glycerol; RQ, respiratory quotient; Kitt (%/min), percentage of plasma contains two populations of neurons that express Ob-Rs:
glucose concentration decline per minute; b. wt., body weight. Total
cholesterol, HDL, TGL and glucose were measured in serum and leptin
(i) orexigenic neurons, which co-express NPY and AgRP,
in plasma. and when activated, promote feeding; and (ii) anorexigenic
Reprinted, with permission from Elsevier, from Speretta GF, et al., 2018 neurons, which express melanocortin peptides derived from
(350). POMC, and when activated, suppress feeding behavior.
In nonobese adult models, the summation of the effect of
leptin is to induce satiety and to increase energy expenditure.
exhibited attenuated ventilatory response to CO2 and have Thus, leptin decreases the activity of orexigenic neurons
a normal ventilatory response to hypoxia, suggesting that (NPY/AgRP) and activates anorexigenic neurons (POMC).
the melanocortin system appears to mediate the ventilatory In contrast, in rodents, during the first weeks of postnatal
response to hypercapnia more than hypoxia (287). development leptin binding to orexigenic neurons actually
Considering the effects of leptin on sympato-respiratory depolarizes neurons and has little effect on the membrane
coupling and the possible involvement of the melanocortin potential of POMC neurons (23).
system as a mediator of these actions, a recent study was The anorectic effect of leptin, in rodents, occurs after wean-
designed to determine the role of CNS MC4R on CIH-induced ing between 4 and 6 weeks of postnatal life, at which time
hypertension and ventilatory responses to hypercapnia (85). the membrane electrical properties of the NPY and POMC
Experimentally induced CIH during sleep in animals is neurons, as well as their axonal projections, are fully devel-
commonly used as a model of OSA that occurs in humans. oped (42, 137). Baquero et al. (23) concluded, from a series
Similar to humans, experimental animals exposed to CIH of well-designed experiments, that acquisition of functional
have augmented chemoreceptor reflexes (175, 289, 290), ATP-sensitive potassium channels in NPY/AgRP expressing
sympathoexcitation, reduced cardiac parasympathetic activ- neurons leads to hyperpolarization versus depolarization
ity, decreased baroreflex sensitivity, and hypertension (204, prior to 4 weeks of postnatal life in response to leptin binding
249, 403). do Carmo et al. (85) demonstrated that obese to Ob-Rs on these neurons. Barquero and colleagues also
MC4R knockout rats exposed to 7 to 18 days of CIH had reported, that prior to 4 to 6 weeks of postnatal age in rodents,
reduced food intake with no change in plasma glucose, leptin, leptin functions more like a trophic factor, depolarizing NPY
or insulin concentrations. Although, lean pair-weight-MC4R neurons to shape the neuronal circuit that forms the intricate
deficient rats exhibited attenuated arterial pressure responses network that regulates feeding behavior and metabolism. In
to CIH. Thus, endogenous CNS MC4R does not appear to the absence of leptin, this neuronal circuit does not properly
play an essential role in elevating MAP during CIH in obese develop as illustrated in the figure created by Bouret and

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Comprehensive Physiology Leptin in the Control of Breathing

Hypothalamic projections to brainstem

Fat cells
Leptin CNS action
Leptin
Brainstem
LC
POMC NTS
Hypothalamus DMV M

N
C3

PB
/4
R
KF
NPY/AgRP POMC NA
7N BötC Pre-BötC VRG
Arcuate nucleus
RVLM
α-MSH RTN/pFRG

4R
3/
C
M

PVN
Heart and
Food intake Diaphragm
blood vessels
RSNA AP Abdominal
Ventilation

Obese
Increase in food intake
Increase in body weight
Reduced HCVR
LepR/POMC-cre Leptin resistance

Figure 8 Schematic diagram depicting of main central nervous system (CNS) sites of
leptin action to modulate ventilation including proopiomelanocortin (POMC) neurons.
Upper panel: Leptin activates leptin receptors (LRs) in the ARC nucleus causing inhibition of neuropep-
tide Y/agouti-related peptide (NPY/AgRP) and depolarization of POMC neurons leading to the release
of alpha melanocyte-stimulating hormone (α-MSH) which, in turn, activates the melanocortin 3 and 4
receptors (MC3/4R) mainly in the arcuate nucleus (ARC) as well as in the others nuclei located in brain-
stem such as nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). The evoked
responses induced by leptin in the CNS are a reduction in the food intake, increase in renal sympa-
thetic activity (RSNA), increase in arterial pressure and in the ventilation. Lower panel: LepR/POMC-cre
mice are obese and have reduced hypercapnic ventilatory response (HCVR). Abbreviations: AP, arte-
rial pressure; BötC, Bötzinger complex; DMV, dorsal motor nucleus of the vagus; 7N, facial nucleus;
KF, Kölliker Fuse; LC, locus coeruleus; NA, nucleus ambiguous; PBN, parabrachial nucleus; PVN, par-
aventricular nucleus of the hypothalamus; pre-BötC, pre-Bötzinger complex; RTN/pFRG, retrotrapezoid
nucleus/parafacial respiratory group; and VRG, ventral respiratory group. Modified, with permission,
from Bassi M, et al., 2015 (28).

Simerly (42) which schematically depicts the ontogeny of the
ARC projections in wild type and ob/ob mice (lack the leptin
gene) (Figure 9) (42). Although of normal weight at birth,
ob/ob mice exhibit hyperphagia, severe obesity, metabolic
features of type II diabetes, hypogonadism, infertility, as well
as OSA (391). Thus, the absence of leptin during fetal and
early postnatal development can have profound effects on the
development and function of the ACR of the hypothalamus,
and other organ systems (19–21).
Leptin is detected in the human fetus as early as 18 weeks
gestation (168). Leptin is also produced by the placenta, and
placental leptin contributes to fetal and maternal levels, while
maternal leptin does not appear to contribute to fetal leptin
levels (17, 335). A leptin surge occurs postnatally in many
mammalian species (42), peaking between postnatal days 7
and 10 in rodents (79), and increasing exponentially from
34 to 40 weeks of gestation in humans (168). This surge is
directly proportional to fat mass, which rapidly increases in
the human fetus after 34 weeks of gestation. It is important
that energy intake meets the metabolic demand for the rapid
growth and organ development that occurs in the fetus and
newborn; thus, in the fetus and newborn, leptin does not
lead to satiety, or other metabolic effects even though leptin
levels are higher in rodents during the first and second week
of postnatal life, being 2–3 times adult levels. Moreover,
intraperitoneal leptin administration (1 mg/kg body weight)
to lean and ob/ob mice pups from 7 to 10 days of age did
not affect milk intake, oxygen consumption, body weight, or
weight of epididymal fat pad (230); intracerebroventricular
injection of (1 mcg) leptin also did not affect feeding behavior
and metabolism until the mice were 3 to 4 weeks postnatal
age (230).
Early life exposure to undernutrition/intrauterine
growth restriction and leptin signaling
It is highly likely that leptin provides trophic support for the
development of the neuronal network that regulates feeding
and energy expenditure during early development. Of course,
biochemical, neurophysiological, and tract tracing studies

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Leptin in the Control of Breathing Comprehensive Physiology

P6 P12

WT Lepob/Lepob WT Lepob/Lepob
AVPV AVPV

MPN MPN

PVH PVH

ARH ARH
LHA LHA

DMH DMH

P16 Adult
WT Lepob/Lepob WT Lepob/Lepob
AVPV AVPV

MPN MPN

PVH PVH

ARH ARH
LHA LHA

DMH DMH

Figure 9 Schematic diagram showing the effect of leptin deficiency on the ontogeny
of projections of the ARH through the hypothalamus during development. Left panel
(wild-type WT) and right panel leptin deficient (Lepob /Lepob ) on postnatal day (P) P6, P12, P16,
and adults (P60). Leptin deficiency permanently disrupts the formation of projections from the arcu-
ate nucleus to each major target nucleus. The relative size of each pathway is roughly proportional to
the thickness of the lines associated with it. AVPV, anteroventral periventricular nucleus; MPN, medial
preoptic nucleus; DMH, dorsomedial hypothalamus; PVH, periventricular hypothalamic nuclei; and
LHA, lateral hypothalamic area. Leptin deficient mice are slow to develop and have a reduced number
of projections from the ARH to other key areas of the hypothalamus that regulate feeding behavior.
Adapted, with permission, from Bouret SG and Simerly RB, 2004 (42).

cannot be done in human infants to delineate exactly how
leptin “programs” feeding behavior during early development
and across the life span. However, several “natural experi-
ments” exist in humans from which the potential mechanism
of leptin effects during early development can be gleaned.
Spontaneous mutations in the genes that encode leptin and
Ob-Rs may occur, and the phenotypes of patients with these
gene mutations have been described in case reports (89, 237).
These patients present with hyperphagia starting within days
of birth leading to severe early-onset obesity with a rapid
and dramatic increase in body weight within months of birth,
hypogonadotropic hypogonadism, and increased risk of infec-
tion. Those patients who were homozygous for the mutation
in the leptin gene had low levels (<1 ng/mL) of circulating
leptin (89, 237). Daily administration of recombinant leptin
to these patients improves many of the metabolic, feeding
and endocrine problems (274). Mutations in human genes
coding for Ob-Rs also lead to severe early-onset obesity,
with a rapid increase in body weight by 4 months of age, and
associated comorbidities throughout life (237). However, in
those patients with nonfunctioning Ob-Rs, exogenous leptin
is not an effective treatment.
Undernutrition resulting in leptin deficiency in
premature and small for gestational age infants to
SGAs infants: translational perspective
Leptin deficiency may also occur when infants are born pre-
maturely and/or SGA, birth weight less than 10th percentile
for age. Although leptin can be detected in human fetal cord
blood as early as 18 weeks gestation, circulating leptin levels
remain quite low (median 0.61 ng/mL; range 0.41–6.5 ng/mL)
until 34 weeks gestation at which time leptin levels markedly
increase (median 3.5 ng/mL; range 0.7–39 ng/mL) by term
gestation (37–40 weeks) (168). In human infants, similar to
adults, the rise in leptin levels is proportional to the increase
in fat mass which rapidly increases from 34 weeks to term
gestation (Figure 10), and sexual dimorphism occurs early
in gestation with females having higher leptin levels than
term male infants after controlling for fat mass (168). Infants
who are SGA, particularly those who have not grown well
in utero and have intrauterine growth restriction (IUGR)
have less fat mass, and thus lower levels of leptin than their
appropriate for gestational age (AGA) counterparts. Male
infants who are both premature and IUGR have the lowest

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Comprehensive Physiology
45
40
35
30
Leptin (ng/mL)
25
20
15
10
5 prematurely and is even lower in the breastmilk from mothers
0 leptin in infant formula or human milk that had either been
15 20 25 30 35 40 45
Gestational age (week)
Figure 10 Serum leptin concentrations in cord blood
(ng/mL) according to gestational age (weeks) in fetuses
and newborns. Blue symbol represents values obtained from fetuses
and newborns with normal growth; red circles, represents values from
fetuses and newborns with IUGR. Modified, with permission, from
Jaquet D, et al., 1998 (168).
leptin levels (<1 ng/mL) of all other infant groups, and the
levels can remain low for many months after birth (96, 371)
and reviewed in Ref. 122. Hellgren et al. (150) longitudinally
followed leptin levels in infants born less than 28 weeks
gestation and reported that leptin levels were consistently low
until infants reached a weight of 1900 g. These low leptin
levels in IUGR infants are similar to levels in patients with
mutations in the leptin gene (89, 237).
Postnatal weight gain is always less than in utero weight
gain, and thus, leptin levels remain quite low at a time
when trophic influence of leptin on organ development is
quite important (44). For example, infants born at 28 weeks,
4 weeks later, at postmenstrual age of 32 weeks, median lep-
tin levels were 0.01 ng/mL (min–max of 0.00–2.40 ng/mL)
which did not differ from the levels at birth. On the other
hand, infants born at 32 weeks of gestation had median leptin
levels of 0.63 ng/mL (0.00–6.48 ng/mL) (150). Similar to
infants who have congenital leptin deficiency, infants who
are born IUGR have increased risk of developing metabolic
syndrome (MetS) with hyperphagia, obesity, insulin resis-
tance, hypertension, and cardiovascular disease reviewed in
Ref. 174. While genetic mutations in the leptin gene and
the Ob-R are rare, being born prematurely and IUGR is
not, occurring in 10% to 15% of all pregnancies, American
College of Obstetrics and Gynecology. As clinical care of
high-risk pregnancies continues to improve more infants
with IUGR will be born, and with the rapid advances in
neonatology, these infants will survive with low leptin levels
at a critical period of organ development. Moreover, the
limit of viability continues to decrease, such that infants born
between 22 and 23 weeks gestation are surviving and growing
into childhood. Leptin levels are undetectable at birth and
Volume 10, July 2020
Leptin in the Control of Breathing
remain quite low for many weeks when many of the organs
are developing, specifically the brain, kidney, pancreas, and
cardiovascular system. Obesity and metabolic comorbidities
observed in ob/ob mice are similar what is observed in
models and infants who are exposed to undernutrition or
overnutrition during fetal development; thus comorbidities
(MetS, hypertension, and cardiovascular disease) that occurs
in adulthood in former IUGR infants could be explained by
insufficient leptin levels during organogenesis.
Leptin is expressed by the mammary gland and is in fat
droplets of freshly expressed breastmilk (184, 347); it is in
lower concentrations in breastmilk from mothers who deliver
of IUGR infants (90, 258). Resto et al. (302) did not detect
sterilized or pasteurized; thus, donor milk is not a significant
source of leptin. Of note, leptin was detected in commercially
available bovine formulas prepared in Spain (188), but this
has not been a consistent finding reported by others using
infant formulas from other manufactures. Thus, SGA and
IUGR infants, especially those who are born less than 34
weeks of gestation and who already have undetectable leptin
levels at a key time during organ development, do not receive
leptin from human milk or commercially available premature
formulas or human milk fortifiers. Ob-Rs are present in the
stomach of newborn animals and human adults (51, 348).
Exogenously administered leptin to nursing dams increases
milk leptin levels and circulating leptin in nursing rat pups
(323). Human recombinant leptin is available and FDA
approved to be used in patients with congenital leptin defi-
ciency. The other populations who may benefit from leptin
supplementation are extremely premature infants and infants
who are IUGR. Leptin supplementation for at-risk infants
should be considered (354). Studies to determine efficacy and
safety of leptin supplementation to reduce the risk of adverse
metabolic and cardiovascular outcomes in this population
should be considered.
Early Life Exposure to Overnutrition
HFD/obesity during pregnancy modifies leptin
POMC signaling pathways in offspring
Similar to undernutrition, overnutrition during fetal or early
postnatal life can also cause lifelong changes to metabolic
systems often leading to obesity in adulthood (261, 310).
These metabolic changes also increase the susceptibility of
developing obesity-associated comorbidities such as diabetes,
cardiovascular disease, and suboptimal mental health (36).
Studies using animal models of maternal undernutrition, and
overnutrition show that changes in nutritional environment
may increase susceptibility to obesity in adult offspring
by compromising the proper development of hypothalamic
pathways regulating appetite (41, 42). Early overnutrition
increased body weight, susceptibility to obesity, hyper-
leptinemia, and leptin resistance later in life (54, 125).
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Leptin in the Control of Breathing
Leptin regulates energy balance and exhibits neurotrophic
effects during critical developmental periods (178, 321).
How HFD and high circulating leptin levels alter metabolic
function appear to be, in part, associated with a reduced abil-
ity of POMC neurons to respond to leptin, which is critical for
the regulation of POMC and other hypothalamic regulatory
neuronal projections (125, 143). One mechanism by which
leptin activates POMC neurons is through phosphorylation of
STAT3 and downstream signaling. Leptin induced phospho-
rylation of STAT3 is attenuated in models of early overnutri-
tion (125). POMC neurons of diet-induce-obesity (DIO) mice
are resistant to activation of STAT3 phosphorylation by lep-
tin. Indeed, these DIO animals had overexpression of both
leptin receptors selectively in hypothalamic POMC neurons
and the SOCS3 mRNA in the arcuate (ARC) nucleus of DIO
mice (117).
Hypothalamic systems that regulate appetite may be per-
manently modified during early development in response to
suboptimal nutritional states. Adult offspring of rodents fed
an obesogenic diet prior to and throughout pregnancy and
lactation have hyperphagia and an increased adiposity (178).
Juvenile (Day 30) offspring of obese dams were resistant
to the inhibitory effects of leptin on food intake and body
weight, at a time when serum leptin levels were normal; the
leptin resistance was still present in adulthood (Day 90) when
the animals were obese and hyperleptinemic (178). Offspring
of obese dams have amplified and prolonged neonatal lep-
tin surge, which is accompanied by elevated leptin mRNA
expression in their abdominal white adipose tissue. At postna-
tal day 30, before the onset of hyperphagia, in these animals,
serum leptin levels are normal, but leptin-induced appetite
suppression and phosphorylation of STAT3 in the ARC are
attenuated (41, 178). The level of AgRP immunoreactivity
in the PVN, which is derived from neurons in the ARC, is
developmentally dependent on leptin and is also diminished
in these animals (178).
Roberts et al. (310) have characterized the synaptic devel-
opment of POMC neurons in the ARC, their sensitivity to
leptin, and the impact of early overnutrition on the develop-
ment of these neurons. Accordingly, leptin’s overall effects on
POMC neurons are excitatory during late development and
into adulthood (256). In early development, chronic postna-
tal overnutrition (CPO) promotes an increase in the ampli-
tude of postsynaptic inhibitory currents of POMC neurons,
while during late development, CPO decreases the amplitude
of these currents and the excitatory effect of leptin on these
currents. Taken together, these studies suggest that postna-
tal overfeeding alters the postsynaptic development of POMC
neurons and induces long-lasting leptin resistance in ARH-
POMC neurons.
Moreover, maternal diet-induced obesity is associated
with cardiovascular dysfunction in male offspring during
adulthood (37, 320, 364) (Figure 11). These offspring have
cardiac hypertrophy and impaired systolic and diastolic func-
tion. Interestingly, these cardiac changes occur independently
of differences in the bodyweight of the offspring (37). The
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Comprehensive Physiology
Fetal/neonatal Excessive adiposity Pregnancy
hyperleptinaemia (overnutrition) and lactation
Leptin
resistance and
impaired neurotrophic Selective leptin resistance
action
in the hypothalamus
Metabolic SNS Offspring
action activity phenotype
Altered leptin
signalling in
Hyperphagia
hypothalamus Hypertension
and obesity
in adulthood
Figure 11 Overnutrition and excessive adiposity during pregnancy
and lactation alter the fetal programming leading to obesity and hyper-
tension. The altered leptin signaling in the hypothalamus promotes a
selective leptin resistance in which the anorexic effects of leptin are lost,
whilst the pressor effect of leptin is enhanced. Adapted, with permission,
from Taylor PD, et al., 2014 (364).
exposure to high leptin levels in the immediate postnatal
period, from increased fetal adiposity, leads to selective
leptin responsiveness, hypertension, and altered myocar-
dial function. The increase in low: high-frequency ratio of
heart rate variability (marker of sympathetic tone) in 30-day
leptin-treated animals is indicative of heightened sympathetic
efferent tone (320). Experiments using transgenic technology
to restore MC4R in the PVN of Mc4rKO mice showed that
these mice develop higher blood pressure than Mc4rKO or
wild-type (WT) mice, suggesting that neonatal hyperleptine-
mia due to maternal obesity induces persistent changes in
the central melanocortin system, thereby contributing to
hypertension in offspring (322).
Respiratory function can also be altered in offspring of
dams who have been feed a dyslipidaemic (DLP) diet during
pregnancy and lactation. At postnatal day (P)30, the offspring
of DLP rats had increased circulating levels of triglycerides
and cholesterol levels. At P90, DLP offspring exhibited
higher MAP and augmented cardiorespiratory chemoreflex
response to hypercapnia and hypoxia (140). Taken together,
these data suggest that maternal dyslipidemia alters cardiores-
piratory reflex in offspring and may be a predisposing factor
for hypertension and disordered breathing in adulthood.
Leptin and Peripheral Chemoreceptors
Peripheral chemoreceptors
The peripheral chemoreflexes contribute significantly to the
cardiorespiratory responses to hypoxia, hypercapnia, and
acidosis by altering respiratory amplitude and frequency, and
by activating the sympathetic nervous system. The peripheral
chemoreceptors include the aortic bodies, and in particular,
the CBs that modulate respiration and sympathetic output.
The CBs, the most vascularized organs in the body, are
located bilaterally in the bifurcation of the carotid artery
and sense arterial PO2 (PaO2 ), arterial PCO2 (PaCO2 ), pH,
and temperature. They are responsible for the greatest part
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Comprehensive Physiology Leptin in the Control of Breathing

of the hyperventilatory response during hypoxia and con-
tribute to the hyperventilation that accompanies respiratory
or metabolic acidosis (130). In response to hypoxia, hyper-
capnia, and acidosis, type 1 CB cells—the chemoreceptor
unit of the CB—release neurotransmitters/neuromodulators
that bind to the carotid sinus nerve, thereby modulating its
firing rate (130). CSN activity is integrated into the NTS
in the brainstem (Figure 2) (120) output to neurons that
innervate the muscles of respiration (130), and to the RVLM
that output to the sympathetic nervous system that regulates
blood pressure (220).
Despite the growing knowledge as to how several stimuli
activate the CB, no consensus has been achieved as to how
the CB senses the classical CB stimulus, low arterial O2 ,
and its molecular identity and how O2 sensing translates into
increased chemosensory activity and to a systemic cardiores-
piratory response (297). However, it is generally accepted
that the stimulus-secretion coupling in type I cells during
CB activation by hypoxia triggers a series of molecular
and cellular responses that are schematically depicted in
Figure 12, and outlined here: (i) O2 -sensing at an O2 -sensor,
(ii) activation of coupling mechanisms with K+ channels,
(iii) change in kinetics of these K+ channels resulting in a
decrease in their opening probability, (iv) cell depolarization,
(v) activation of voltage-operated channels, (vi) Ca2+ entry
and increase in intracellular free Ca2+ , (vii) activation of
exocytosis and neurotransmitter release (129, 130).
The type I cells in the CB contain catecholamines
(dopamine and norepinephrine), serotonin, ACh, GABA,
neuropeptides (substance P and enkephalins), adenosine, and
ATP; for a review see Refs 62, 185. All these neurotransmit-
ters/neuromodulators, as well as agonists and antagonists of
their receptors, are capable of modifying carotid sinus nerve
activity. The CB also contains glial-like type II cells that enve-
lope type I cells. Although originally thought to only play a
supportive role (130), new data from several studies show that
type II cells have many important functions in the CB. They
contribute to neurogenesis in vivo in response to prolonged
hypoxia, contribute to paracrine signaling, and to purinergic
catabolic pathways by integrating the sensory output of the
CB during chemotransduction (259, 270, 284, 285).
Besides its substantial role in the control of ventilation,
it has been proposed that the CB is also a metabolic sen-
sor; implicated in the control of energy homeostasis (65,
182, 183) and more recently in the regulation of peripheral
insulin sensitivity and glucose homeostasis (63, 65, 306,
315). Data from previous work performed, in cats (6–8) and
dogs (182, 183), and more recently in humans (381), sup-
ported a role for the CB in the counter-regulatory responses
to hypoglycemia. However, from the conclusions based
on the results of the experiments published by Pardal and
Lopez-Barneo in 2002 (269), the hypothesis that the CB has
glucose-sensing properties was born. Nevertheless, while
many agree that the CB is involved in the counter-regulatory
responses to hypoglycemia, the hypothesis that the CB
is a glucose sensor is often refuted; recently reviewed by
Conde et al. (64); thus, the sensitivity of the CB to hypo-
glycemia remains a hot topic in the field and with no clear
consensus.
More recently, results from Conde and co-workers (306)
showed that other metabolic stimuli, such as insulin activate
CB chemoreceptors: They report that (i) insulin receptors are
present and undergo phosphorylation in response to insulin
in the whole CB, (ii) insulin increases the levels of [Ca2+ ]i
in type I cells and induces neurosecretion of dopamine and
ATP from the CB, and (iii) insulin administered to adult

ANG ll Leptin Insulin Respiratory

PO2 responses
K+ Channel
PCO2

CSN Cardiovascular
activit responses
y
[Ca2+]

Renal responses
Carotid body
Carotid body Type I cell

Neuroendocrine
responses

Figure 12 Schematic representation of some stimuli that activate carotid body (CB)
chemoreceptors and the responses elicited by the carotid body. Decreased arterial oxygen
pressure (PO2 ), increased carbon dioxide arterial pressure (PCO2 ), angiotensin II (ANG II), leptin, and
insulin are examples of stimuli that activate the CB. In general, these stimuli originate type 1 CB cell depo-
larization, increase in intracellular Ca2+ and the release of neurotransmitters that act on the CB sensitive
nerve, the carotid sinus nerve (CSN), to increase its activity aiming its integration at the central nervous
system level to produce respiratory, cardiovascular, renal, and endocrine responses.

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Leptin in the Control of Breathing
rodents increases ventilation in a dose-dependent manner
during an euglycemic clamp; an effect that was abolished
with bilateral denervation of the CSN (306). Also, the same
authors propose that the CBs are involved in the genesis
of peripheral insulin resistance and deregulation of glucose
metabolism; in animals who are fed a hypercaloric diet,
the CB is overactivated, and metabolism and hemodynamic
responses are dysregulated; these altered effects, induced by
hypercaloric diet, were prevented or reversed after chronic
denervation of the CSN (306, 313, 315). From these data,
Conde et al. (65) proposed that hyperinsulinemia, induced
by hypercaloric diets, is one of the key drivers for CB over-
activation. However, obese animals with insulin resistance
have a greater increase in spontaneous ventilation, ischemic
hypoxia-induced hyperventilation, CB weight, and tyrosine
hydroxylase expression within the CB than lean animals
with hyperinsulinemia and insulin resistance (306), sug-
gesting the existence of an obesity-related factor, such as
leptin, may contribute to CB stimulation when metabolism is
dysregulated.
In addition to obesity, OSA is another chronic disorder
associated with increased CB activity and altered hypoxic
ventilatory responses (131, 250, 275, 303); patients with
OSA are often obese (22, 39, 387). Among the several risk
factors that can contribute to the development of OSA,
obesity plays an important role in its pathogenesis. Approx-
imately 40% of obese individuals also present with OSA,
and approximately 70% of individuals with OSA are obese
(74, 375). More specifically, visceral obesity is common in
subjects with OSA and is positively correlated with apnea
index (341); circulating leptin is increased in OSA patients
(165, 375), and correlate with OSA severity (165). Thus, it
can be postulated that part of the increased CB activity and
altered hypoxic ventilatory responses in patients with OSA
and obesity might involve a direct effect of leptin on CB
activity.
The role of leptin in acute peripheral chemoreceptors
responses to hypoxia and hypercapnia
Indubitable evidence supports the role of leptin in the central
control of breathing with classically experiments published
by O’Donnell et al. in 1999 showing leptin replacement in
(ob/ob) leptin-deficient mice (260, 363) reversed baseline
hypoxemia and hypercapnia. However, it was only in this
century that leptin’s action on peripheral chemoreceptors
was first explored (136). In this seminal study, Groeben and
co-workers (136) assessed CB function, as the % decrease
in respiratory parameters (respiratory rate and tidal vol-
ume) in normoxic to hyperoxic transitions (50, 76, 189),
in wild type (+/+) and leptin-deficient (ob/ob) mice with
and without leptin supplementation. They suggested, for
the first time, that leptin may be contributing to peripheral
control of breathing. They found that (i) hyperoxia decreased
respiratory rate by 10% from baseline in +/+ mice, but
had no effect on respiratory rate in ob/ob mice; (ii) after
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Comprehensive Physiology
leptin replacement in ob/ob mice, respiratory rate decreased
between 11% and 13%, whereas respiratory rate was unaf-
fected in vehicle-treated ob/ob mice; and (iii) hyperoxia
decreased tidal volume by 13%, with this component of
the hypoventilatory response to hyperoxia being absent
in +/+ or vehicle-treated mice. Taken together these data
supported a direct or indirect effect of leptin on CB function
in the hypoventilatory response in normoxic to hyperoxic
transitions (136). Seven years after Groeben’s publication
in 2004 (136), Porzionato and co-workers (288) reported
the presence of leptin and leptin receptor isoforms in type
I, but not in type II, chemoreceptor cells of both rat and
human CB; approximately 40% of human CB type I cells
were positive for leptin immunoreactivity with more than
50% being immunopositive for all leptin receptor isoforms
of which 30% being reactive for the isoform Ob-Rb. Cor-
roborating the findings reported by Porzionato et al. (288),
Messenger et al. (228) found that rat CB cells co-expressed
immunoreactivity for Ob-Rb and tyrosine hydroxylase
(marker for type I cells), indicating that this receptor is
present in type I CB cells. More recently, in 2019, Caballero-
Eraso et al. (46) reported that Ob-Rb immunoreactivity is
present in approximately 74% of mice CB type I cells. Taken
together, these results promoted the idea that the ventilatory
effects of leptin are, at least in part, mediated by the CB
chemoreceptors.
Further supporting the role of leptin in modulating the
contribution of the CB to ventilation, leptin given to Wis-
tar rats either intravenously (262, 305) or in the carotid
artery close to the CB, dose-dependently increased baseline
ventilation and ventilation in response to occlusion of the
common carotid artery (including ischemic in the CB) (305).
Similarly, in C57BL/6J mice, subcutaneous infusion of lep-
tin (120 μg/day) increased minute ventilation and hypoxic
ventilatory response that was abolished by CB denervation
(46). These data, thereby, confirmed the contribution of
CB to leptin effects on basal ventilation and in response to
acute hypoxia. Lastly, Ribeiro et al. (304) tested the acute
effect of leptin on basal ventilation in rats submitted to
CSN denervation and showed that the CB contributed with
approximately 30% to baseline ventilation. On the other
hand, chronic administration of leptin for 7 days (60 μg/day)
to adult rats did not change resting respiratory parame-
ters but did increase hypoxic ventilatory response (399),
suggesting that acute and chronic effects of leptin might
be mediated by different signaling pathways and thereby
modifying the contribution of the CB to the response. Apart
from contributing to basal ventilation and to responses
to acute hypoxia, leptin seems to be involved also in the
responses to acute hypercapnia, as (ob/ob) mice showed
significant reductions in hypercapnic ventilatory sensitivity
relative to +/+ homozygotes mainly due to an attenuated
tidal volume (362).
Apart from the apparent consensus on the contribution
of the CB to the effects of leptin on spontaneous baseline
ventilation, role of CB in mediating leptin effects during acute
Volume 10, July 2020
Comprehensive Physiology
hypoxic and hypercapnic responses are far from being con-
clusive. For example, Ribeiro et al. (305), using a superfused
ex vivo preparation of the rat CB, found that leptin increased
basal CSN electrical activity in rats without affecting the
hypoxic response whereas Caballero-Eraso et al. (46), using
adult mice in vivo preparation, found that leptin infused
intravenously augmented both baseline activity of the CSN
and activity in response to acute hypoxic exposure. Leptin-
induced increase in hypoxic chemosensitivity of the mice
CSN, using an in vivo preparation, had also been reported
by Shirahata et al. (342). In these mouse experiments, leptin
(25–100 ng/mL) perfused for 5 min did not change baseline
CSN activity but did increase CSN activity in response to
hypoxia, an effect that was blocked by the nonspecific tran-
sient receptor potential (Trp) channel blockers SKF96365
and 2-APB (342).
The different effects of leptin on the CB responses to
hypoxia between the ex vivo versus in vivo preparations sug-
gests that the potentiation of CSN activity in acute hypoxia
promoted by leptin can be due to other factors than the direct
action of leptin within the cells of the CB or its signaling
pathways within the organ, as the action on specific type of
cells within the CB or in the efferent pathway that innervates
the CB, which is absent in the ex vivo preparation. Species
differences might also explain the diverse effects of the leptin
on the CB hypoxic responses; in the CB from mice, leptin
potentiated CSN responses to acute hypoxia (46, 342) but not
in the CB from rats (305).
Leptin directly affects molecular and cellular response
of the type I cell. Acute application of leptin (200 ng/mL)
to isolated type I cells from the rat, increased intracellu-
lar calcium (291) and BKCa currents, but failed to alter
the resting membrane potential or modify anoxic/acidic
depolarizations (291), suggesting that leptin receptors are
functional on type I cells but that their acute activation does
not alter chemosensory properties. On the other hand, also
using isolated type I cells from the rat, Ribeiro et al. (305)
reported that leptin (40 ng/mL) was unable to increase Fura-2
ratio in rat CB isolated type I cells (i.e., intracellular Ca2+
levels) both at resting and in response to acute hypoxia.
These differences in calcium responses between the two
studies may be explained by the fivefold increase in leptin
concentration in the superfusate used in experiments reported
by Pye et al. (291) in comparison to that used in experiments
reported by Ribeiro et al. (305). Consistent with lack of
leptin-induced changes in intracellular response reported by
Ribeiro et al. (305), leptin also did not induce secretion of
catecholamines from the whole rat CB (262), but did induce
adenosine release (305), an excitatory mediator involved in
the responses of CB to hypoxia. Additionally, it should be
considered that acute leptin administration (291, 305, 342)
might have different effects on the whole CB in vivo via
activation of different leptin signaling pathways, and there-
fore produce different effects on spontaneous ventilation and
hypoxic ventilation responses in situations associated with
chronic exposure to high levels of leptin.
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Leptin in the Control of Breathing
The role of leptin in sensitization of peripheral
arterial chemoreceptors in chronic conditions
While the role of leptin on the peripheral chemoreceptor
responses to hypoxia and hypercapnia is inconsistent (46,
262, 291, 305, 342), a consistent observation is that condi-
tions leading to hyperleptinemia, such as OSA and obesity,
leptin signaling in the CB augments spontaneous ventilation
and hypoxic ventilator responses (165, 280, 325).
Chronic intermittent hypoxia
CIH, characterized by cyclic hypoxic episodes of short
duration followed by normoxia, occurs in patients with OSA.
Several well-designed experiments in animals implicate the
overactivation of the CB as the genesis of OSA-mediated
hypertension, due to increased activity of the sympathetic
nervous system (104, 275, 276, 303). Moreover, patients with
OSA have increased peripheral CB drive (for a review see
Ref. 65). The increased CB drive with heightened sympa-
thetic activity is evidenced by the increase in tidal volume
at baseline (207) and augmented ventilatory and cardiovas-
cular reflex responses induced by acute hypoxia (119, 250,
349) observed in these patients. Among the several factors
that have been proposed to be responsible for the increased
sympathetic nerve activity in cardiovascular and metabolic
abnormalities are hyperinsulinemia (191–193, 300) and
hyperleptinemia (149, 294). Indeed, CIH in rats increased
circulating leptin levels (227, 228, 262) concomitantly with
increased sympathetic tone, increased minute ventilation, and
increased hypoxic ventilatory responses (262).
In addition to the increased leptin levels induced by CIH,
CIH also promotes visceral adipose tissue dysfunction in
both lean and obese animals (245, 314). Therefore, it can be
hypothesized that CIH induces upregulation of leptin pro-
duction by adipose tissue; elevated circulating leptin levels
induces CB sensitization thereby augmenting sympathetic
tone and hypoxic ventilatory responses. In support of this
hypothesis, adult rats exposed to 8 h of CIH have altered lep-
tin protein expression and leptin signaling pathways within
the CB (227, 228). Indeed, CIH increased leptin, ERK1/2,
and Fra-1/2 immunoreactivity within CB type I cells (227,
228), an effect attributed to activation of the leptin signal-
ing cascade. Similarly, immunoreactivity for downstream
signaling molecules (ERK1/2 and Fra-1/2) induced by CIH
is also observed in CB type I cells (227, 228). Moreover,
8 h of CIH also increased protein expression of leptin, the
short form of the leptin receptor (Ob-R100 kDa) and SOCS3
while protein levels for the long form of leptin receptors
(Ob-Rb) protein were decreased (228), suggesting that leptin
produced via autocrine/paracrine mechanisms or leptin from
other sources increased excitation of CB cells and modulates
CB chemosensitivity in CIH conditions.
The downstream effects mediated by CIH on leptin pro-
duction and activation of leptin signaling pathways within the
CB are likely to differ between the experimental paradigms
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Leptin in the Control of Breathing
of CIH related to time, duration and level of hypoxia. For
example, CIH for 7 and for 95 days decreased leptin protein
levels, increased the long-form leptin receptor (Ob-Rb)
expression without changing the levels of protein expression
of the short form leptin receptor (Ob-R100) (229) in the
CB. These effects on the abovementioned proteins differed
from what was described after 8 h of CIH (227, 228). CIH
for 8 h increased protein expression for leptin, Ob-R100
kDa and SOCS3 while protein levels for Ob-Rb decreased
(228).
The upregulation of Ob-Rb isoform of the leptin recep-
tor may be explained by a feed-forward mechanism that
produces CB overactivation contributing to sympathetic
nervous system activation and increased hypoxic ventilatory
responses. In fact, protein expression for leptin receptors
within the CB is increased in animal models of obesity and
insulin resistance (305), conditions known to be associated
with hyperleptinemia.
The duration of CIH affects which leptin signaling path-
ways will be activated within the CB with pSTAT3 protein
levels being significantly decreased in the homogenates of
the CB after 7 days of exposure to CIH, but not after 95 days,
whereas SOCS3 protein levels were elevated after 7 days and
pERK1/2 was elevated after 95 days of CIH (229). Taken
together these data support the notion that leptin signaling
in the CB is dependent on the intensity and chronicity of
the stimuli. The summation, however, of the effects of CIH,
regardless of the signaling pathway involved, is that CIH
increases circulating leptin levels, which then directly acti-
vates CB type I cells leading to an increase in CSN activity
(46, 305, 342); thus, the increased CB chemosensitivity in
models of CIH is mediated by leptin.
Several lines of evidence suggest that leptin signaling in
the CB may also be regulated by the angiotensin system.
Angiotensin II (ANG II) promotes leptin production and
secretion (177, 343), ANG II type 1 receptors (AT1Rs) are
expressed within the CB, and ligand binding to ANG II
receptors in the CB increases CSN activity (5); ANG II
also mediates CB overactivation in sympathetic mediated
diseases, such as chronic heart failure (HF) (203, 330). Both
captopril (an angiotensin-converting enzyme inhibitor) and
losartan (blocks AT1Rs) are commonly used to treat hyper-
tension and some types of congestive HF in humans. Using
these drugs, Moreau et al. (241), investigated the effects of
ANG II blocking on leptin and leptin signaling in the rat
CB. They reported that 3 days of treatment with captopril,
abolished the increase in plasma leptin levels induced by 8 h
of CIH; whereas, losartan treatment had no effect on plasma
leptin levels (241). Additionally, both captopril and losartan
abolished the CIH-induced increased protein expression for
leptin, Ob-R100, and the CIH-induced changes in pSTAT3
and (pERK1/2) protein levels in the CB (241), suggesting
that ANG II can regulate leptin action in the CB as a result of
CIH. These findings, taken together with the previous obser-
vations that ANG II modifies CB chemosensitivity to increase
sympathetic tone and hypoxic chemosensitivity (202, 330),
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Comprehensive Physiology
suggest an interaction/integration of different pathways
within the CB, which in turn may influence chemoreceptor
activity.
Obesity
Pathological weight gain contributes significantly to morbid-
ity and mortality worldwide due to its comorbidities, which
are thought to be responsible for 1 in 5 deaths in the world
(128, 386), Obesity comorbidities include cardiovascular
disease, type 2 diabetes (T2D), hypertension, and some
cancers (386) and play a key role in the development of OSA
and obesity hypoventilation syndrome (OHS), two important
breathing disorders. The pathophysiology underlying the
generation of obesity and obesity-related illnesses are not
completely understood, but it is generally believed that the
sympathetic nervous system plays a role in the generation of
both obesity and obesity-related illness (191, 192, 365), and
several lines of evidence suggest a link between breathing
disorders and altered peripheral control of sympathetic activ-
ity (110, 299), supporting the hypothesis that CB insulin/and
or leptin action is contributing to the CB response (63, 305,
306). Trayhurn and Wood in 2004 (366, 367) suggested
that obesity-related white adipose tissue hypoxia as the key
underlying mechanism triggering adipose tissue dysfunction.
Since then, several studies have been undertaken both in in
vitro and in animal models (99, 366, 367, 393), with only a
very limited clinical investigation to prove this concept (132,
154, 377). Hypoxia does develop within the adipose tissue as
the tissue mass expands and the reduction in interstitial PO2
induces a pro-inflammatory response (115, 271, 366). The
secretion IL-6, TNFα adipokines are upregulated by hypoxia
(115, 366). In addition to inducing a pro-inflammatory
response, local hypoxia promotes insulin resistance in fat
cells (217, 301, 392), and stimulates the secretion of leptin,
even with a normoxic systemic PaO2 (154, 366). Although
leptin contributes to the control of breathing in obesity, as
the administration of the hormone reverses the hypoxia and
hypercapnia commonly encountered in animals with absence
of the functional hormone (260, 363), the mechanisms by
which obesity affects hypoxic ventilatory responses and
the contribution of the peripheral chemoreceptors to these
mechanisms were not clearly understood until very recently.
It was found that the effect of leptin in increasing spon-
taneous and ventilation in response to ischemic-hypoxia
induced by carotid artery occlusion and augmenting CSN
activity was blunted in animals submitted to 3 weeks of HFD
(305). Associated with these effects, the CBs from these
animals exhibited 35% overexpression of leptin receptors,
suggesting a feed-forward mechanism aiming to increase CB
activity or the saturation of Ob-R caused by diet-induced
hyperleptinaemia; a similar effect has been described for the
CNS of animals exposed to HFD (316). Taken together the
authors postulated that although leptin might be involved in
triggering CB overactivation in initial stages of obesity and
dysmetabolism, resistance to leptin signaling and blunting of
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Comprehensive Physiology
responses develops in animal models of MetS, which is in
agreement with the lack of increase in minute ventilation in
rats exposed to hyperlipidic diets for 8 (399) and 16 weeks
(296). In parallel with the study of Ribeiro et al. (305), Yuan
and co-workers (399) showed that obese Zucker rats, that lack
the gene that codes for Ob-R, have decreased hypoxic ven-
tilatory responses, and that chronic administration of leptin
to Zucker lean littermates did not alter baseline ventilation,
but produced a heightened hypoxic ventilatory response;
effects abolished by CSN denervation. Additionally, the
expression of pSTAT3, as well as putative O2 -sensitive K+
channels including TASK-1, TASK-3, and TASK-2 within
the CB was reduced in obese Zucker rats, effects also abol-
ished by CSN denervation (399). Moreover, chronic leptin
administration increased the expression of pSTAT3 and
TASK channels in Zucker lean littermates, suggesting that
leptin signaling in the CB via pSTAT3 and TASK channels
contributes to the increased hypoxic ventilatory responses in
obesity. Confirming the role of the CB in mediating leptin
effects on spontaneous ventilation and hypoxic ventilatory
responses in obesity, Caballero-Eraso et al. (46) reported
that obese db/db mice transfected with Ob-R in the CBs
had increased minute ventilation during wakefulness and
sleep and increased the hypoxic ventilator response. The
authors speculated that leptin signaling in the CB could
maintain respiratory function in severe obesity by preventing
the development of OHS. Moreover, leptin signaling in the
CB may contribute to maintaining oxygenation in hypoxic
conditions, such as during exposure to high altitude, and in
patients with cardiorespiratory disease. Nevertheless, we can-
not forget that leptin significantly augments sympathetic tone
thereby contributing to the development of obesity-induced
cardiometabolic and respiratory comorbidities (32, 181, 215,
373) (Figure 13).
Future directions: filling the gaps on leptin’s action
on peripheral chemoreceptors
In the last decades, a growing body of evidence emerged
linking leptin to the peripheral control of breathing. It is
now generally accepted that leptin acts on the CB to modify
spontaneous minute ventilation and hypoxic ventilatory
responses in acute and chronic conditions such as obesity and
CIH (46, 305, 399). However, there remains a significant gap
in knowledge regarding the specific mechanisms and signal
pathways by which leptin activates or modifies CB action
and CSN activity promoting alterations in ventilation and
the sympathetic nervous system both in acute and chronic
diseases. For example, a greater understanding of which
leptin signaling pathways are activated in the CB in acute and
chronic diseases could potentially lead to new therapeutic
targets for the treatment of obesity-related respiratory dis-
eases. Another point of interest is how the CB contributes to
sympathetic overactivation in sympathetic mediated diseases,
such as MetS, T2D, hypertension associated with OSA and
essential hypertension, some of which co-occur with of
Volume 10, July 2020
Leptin in the Control of Breathing
Hypercaloric diets,
obesity,
chronic intermittent hypoxia
Adipose tissue dysfunction
Increased circulating leptin
Carotid body
overactivation
Sympathetic
Spontaneous nervous system activity
ventilation
Hypoxic ventilatory
response
Hypertension Insulin resistance
Figure 13 Diagram representing the involvement of carotid
body in leptin effects in the control of breathing and on
sympathetic overactivation that participates in genesis of
insulin resistance and hypertension. Hyperleptinemia produced
by adipose tissue dysfunction induced by dysmetabolism, obesity
and/or by chronic intermittent hypoxia originates an increase in
carotid body sensitization that is on the basis of increased spontaneous
ventilation, increased hypoxic ventilatory response, and augmented
sympathetic activity.
obesity, for a review see Conde et al. (63); leptin’s action
within the CBs might have a role in promoting sympathetic
overactivation in all these conditions. Recently, Ribeiro et al.
2019 (304) tested the contribution of CB to acute leptin
effects on sympathetic activity and mean blood pressure in
control and obese rats after CSN denervation. Preliminary
data showed that the CB contributes to the effect of leptin
on sympathetic activity, an effect that is decreased in obese
animals probably due to CB leptin resistance in obesity (304).
Additional research is needed to fully understand leptin’s
action in the CB as well as its contribution to chemoreflex
responses. Obesity, hypertension, metabolic dysregulation,
and breathing disorders occur throughout the life span.
Essentially nothing is known about the effect of leptin on
peripheral control of breathing during development and
aging.
Leptin Dysregulation Mediating
Disordered Breathing and Therapeutic
Interventions
Effect of exercise training on leptin sensitivity
Previous studies have consistently shown that changes in
lifestyle such as hypocaloric diet and exercise training
reduce obesity, high blood pressure, and diabetes (190,
368). These nonpharmacological interventions also improve
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Leptin in the Control of Breathing
chemorespiratory function in patients with MetS and decrease
the severity of OSA (370). A 10% reduction in body weight
is associated with a 30% reduction in apnea-hypopnea index
(AHI) (264, 278). However, the mechanisms explaining the
effects of diet and exercise training in patients with MetS and
comorbidities in OSA are unknown.
Aerobic (180, 283) and resistance (196, 351) training is
recommended for the prevention and treatment of obesity-
induced cardiovascular disorders. Exercise training (10 weeks
of moderate-intensity resistance in a vertical ladder) prevented
the cardiovascular and inflammatory responses (increases in
TNF-α and IL-1β) produced by HFD in sedentary rats (351).
Interestingly, the anti-inflammatory markers (IL-10; ATII
and Mas receptors and others) were increased in the NTS
after the resistance training compared to sedentary HFD rats
(351). These data demonstrated that moderate intensity of
resistance exercise prevented obesity-induced cardiovascular
disorders and reduced inflammatory responses in the NTS,
an important region of the brain that mediate cardiovascular
and respiratory function, as explained in the section “Leptin
and Central Control of Breathing”, page 4.
In addition, the combination of hypocaloric diet
(500 kcal/day for 4 months) and exercise training (three
60-min sessions three times/week for 4 months) improved
sympathetic peripheral chemoreflex sensitivity and venti-
latory central chemoreflex hypersensitivity in patients with
MetS and OSA (213). Body weight, waist circumference,
glucose levels, systolic/diastolic blood pressure, and AHI
were reduced after the hypocaloric diet and exercise ses-
sions. Indeed, in the same study, muscle sympathetic nerve
activity (MSNA) at rest and in response to hypoxia and
hypercapnia after exercise was also reduced, suggesting that
the less MSNA in patients with MetS and OSA depends
on the reduction of OSA severity and the normalization of
chemoreflex (213).
Improvement of insulin sensitivity and decreased waist
circumference after exercise is associated with amelioration
of OSA in some subjects. Sleep apnea in obese subjects
causes CIH and sleep fragmentation which leads to and
exacerbate obesity and T2D by increasing sympathetic activ-
ity, oxidative stress, inflammation, and lipolysis. Moreover,
obesity or diabetes can influence chemosensitivity and sleep
apnea either directly or via action on sympathetic activity,
inflammation, or other mechanisms (151). Indeed, long-term
improvements in insulin action due to continuous positive
airway pressure (CPAP) would support the hypothesis that
OSA leads to or exacerbates insulin resistance and under-
mines the hypothesis that insulin resistance itself leads
to OSA. In nonobese, HFD fed rats, metformin treatment
increased insulin sensitivity and prevented the development
of sleep apnea independent of body weight (298).
Changes in circulating leptin levels is another potential
mechanism by which exercise optimizes the cardiorespi-
ratory function in OSA and MetS patients. As outlined
above, leptin is a hormone produced by fat tissue that acts
in the CNS mediating many biological functions including
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Comprehensive Physiology
energy balance, sympathetic activity, blood pressure, and
ventilation. In this context, the effect of physical exercise
on leptin concentrations has been studied. Several studies
suggest that short-term exercises (<60 min) and exercises
that generated energy expenditure lower than 800 kcal do
not modify serum concentrations of leptin (40, 194, 383).
Instead, long-term and high-intensity exercise lower lep-
tin concentrations in trained males running on a treadmill
burning 800 and 1500 kcal (97). These exercise conditions
decreased plasma leptin concentrations after 48 h which was
preceded by a decrease in insulin concentrations. These data
suggest that the decline in leptin concentration was likely
from disruption in metabolic homeostasis created by high-
intensity, long duration, energy expenditure and subsequent
excess post-oxygen consumption (after-burn). Data from
other studies show that leptin concentrations were signifi-
cantly lower immediately after exercise (70% of Vo2 max,
energy expenditure > 800 kcal), 10 and approximately 20 to
48 h post exercise (257, 263).
The low Vo2 max is a good predictor of mortality in obese
subjects (127). High-intensity interval training (HIIT) is an
interesting alternative to improve the Vo2 max and to reduce
body fat. HIIT can favorably impact the neuroendocrine
axis (i.e., leptin levels) and improves lipid metabolism in
overweight/obese and lean subjects (38, 47, 162). Six weeks
of isocaloric training, HIIT or moderate-intensity continu-
ous training (MICT) in adult men with obesity, promoted
similar adaptation to Vo2 max and blood pressure values
(124). Although both exercise protocols were able to increase
Vo2 max, neither MICT nor HIIT changed lipid profile,
body composition or leptin concentrations. In this study,
neither HIIT nor MICT was associated with a change in fat
mass possibly accounting for no change in circulating leptin
levels. However, in two additional studies from the same
group, they found reductions in leptin concentrations after
5 (47) and 8 weeks of aerobic training without a reduction
in fat mass in participants (162). In both studies, partici-
pants were young, normal weight, physically active males,
and the reduction in leptin levels seems to be related, as
outlined above, to high energy expenditure during exercise
sessions.
The effects of HIIT and MICT exercise programs on
cardiorespiratory function have been investigated. The results
obtained in obese people (adult men) show that anaerobic
contribution was more pronounced after HIIT. Both exercises
improved the Vo2 max and decreased systolic blood pressure
without changes in the visceral or subcutaneous fat mass.
Moreover, 6 weeks of HIIT or MICT exercise improve
cardiorespiratory function and blood pressure in obese men
(124). The after-mentioned findings are in accordance with
previous studies that showed that short-term aerobic training
was able to improve Vo2 max (31) and body fat even with-
out reduction in weight (384). Thus, exercise, specifically
HIIT, is an important therapeutic intervention to mini-
mize the pathogenesis of obesity-induced cardiorespiratory
disorders.
Volume 10, July 2020
Comprehensive Physiology
Effect of bariatric surgery on leptin sensitivity and
breathing
OHS is a serious disorder characterized by daytime
hypercapnia, disordered breathing, and a reduction in chemo-
sensitivity. Bariatric surgeries, including vertical sleeve
gastrectomy (VSG) and the laparoscopic adjustable gastric
band (LAGB), (Figure 14) (126) contribute to OSA improve-
ment due to a decrease of body weight and uptake of glucose
metabolism (324). However, it was suggested that the VSG
surgery improved glucose and leptin levels through weight
independent mechanism (13). For this reason, VSG was
considered more effective than LAGB technique (48, 159).
VSG, a bariatric surgical procedure resulting in weight
loss and weight independent improvements in glucose
metabolism, is associated with substantial improvement in
sleep-disordered breathing (SDB). However, it is hard to
dissociate the effects of obesity per se from metabolic and
hormonal influences in obese people on the chemorespiratory
function in OHS patients (14).
Results from human studies performed in obese subjects
indicate that fat mass imposes a physical, mechanical load on
respiratory muscles which in turn can lead to hypoventilation
(268). Indeed, obesity results in significantly elevated leptin
(A) Laparoscopic adjustable (B) Roux-en-Y gastric
gastric banding (LAGB) bypass (RYGB)
Inflatable Distal jejunum
band
Biliopancreatic
secretions
Proximal jejunum
(C) Sleeve gastrectomy (SG) (D) Biliopancreatic diversion
with duodenal switch (BPD-DS)
Duodenum
Ileum
Jejunum
Figure 14 Graphic depiction of types of bariatric surgery.
Printed, with permission, from Gletsu-Miller N and Wright BN, 2013
(126).
Volume 10, July 2020
Leptin in the Control of Breathing
levels and, in some cases, glucose intolerance. Interestingly,
the respiratory stimulant effect of leptin compensates for
increased mechanical loads on the diaphragm (363) and
improving chemosensitivity (26, 29) in ob/ob mice. How-
ever, it is possible that a breakdown in leptin signaling,
potentially through obesity-induced leptin resistance directly
contributes to the pathogenesis of OHS independent of the
physical, mechanical load of obesity (246). Alternatively, lep-
tin may indirectly improve chemosensitivity and disordered
breathing through its effect on glucose metabolism (243).
Preclinical studies have identified a link between glycemic
control and insulin action on chemosensitivity and disordered
breathing (107).
In animal models, simulation of OSA using CIH has greatly
advanced the knowledge of how OSA may impact disease
states via cyclic drops in blood oxygen. In both rodents and
humans, previous studies demonstrated that CIH increased
circulating levels of glucose and leads to gluconeogenesis
(255, 286, 327, 382). Thus, in OSA patients, it is possible
that CIH alters the glucose metabolism (226).
Once T2D patients have autonomic dysfunction and asso-
ciated cardiorespiratory disorders, autonomic dysfunction
is a potential mechanism for glucose intolerance and OSA
(34). CIH increases tonic and reactive afferent chemoreceptor
activity from the CB which in turn increases plasma cate-
cholamine levels (166, 334), fasting hyperglycemia (340),
and hypertension (166). Peripheral chemoreceptors are more
sensitive to O2 and glucose then CO2 . However, any dis-
ruption of glucose can affect the sensitivity to O2 and CO2
impairing respiratory function (118). Addition of 2-deoxy-
d-glucose (2DG; a glucoprivic agent) in the drinking water
of rats can prevent phrenic long-term facilitation, a form of
respiratory motor plasticity, suggesting that alterations in
glucose sensing can directly alter breathing (209).
The reciprocal interaction between O2 and glucose sensing
and control of breathing is suggested from data obtained from
human studies in patients with two types of bariatric surgery
(VSG and LAGB), with the intent to improve T2D and obe-
sity (Figure 14) (126). Twice as many patients had resolution
of OSA 1 year after VSG when compared to patients who had
LAGB (48, 159), suggesting that more than reducing body
weight, the improvement in metabolic function ameliorate
the symptoms of OSA. Moreover, in OHS patients who had
bariatric surgery, arterial blood gases normalized acutely and
remained normal overtime (356, 357).
The role of leptin in modulating chemosensitivity and
disordered breathing following bariatric surgery is largely
unknown. The hypothesis that VSG alters chemosensitivity
and ventilatory drive through a leptin-dependent mech-
anism (103) has been tested in animals. VSG improves
chemosensitivity and lowers leptin levels independent of
changes in body and fat mass in WT mice with diet-induced
obesity (103). On the other hand, leptin-deficient ob/ob
mice undergoing VSG failed to show an improvement in
hypercapnia ventilatory response (HCVR); however, HCVR
did improve with leptin replacement in these animals.
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Leptin in the Control of Breathing
Thus, VSG in ob/ob mice was associated with a reduction
in body mass index (BMI), fat mass, and improvements in
glucose metabolism. Of note, leptin deficiency prevented
VSG-induced improvements in chemosensitivity, suggesting
that VSG improves chemosensitivity and ventilatory drive
through a leptin-dependent mechanism (103).
Besides the effects of bariatric surgery in improving lep-
tin’s effect on food intake and body weight (353), it is also
possible that the VSG surgery improved the action of leptin
on chemoreception. Modulating central leptin signaling
specifically in the periaqueductal gray leads to disordered
breathing and reduces the HCVR (103). Thus, VSG not
only affects central control of feeding behaviors and glucose
regulation, but it also affects ventilation and chemosensitivity.
Substantial evidence from preclinical and clinical studies
suggests that bariatric surgeries can improve glucose reg-
ulation through weight-independent pathways; it is likely
that other pathophysiological states associated with obesity
may also improve. Taken together, these results reinforce the
evidence that metabolic surgery, as well as leptin, may be
employed as future treatments to optimize chemosensitive
function and respiratory disorders.
Effect of CPAP on leptin sensitivity, breathing, and
energy balance
Chronic OSA with recurrent episodes of apneas, CIH and
sleep fragmentation over years alters metabolic balance and
alters the function of many organ systems, including the
brain and the cardiovascular system (43, 139). These adverse
effects lead to a variety of clinical sequelae including daytime
sleepiness from nocturnal sleep fragmentation in 80% of the
patients with OSA. As the disorder progresses, the sleepi-
ness becomes increasingly dangerous, causing impaired
performance at work and major work-related and road
accidents (139, 170). Many patients can develop cognitive
and neurobehavioral dysfunction, inability to concentrate,
memory impairment and depression. If untreated, OSA is
a major determinant of cardiovascular morbidity and mor-
tality (43, 398). Insulin resistance, T2D, and altered serum
lipid profile occur frequently in patients with OSA further
increasing the risk of cardiovascular morbidity (170, 337). Of
importance, metabolic impairment can occur in patients with
OSA independent of body weight.
CPAP, available since the beginning of the 1980s, is rec-
ognized as most effective and is commonly used to treat
patients with OSA (358). Alternative options include weight
control (diet and exercise), mandibular advancement devices,
and a number of upper airway surgical approaches. However,
nasal CPAP is highly effective in controlling symptoms,
improving quality of life and reducing the clinical sequelae
of sleep apnea. A short period of CPAP treatment amelio-
rated nocturnal obstructive events, SaO2 desaturations, and
daytime sleepiness (273, 352). A large meta-analysis, which
included 32 studies with a total of 1948 patients, showed that
CPAP treatment is associated with a modest, but significant
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Comprehensive Physiology
reduction in diurnal and nocturnal systolic and diastolic blood
pressure (238). Another recent meta-analysis systematically
analyzed six studies addressing the effect of CPAP on diur-
nal blood pressure in patients with OSA and drug-resistant
hypertension, and found a favorable reduction after treatment
with CPAP (160). The meta-analysis by McEvoy et al. (225)
inclusive of 2717 eligible adults between 45 and 75 years
of age, who had moderate to severe OSA and coronary
or cerebrovascular disease, concluded that subjects who
received CPAP had reduced snoring and daytime sleepiness
and improved health-related quality of life and mood when
compared to subjects who received usual care without
CPAP. However, both groups had similar rates of death
from cardiovascular causes, myocardial infarction, stroke, or
hospitalization for HF, unstable angina, or transient ischemic
attack. Importantly, the effects of CPAP therapy on cardiovas-
cular morbidity occurred only in patients who were adherent
to treatment longer than 4 h per night (225).
The AHI is associated with high plasma leptin levels.
IH increases leptin production, and serum leptin levels are
elevated in OSA patients, independent of obesity (165, 169,
312). However, in some cases, OSA seems to be unrelated
to leptin plasma levels, as is the case of subjects with OSA
but with controlled body weight (24, 272, 328). Rodent
studies (29, 260, 363) have delineated how leptin influences
breathing stability, findings that have been translated to our
understanding of leptin’s influence on the development of
OSA in humans. Some studies implement hyperleptinemia
and leptin dysregulation as contributing to OSA. Alterna-
tively, OSA can cause leptin serum levels to rise as a result of
intermittent hypoxemia, sleep fragmentation, or heightened
sympathetic activity. A drop in serum leptin levels observed
in patients with OSA after nocturnal CPAP supports this idea
(24, 146, 165, 339).
The relationship between CPAP therapy, changes in BMI
and leptin levels is not consistent across all studies. CPAP
therapy for 8 weeks decreases leptin levels without affecting
BMI in cohort of patients with OSA (146). CPAP use for
≥4 h per night, reduced total cholesterol, low-density lipopro-
tein, and leptin levels. Indeed, circulating leptin levels were
significantly correlated with insulin resistance. In patients
with moderate-to-severe OSA, compliant CPAP usage may
improve insulin secretion (69). Results of a meta-analysis
showed that CPAP could significantly reduce leptin levels in
obesity sleep apnea and hypoventilation syndrome (OSAHS)
patients without concomitant weight loss (55).
On the other hand, Drummond et al. (88) reported that in
response to CPAP therapy, mean leptin serum levels decreased
to 11.0 μg/L, and 6 months later it was 11.4 μg/L, suggest-
ing that CPAP has a small effect on leptin levels. Yosunkaya
et al. (397) found no correlation between serum leptin levels
and AHI, oxygen saturation, or excessive daytime sleepiness.
CPAP treatment did not significantly change the BMI, waist
and neck circumference, or leptin levels in OSAS patients.
Thus, the authors concluded that CPAP treatment does not
significantly affect serum leptin levels (397).
Volume 10, July 2020
Comprehensive Physiology
While weight loss improves OSA, it remains unclear why
CPAP is often associated with weight gain (338). CPAP
likely affects eating behavior and/or metabolism involved
in regulating energy balance. As outlined above, CPAP can
change the hormonal profile by reducing abnormally high
circulating levels of leptin and ghrelin in patients with OSA
which reduces excessive food intake. CPAP may alter energy
metabolism by reducing the metabolic rate in wakefulness
and sleep, although studies supporting this observation are
limited and inconsistent. Moreover, CPAP use in patients
with OSA is not consistently associated with altered physical
activity (336). Thus, combining CPAP with other weight loss
approaches should be used to encourage optimal outcomes
in OSA patients (338). The results from a recent study sup-
port this recommendation. When CPAP was combined with
exercise training in patients with OSA, AHI did not change
significantly in the control group, decreased moderately in the
exercise group, and decreased significantly in the CPAP and
exercise CPAP groups. Both exercise and CPAP improved
subjective excessive daytime sleepiness and quality of life
in HF patients. However, compared with the control group,
changes in the quality of life were significant only in the
exercise groups. Furthermore, peak oxygen consumption,
muscle strength, and endurance improved only in the exercise
groups compared with the CPAP group. Interestingly, there
was a trend in improved sexual function when exercise was
combined with CPAP (336). These data suggest that exercise
could be a therapeutic option for patients with HF and OSA
who refuse or who are intolerant to CPAP.
Chirinos et al. (56), randomized patients with moderate to
severe OSA (without HF) to undergo a weight loss program,
CPAP, and a combination of the two interventions. They
report that that subjects in the weight loss program only and
those assigned to the combined interventions had less insulin
resistance and lower levels of C-reactive protein and serum
triglyceride levels. None of these changes were observed in
the group receiving CPAP alone. These results emphasize the
importance of adjunctive therapy to CPAP for the treatment
of OSA with additional weight loss and exercise programs
when applicable.
Effect of intranasal leptin treatment on breathing and
energy balance in preclinical model of OSA
Activating leptin receptors in the CNS via intranasal instilla-
tion of leptin is potentially a novel therapeutic intervention for
appetite control. As cited before, obese people and animals
are hyperleptinemic and are leptin resistance when compared
to lean controls (246). Leptin bypasses the blood-brain barrier
via nonsaturable direct transport mechanism from nose to
brain, which is not impeded by elevated peripheral levels
of leptin (105). Leptin resistance likely occurs as a result
of alterations in leptin receptors signaling in hypothalamic
neurons, especially in the ARC, and/or decreased leptin
transport across the blood-brain barrier (92). In normal adult
rats, intranasal leptin reduces food intake and weight gain and
Volume 10, July 2020
Leptin in the Control of Breathing
affects hypothalamic neuropeptides involved in body weight
homeostasis (332). It also induced significant weight loss and
reduced adipose tissue mass in both lean and diet-induced
obese animals. On the other hand, the energy intake was
less affected in lean animals during the 32-week diet (331).
Weight reduction without changes in energy intake may be
explained by the thermogenetic effects of leptin (378), an
open question for future experiments.
Fliedner et al. (105) administered intranasal leptin
(0.2 mg/kg) to Wister rats. This dose would achieve a tissue
concentration of 50 ng/g within the hypothalamus; 120 times
the physiological level (105). Perhaps, this concentration is
necessary to activate hypothalamic neurons in obese subjects
with leptin resistance. However, for intranasal leptin to be
considered a therapeutic option for the treatment of obesity,
more preclinical studies are required to better understand the
long-term effects that may be undesirable.
The ARC is a major target for leptin in the hypothalamus
(246) and in this nucleus, leptin receptors are present on two
different populations of neurons, one of which synthesizes
NPY and AgRP and a second population of neurons that
express POMC and CART immunoreactivity (333). The
orexigenic NPY/AgRP neurons are inhibited, whereas the
anorexigenic POMC/CART neurons are activated (3, 246).
Conversely, POMC gene expression in the ARC is decreased
in leptin-deficient ob/ob mice and in db/db mice with an LR
mutation (232). CART expression in the hypothalamus is
dependent on the energy status and differs in animals depend-
ing on their susceptibility for diet-induced obesity (157),
and centrally or peripherally applied leptin directly acts on
CART neurons in distinct nuclei of the rat hypothalamus
(9, 94). Intranasal leptin treatment increases POMC mRNA,
and POMC reduces appetite and body weight. However,
intranasal application of leptin downregulates NPY mRNA
in the hypothalamus (233, 234, 331), which could lead to
a reduction in NPY levels, and therefore, less activation of
orexinergic pathways.
Since patients with OHS hypoventilate and have high cir-
culating leptin levels, they are leptin resistant (246). Berger
et al. (33) demonstrated in an elegant translational study
in leptin-resistant mice with diet-induced obesity, that a
single dose of intranasal leptin ameliorates the upper airway
obstruction and hypoventilation during sleep, independent of
metabolism. Intranasal leptin, but not leptin given intraperi-
toneally, induced leptin receptor signaling in hypothalamic
and medullary centers involved with respiratory control.
Thus, the study suggests that intranasal leptin can be tested
as a potential therapy in patients with SDB. More research
is needed to determine the long-term efficacy of intranasal
leptin in alleviating SDB; whether the dose needs to be
adjusted based on the therapeutic goal; what mechanisms are
mediating the leptin intranasal effect on respiratory network
need to be more completely described.
This novel finding of intranasal leptin treatment alleviat-
ing hypoventilation and upper-airway obstruction in an obese
1071
Leptin in the Control of Breathing
mouse model is exciting and provides a much-needed novel
therapeutic approach for the management of SDB.
Leptin and adiponectin: the Yen and Yang
We have reviewed what is currently known about the effect
of leptin on mechanisms that control breathing, and the
association between obesity, leptin resistance, and disordered
breathing. While much of this review is focused on the
specific role of leptin on physiology and pathophysiology
obesity, individuals with obesity also have low plasma levels
of adiponectin. The adiponectin protein was first identified in
1995 by Scherer et al. (329) and named Acrp30. It was also
discovered by three other investigative teams, independently,
and named AdipoQ, apM1, and GBP28 (156, 211, 247).
Adiponectin, similar to leptin, is produced by adipocytes but
in much higher concentrations. It is the most abundant plasma
protein with concentrations between 5 and 10 micrograms/mL
of plasma or 0.01% of total protein. While leptin levels are
directly proportional to fat mass throughout the lifespan,
adiponectin levels are only proportional to fat mass prior to
5 years of age after which time it is inversely related to fat
mass (195). Similar to leptin, females have higher circulating
levels of adiponectin than men, even after controlling for
fat mass (59, 221); testosterone decreases adiponectin levels
(109). Lastly, in contrast to leptin, which is pro-inflammatory
and pro-oxidant, adiponectin is anti-inflammatory and
antioxidant (for review see Ref. 100).
Adiponectin is a complex protein, comprised of 244 amino
acids, encoded by the ADIPOQ gene on the long arm of
chromosome 3 (3q27) (211). It is transcriptionally upreg-
ulated by peroxisome proliferator-activated receptor-𝛾
(PPARy), CCAAT/enhancer-binding protein-α (C/EBPs),
sterol-responsive-element-binding protein-1c, forkhead
box 1, and specificity protein 1 (87, 98, 292, 293, 395),
and downregulated by reactive oxygen species, TNFα and
IL-6 (reviewed in Ref. 205). PPAR𝛾 directly increases
adiponectin gene transcription through peroxisome prolifer-
ator response elements (PPRE) (205). Adiponectin binds to
four different receptors: AdipoR1 and AdipoR2, which are
widely distributed throughout the body; T-cadherin, which is
expressed in the vasculature but does not have a cytoplasmic
domain (112, 222), and calreticulin (calregulin), which is
expressed on macrophages and when activated removes apop-
totic debris (360). Of the adiponectin receptors, AdipoR1 and
AdipoR2 are xthe best characterized (389). AdipoR1 is most
abundantly expressed in skeletal muscle, enhancing fatty acid
oxidation through phosphorylation of AMPK. AdipoR2 is
most abundantly expressed in the liver and its activation low-
ers glucose levels by decreasing hepatic glucose production
and reduces oxidative stress (388, 389). Thus, ligand binding
to these receptors on cells throughout the body, regulates
systemic and pulmonary vascular homeostasis, fatty acid
oxidation, insulin sensitivity, and reduces oxidative stress
and suppresses inflammation (Figure 15) (359). Accordingly,
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Comprehensive Physiology
adiponectin plays a major role in the pathogenesis of MetS
(73, 379, 385).
Circulating adiponectin levels are much lower in indi-
viduals with obesity (15) and are inversely correlated with
insulin resistance and other metabolic signatures of MeS.
Without affecting leptin levels, adiponectin-deficient mice
are insulin resistance and more susceptible to developing
metabolic and vascular disease (i.e., systemic and pulmonary
hypertension) than WT mice (359). Moreover, adiponectin
deficient mice when feed a high-calorie diet become even
more insulin-resistant (141). Overexpression of adiponectin
in ob/ob mice normalized glucose levels even though the
animals had a higher volume of fat mass compared to their
ob/ob littermate controls (176). Therapeutics that improve
insulin sensitivity and glucose regulation, specifically the
thiazolidinedione (TZD) class of drugs (i.e., rosiglitazone and
pioglitazone) which are PPAR𝛾 agonists, are potent inducers
of adiponectin gene expression (206, 281, 369). Adiponectin
KO mice are resistant to the metabolic and cardioprotective
effects of the TZD class of drugs (201).
The proposed mechanism for lower levels of adiponectin in
obese subjects is through the action of TNFα, which is in high
concentrations in adipose tissue (52, 236). Adipocytes pro-
duce and secrete TNFα but activated macrophages, within the
stromovascular fraction of white fat, are the major source of
this pro-inflammatory cytokine. TNFα inhibits the transcrip-
tion of PPARy and C/EBPα genes (reviewed in Ref. 236),
two major transcription factors for adiponectin expression.
Thus, TNFα modulates adiponectin expression by both
paracrine and autocrine mechanisms, indirectly suppressing
adiponectin gene expression because it inhibits the transcrip-
tion of PPARy, the “adipogenic master regulator” (73).
The role of adiponectin and sleep-disordered
breathing
Not much has been published about how adiponectin affects
central or peripheral systems that control breathing dur-
ing health or disease. A recently published meta-analysis,
including 1356 subjects from 28 studies, concluded that
plasma/serum adiponectin levels were lower in adults with
OSAHS than controls (standard mean difference = −0.71,
95% CI = −0.92 to −0.49, P < 0.001). Studies included in
the meta-analysis had previously reported no statistically sig-
nificant difference between OSAHS patients and controls in
terms of age, gender and BMI (208). Al Mutairi et al. reported
an inverse relationship between OSAHS severity in adults
and adiponectin levels after controlling for sex, and BMI (4).
A similar finding in adolescents has also been reported
(116). Yoshikawa et al., in a small cohort of patients with
OSA (n = 22), reported that plasma adiponectin levels were
inversely correlated with the AHI (r = −0.582, P < 0.005) and
% time in oxygen saturation SpO2 less than 90% (r = −0.539,
P < 0.01), and after 3 months of CPAP, plasma adiponectin
levels significantly increased in 50% of the patients (396).
CIH occurs during OSAHS, and CIH decreases adiponectin
Volume 10, July 2020
Comprehensive Physiology Leptin in the Control of Breathing

Oxidative stress
Angiotensin II PPARγ agonist
Adipose
Testosterone
tissue BMI
IL-6
TNF
BMI

Macrophage Adiponectin Liver

Metabolism
NF-κB
TNF
TNF-α
SR-A
Foam cells
AMPK SRF
cAMP-PKA COX-2
AMPK
NF-κB PGE2 mTOR Actin
eNOS

VCAM-1 Proliferation/growth
IL-8 TNF
Endothelial cell Muscle cell

Figure 15 Schematic showing adiponectin signaling in macrophages,

liver, endothelial and muscle cells. Adiponectin is produced by adipose tis-
sue, the agonist to the transcription factor PPAR𝛾 will increase the production of
adiponectin and decrease BMI, while oxidative stress, angiotensin II, testosterone, IL-6,
TNFα, will inhibit the production of adiponectin. Adiponectin binding to adiponectin
receptors on (i) macrophages inhibits the production of NF-𝜅B and SR-A thereby
inhibiting the production of TNFα, and foam cells, (ii) liver cells increases metabolism
and blocks TNFα production, (iii) endothelial cells promoting NO production, and
inhibiting synthesis of chemokines, (iv) muscle cells inhibits the production of TNF and
promotes growth and proliferation. m-TOR, mammalian target of rapamycin; SR-A,
scavenger receptors-A; AMPK, AMP-activated protein kinase; SRF, serum response ele-
ment; COX-2, cyclooxygenase-2; VCAM-1, vascular cell adhesion protein 1; PPAR𝛾,
peroxisome proliferator-activated receptor gamma; BMI, body mass index; IL, Inter-
leukin. Adapted, with permission, from Summer R, et al., 2011 (359).

levels and adiponectin receptor expression (240, 282). The
mechanism by which this downregulation occurs is not
known. In the aforementioned study by Yoshikawa et al.
(396), they also measured TNFα levels in the cohort of
patients with OSA and reported that TNFα levels were pos-
itively correlated with the AHI (r = 0.462, P < 0.05). Thus,
one could speculate that elevated TNFα levels in response
to CIH, may decrease adiponectin levels (52), as outlined
above. Exogenous adiponectin given to animals decreased
the consequences of CIH on several organ systems (82, 83).
Of note, thirteen single nucleotide polymorphisms of the
ADIPOQ gene in Chinese Han subjects have been reported
to be associated with the prevalence and severity of OSA and
AHI (390). How polymorphisms of the ADIPOQ gene equate
to plasma/serum adiponectin levels has not to be reported but
would be of considerable interest.
While much is known about how leptin modulates central
and peripheral cardiorespiratory responses as outlined in
this article, less is known about how adiponectin might
modify these responses. Adiponectin can indirectly mod-
ulate blood pressure in the RVLM in animals. Agonist
binding to abnormal cannabidiol G-protein coupled receptor
18 in the brainstem, specifically in the RVLM, elevated
neuronal adiponectin levels and reduced oxidative stress,
which was associated with a decrease in blood pressure
(277). Adiponectin receptors have been localized to neurons
in the medial NTS where it is involved in regulation of
blood pressure (155) but not in the commissural nucleus, an
important nucleus that integrates input from the peripheral
arterial chemoreceptors. Two recent human studies suggest
that adiponectin may be important in positively mediating
sympathetic and parasympathetic tone in adolescent girls
(372) and adults who develop T2D (145).
Relatively low levels of adiponectin, in the microenvi-
ronment of cells and tissues, could be contributing to a
persistent pro-inflammatory, pro-oxidant state, which affects
the activity of cells and neurons that control breathing, such
as the CB. The CB is surrounded by adipocytes, as shown
in the photomicrograph of an organotypic culture of the CB
from a 2-week old rat (Figure 16) (187). The amount of fat
that surrounds the CB increases with the size of the animal.
Might local release of leptin and adiponectin from this local
fat depot surrounding the CB modulate its function? How
does this local fat depot differ in humans and models of
OSA, with respect to local release of TNFα from activated
macrophages? Additional studies are needed to understand
the direct and indirect influences of adiponectin on central and
peripheral systems that control breathing, and the corollary:

Volume 10, July 2020 1073

Leptin in the Control of Breathing
FC
CA
CB
CA
100 μm
Figure 16 Low-power photomicrograph, using Hoffman
contrast microscopy, of an organotypic slice of the carotid
body 24 h in culture. Fat cells are in close proximity to the CB in
vivo. Tissue was removed from a Sprague Dawley rat at 2 weeks post-
natal age. CB, carotid body; CA, carotid artery. Arrows depict fat cells
(FC). Adapted, with permission, from Kwak DJ, et al., 2006 (187).
how disordered breathing and CIH affect adiponectin levels.
Since adiponectin confers significant and substantial car-
dioprotection and protection from atherosclerotic disease,
studies are needed to determine whether therapeutic modula-
tion of adiponectin levels in humans with OSA may modify
cardiovascular morbidities.
Conclusion
Leptin stimulates breathing and leptin deficiency, for
example, obesity leptin resistance, promotes an impair-
ment of the central and peripheral mechanisms that control
breathing, which can be reverted by leptin therapy. Evidence
supports that leptin acts mainly in the NTS in the hindbrain
and dorsal medial nucleus in the hypothalamus. Leptin may
also act in the PeF, DM, and ARC of the hypothalamus
where leptin receptors are also expressed. Administration of
leptin into the lateral ventricle might act in different nuclei
of the hypothalamus, including in PeF, DM and arcuate
(ARC) nuclei that express leptin receptors. Although the
mechanisms and pathways activated by leptin to facilitate
breathing are still under investigation, evidence suggests
that the facilitator effects of leptin on breathing require the
brain melanocortin system, including the POMC-MC3/4R
pathway, the same mechanism activated by leptin that
modulates food intake and sympathetic activity. A better
understanding of how leptin controls ventilation, upper
airway function and sympathetic activity would inform
new approaches for therapeutic interventions to treat obe-
sity related co-morbidites. For example, preclinical studies
in leptin-resistant mice, showing the benefit of intranasal
leptin on metabolism, weight loss, and improved CO2
chemosensitivity, and less respiratory disturbances begs the
question as to whether intranasal leptin may be feasible
and efficacious for the treatment of SDB in humans. How
intranasal leptin will affect sympathetic overexcitation in
individuals with hyperleptinemia would be important to
determine.
1074
Comprehensive Physiology
Leptin also acts on the CB to modify spontaneous minute
ventilation and hypoxic ventilatory responses in acute and
chronic conditions such as obesity and CIH. The contribution
of the CB to ventilatory responses is blunted in obesity, prob-
ably due to leptin resistance within the organ. Information
on leptin signaling pathways in the CB activated in these
acute and chronic conditions would have significant clinical
relevance as leptin or its signaling within the CB might
be therapeutic targets for the treatment of obesity-related
respiratory diseases. Preliminary data also shows that the
CB contributes to leptin action on the sympathetic nervous
system. Knowing that CB contributes to the heightened
sympathetic activity present in cardiometabolic diseases, fur-
ther research on leptin action on CB-mediated sympathetic
activity might unravel new specific therapeutic targets for
cardiometabolic diseases.
Breathing disorders also occur in early development, but
essentially nothing is known about how leptin may be mod-
ulating breathing during development. While preliminary
data are presented in this article, showing that leptin is not
likely to increase CO2 sensitivity prior to 3 weeks postnatal
age in newborn rats or decrease apnea frequency, more data
are needed to substantiate these findings. Most mammalian
species are “leptin resistant” with respect to leptin’s effect
on feeding behavior and energy expenditure during early
development. Instead, leptin’s role during early develop-
ment appears to be critical for normal organ development.
SGA infants have lower and large gestational age (LGA)
infants have higher leptin levels than infants who are AGA
at birth, but yet both SGA and LGA are at increased risk of
developing leptin resistance in adolescence and adulthood
with associated cardiorespiratory comorbidities. Thus, both
excess and absence of leptin during early development pro-
grams the system for adverse cardiorespiratory outcomes.
The mechanisms of this effect are poorly understood; human
studies to better understand how modifying this programming
could lead to new therapeutic targets to improve long-term
outcomes throughout life are needed. Leptin levels in the
fetus exponentially increase after 34 weeks gestation; pre-
mature infants born at the limit of viability (22–24 weeks of
gestation) have undetectable leptin levels. Carefully designed
studies to better understand the consequences of undetectable
leptin levels for many months during organ development in
these infants and whether leptin replacement may be a safe
and efficacious in improving short and long-term outcomes
in this population of high-risk infants are needed.
Adiponectin is another important adipokine that is mainly
produced by adipose tissue. Unlike leptin, adiponectin levels
are low in adults with obesity and obesity-related metabolic
and cardiorespiratory morbidities. Adiponectin promotes
vasoprotection, glucose tolerance, insulin sensitivity, and has
antioxidant and anti-inflammatory properties, and balances
sympathetic and parasympathetic tone (145). Preclinical stud-
ies to determine the specific role of adiponectin on central
or peripheral regulation of sympathetic tone in normal and
disease models are not known. These studies could contribute
Volume 10, July 2020
Comprehensive Physiology
to a more balanced understanding of the role of adipokines
(leptin and adiponectin) on these physiological responses
since the biological effects of these adipokines are closely
linked.
Related Articles
Adiponectin Regulation and Function
Obstructive Sleep Apnea and Vascular Diseases
Acknowledgement
The authors would like to acknowledge Ms. Sonia Dos Santos
for her exceptional administrative support in preparing this
manuscript.
References
1. Abdala AP, Rybak IA, Smith JC, Paton JF. Abdominal expiratory
activity in the rat brainstem-spinal cord in situ: Patterns, origins
and implications for respiratory rhythm generation. J Physiol 587:
3539-3559, 2009.
2. Abraham KA, Feingold H, Fuller DD, Jenkins M, Mateika JH,
Fregosi RF. Respiratory-related activation of human abdominal
muscles during exercise. J Physiol 541: 653-663, 2002.
3. Ahima RS, Saper CB, Flier JS, Elmquist JK. Leptin regulation of
neuroendocrine systems. Front Neuroendocrinol 21: 263-307, 2000.
4. Al Mutairi S, Mojiminiyi OA, Al Alawi A, Al Rammah T, Abdella
N. Study of leptin and adiponectin as disease markers in subjects with
obstructive sleep apnea. Dis Markers 2014: 706314, 2014.
5. Allen AM. Angiotensin AT1 receptor-mediated excitation of rat
carotid body chemoreceptor afferent activity. J Physiol 510 (Pt 3):
773-781, 1998.
6. Alvarez-Buylla R, Alvarez-Buylla E, Mendoza H, Montero SA,
Alvarez-Buylla A. Pituitary and adrenals are required for hyper-
glycemic reflex initiated by stimulation of CBR with cyanide. Am J
Phys 272: R392-R399, 1997.
7. Alvarez-Buylla R, de Alvarez-Buylla ER. Carotid sinus receptors par-
ticipate in glucose homeostasis. Respir Physiol 72: 347-359, 1988.
8. Alvarez-Buylla R, de Alvarez-Buylla ER. Changes in blood glucose
concentration in the carotid body modify brain glucose retention.
Adv Exp Med Biol 360: 293-296, 1994.
9. Ambati S, Duan J, Duff E, Choi YH, Hartzell DL, Della-Fera MA,
Baile CA. Gene expression in arcuate nucleus-median eminence of
rats treated with leptin or ciliary neurotrophic factor. Biofactors 31:
133-144, 2007.
10. Anderson TM, Garcia AJ 3rd, Baertsch NA, Pollak J, Bloom JC, Wei
AD, Rai KG, Ramirez JM. A novel excitatory network for the control
of breathing. Nature 536: 76-80, 2016.
11. Anderson TM, Ramirez JM. Respiratory rhythm generation: Triple
oscillator hypothesis. F1000Research 6: 139, 2017.
12. Andresen MC, Doyle MW, Bailey TW, Jin YH. Differentiation of
autonomic reflex control begins with cellular mechanisms at the first
synapse within the nucleus tractus solitarius. Braz J Med Biol Res 37:
549-558, 2004.
13. Arble DM, Sandoval DA, Seeley RJ. Mechanisms underlying weight
loss and metabolic improvements in rodent models of bariatric surgery.
Diabetologia 58: 211-220, 2015.
14. Arble DM, Schwartz AR, Polotsky VY, Sandoval DA, Seeley RJ.
Vertical sleeve gastrectomy improves ventilatory drive through a
leptin-dependent mechanism. JCI Insight 4 (1): e124469, 2019.
15. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa
J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H,
Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M,
Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an
adipose-specific protein, adiponectin, in obesity. Biochem Biophys
Res Commun 257: 79-83, 1999.
16. Arnold AC, Shaltout HA, Gallagher PE, Diz DI. Leptin impairs car-
diovagal baroreflex function at the level of the solitary tract nucleus.
Hypertension 54: 1001-1008, 2009.
17. Ashworth CJ, Hoggard N, Thomas L, Mercer JG, Wallace JM, Lea
RG. Placental leptin. Rev Reprod 5: 18-24, 2000.
Volume 10, July 2020
Leptin in the Control of Breathing
18. Athanasakis E, Karavasiliadou S, Styliadis I. The factors contributing
to the risk of sudden infant death syndrome. Hippokratia 15: 127-131,
2011.
19. Attig L, Brisard D, Larcher T, Mickiewicz M, Guilloteau P, Boukthir
S, Niamba CN, Gertler A, Djiane J, Monniaux D, Abdennebi-Najar L.
Postnatal leptin promotes organ maturation and development in IUGR
piglets. PLoS One 8: e64616, 2013.
20. Attig L, Djiane J, Gertler A, Rampin O, Larcher T, Boukthir S, Anton
PM, Madec JY, Gourdou I, Abdennebi-Najar L. Study of hypothala-
mic leptin receptor expression in low-birth-weight piglets and effects
of leptin supplementation on neonatal growth and development. Am J
Phys Endocrinol Metab 295: E1117-E1125, 2008.
21. Attig L, Larcher T, Gertler A, Abdennebi-Najar L, Djiane J. Postnatal
leptin is necessary for maturation of numerous organs in newborn rats.
Organogenesis 7: 88-94, 2011.
22. Babu AR, Herdegen J, Fogelfeld L, Shott S, Mazzone T. Type 2 dia-
betes, glycemic control, and continuous positive airway pressure in
obstructive sleep apnea. Arch Intern Med 165: 447-452, 2005.
23. Baquero AF, de Solis AJ, Lindsley SR, Kirigiti MA, Smith MS, Cow-
ley MA, Zeltser LM, Grove KL. Developmental switch of leptin sig-
naling in arcuate nucleus neurons. J Neurosci Off J Soc Neurosci 34:
9982-9994, 2014.
24. Barcelo A, Barbe F, Llompart E, de la Pena M, Duran-Cantolla J,
Ladaria A, Bosch M, Guerra L, Agusti AG. Neuropeptide Y and lep-
tin in patients with obstructive sleep apnea syndrome: Role of obesity.
Am J Respir Crit Care Med 171: 183-187, 2005.
25. Barrington KJ, Finer NN. Periodic breathing and apnea in preterm
infants. Pediatr Res 27: 118-121, 1990.
26. Bassi M, Furuya WI, Menani JV, Colombari DS, do Carmo JM, da
Silva AA, Hall JE, Moreira TS, Wenker IC, Mulkey DK, Colombari
E. Leptin into the ventrolateral medulla facilitates chemorespiratory
response in leptin-deficient (ob/ob) mice. Acta Physiol 211: 240-248,
2014.
27. Bassi M, Furuya WI, Zoccal DB, Menani JV, Colombari DS, Mulkey
DK, Colombari E. Facilitation of breathing by leptin effects in the
central nervous system. J Physiol 594: 1617-1625, 2016.
28. Bassi M, Furuya WI, Zoccal DB, Menani JV, Colombari E, Hall JE,
da Silva AA, do Carmo JM, Colombari DS. Control of respiratory and
cardiovascular functions by leptin. Life Sci 125: 25-31, 2015.
29. Bassi M, Giusti H, Leite CM, Anselmo-Franci JA, do Carmo JM, da
Silva AA, Hall JE, Colombari E, Glass ML. Central leptin replacement
enhances chemorespiratory responses in leptin-deficient mice inde-
pendent of changes in body weight. Pflugers Arch Eur J Physiol 464:
145-153, 2012.
30. Bassi M, Nakamura NB, Furuya WI, Colombari DS, Menani JV, do
Carmo JM, da Silva AA, Hall JE, Colombari E. Activation of the
brain melanocortin system is required for leptin-induced modulation
of chemorespiratory function. Acta Physiol 213: 893-901, 2015.
31. Batacan RB Jr, Duncan MJ, Dalbo VJ, Tucker PS, Fenning AS. Effects
of high-intensity interval training on cardiometabolic health: A sys-
tematic review and meta-analysis of intervention studies. Br J Sports
Med 51: 494-503, 2017.
32. Bell BB, Rahmouni K. Leptin as a mediator of obesity-induced hyper-
tension. Curr Obes Rep 5: 397-404, 2016.
33. Berger S, Pho H, Fleury-Curado T, Bevans-Fonti S, Younas H, Shin
MK, Jun JC, Anokye-Danso F, Ahima RS, Enquist LW, Mendelowitz
D, Schwartz AR, Polotsky VY. Intranasal leptin relieves sleep-
disordered breathing in mice with diet-induced obesity. Am J Respir
Crit Care Med 199: 773-783, 2019.
34. Bernardi L, Bianchi L. Integrated cardio-respiratory control: Insight in
diabetes. Curr Diab Rep 16: 107, 2016.
35. Bianchi AL, Denavit-Saubie M, Champagnat J. Central control of
breathing in mammals: Neuronal circuitry, membrane properties,
and neurotransmitters. Physiol Rev 75: 1-45, 1995.
36. Biro FM, Wien M. Childhood obesity and adult morbidities. Am J Clin
Nutr 91: 1499S-1505S, 2010.
37. Blackmore HL, Niu Y, Fernandez-Twinn DS, Tarry-Adkins JL,
Giussani DA, Ozanne SE. Maternal diet-induced obesity programs
cardiovascular dysfunction in adult male mouse offspring independent
of current body weight. Endocrinology 155: 3970-3980, 2014.
38. Bluher S, Kapplinger J, Herget S, Reichardt S, Bottcher Y, Grimm A,
Kratzsch J, Petroff D. Cardiometabolic risk markers, adipocyte fatty
acid binding protein (aFABP) and the impact of high-intensity interval
training (HIIT) in obese adolescents. Metab Clin Exp 68: 77-87, 2017.
39. Bonsignore MR, Borel AL, Machan E, Grunstein R. Sleep apnoea and
metabolic dysfunction. Eur Respir Rev 22: 353-364, 2013.
40. Bouassida A, Zalleg D, Bouassida S, Zaouali M, Feki Y, Zbidi A,
Tabka Z. Leptin, its implication in physical exercise and training:
A short review. J Sports Sci Med 5: 172-181, 2006.
41. Bouret SG, Gorski JN, Patterson CM, Chen S, Levin BE, Simerly RB.
Hypothalamic neural projections are permanently disrupted in diet-
induced obese rats. Cell Metab 7: 179-185, 2008.
42. Bouret SG, Simerly RB. Minireview: Leptin and development of
hypothalamic feeding circuits. Endocrinology 145: 2621-2626, 2004.
1075
Leptin in the Control of Breathing
43. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular
consequences. Lancet 373: 82-93, 2009.
44. Briffa JF, McAinch AJ, Romano T, Wlodek ME, Hryciw DH. Leptin
in pregnancy and development: A contributor to adulthood disease?
Am J Phys Endocrinol Metab 308: E335-E350, 2015.
45. Buchanan GF. Impaired CO2 -induced arousal in SIDS and SUDEP.
Trends Neurosci 42: 242-250, 2019.
46. Caballero-Eraso C, Shin MK, Pho H, Kim LJ, Pichard LE, Wu ZJ, Gu
C, Berger S, Pham L, Yeung HB, Shirahata M, Schwartz AR, Tang
WW, Sham JSK, Polotsky VY. Leptin acts in the carotid bodies to
increase minute ventilation during wakefulness and sleep and augment
the hypoxic ventilatory response. J Physiol 597: 151-172, 2019.
47. Caldeira RS, Panissa VLG, Inoue DS, Campos EZ, Monteiro PA,
Giglio BM, Pimentel GD, Hofmann P, Lira FS. Impact to short-term
high intensity intermittent training on different storages of body fat,
leptin and soluble leptin receptor levels in physically active non-obese
men: A pilot investigation. Clin Nutr ESPEN 28: 186-192, 2018.
48. Carlin AM, Zeni TM, English WJ, Hawasli AA, Genaw JA, Krause
KR, Schram JL, Kole KL, Finks JF, Birkmeyer JD, Share D,
Birkmeyer NJ, Michigan Bariatric Surgery C. The comparative effec-
tiveness of sleeve gastrectomy, gastric bypass, and adjustable gastric
banding procedures for the treatment of morbid obesity. Ann Surg
257: 791-797, 2013.
49. Carrive P, Gorissen M. Premotor sympathetic neurons of conditioned
fear in the rat. Eur J Neurosci 28: 428-446, 2008.
50. Carroll JL, Bureau MA. Peripheral chemoreceptor CO2 response
during hyperoxia in the 14-day-old awake lamb. Respir Physiol 73:
339-349, 1988.
51. Casabiell X, Pineiro V, Tome MA, Peino R, Dieguez C, Casanueva
FF. Presence of leptin in colostrum and/or breast milk from lactating
mothers: A potential role in the regulation of neonatal food intake.
J Clin Endocrinol Metab 82: 4270-4273, 1997.
52. Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett
582: 117-131, 2008.
53. Chang Z, Ballou E, Jiao W, McKenna KE, Morrison SF, McCrimmon
DR. Systemic leptin produces a long-lasting increase in respiratory
motor output in rats. Front Physiol 4: 16, 2013.
54. Chen H, Simar D, Morris MJ. Hypothalamic neuroendocrine circuitry
is programmed by maternal obesity: Interaction with postnatal
nutritional environment. PLoS One 4: e6259, 2009.
55. Chen L, Pei JH, Chen HM. Effects of continuous positive airway pres-
sure treatment on glycaemic control and insulin sensitivity in patients
with obstructive sleep apnoea and type 2 diabetes: A meta-analysis.
Arch Med Sci 10: 637-642, 2014.
56. Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA,
Townsend R, Foster GD, Maislin G, Saif H, Broderick P, Chittams J,
Hanlon AL, Pack AI. CPAP, weight loss, or both for obstructive sleep
apnea. N Engl J Med 370: 2265-2275, 2014.
57. Cinaz P, Sen E, Bideci A, Ezgu FS, Atalay Y, Koca E. Plasma leptin
levels of large for gestational age and small for gestational age infants.
Acta Paediatr 88: 753-756, 1999.
58. Ciriello J, Moreau JM. Leptin signaling in the nucleus of the solitary
tract alters the cardiovascular responses to activation of the chemore-
ceptor reflex. Am J Physiol Regul Integr Comp Physiol 303: R727-
R736, 2012.
59. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko
EJ, Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE. Relation-
ship of adiponectin to body fat distribution, insulin sensitivity and
plasma lipoproteins: Evidence for independent roles of age and sex.
Diabetologia 46: 459-469, 2003.
60. Coleman DL. Effects of parabiosis of obese with diabetes and normal
mice. Diabetologia 9: 294-298, 1973.
61. Collin M, Hakansson-Ovesjo ML, Misane I, Ogren SO, Meister B.
Decreased 5-HT transporter mRNA in neurons of the dorsal raphe
nucleus and behavioral depression in the obese leptin-deficient ob/ob
mouse. Brain Res Mol Brain Res 81: 51-61, 2000.
62. Conde SV, Monteiro EC, Sacramento JF. Purines and carotid body:
New roles in pathological conditions. Front Pharmacol 8: 913, 2017.
63. Conde SV, Ribeiro MJ, Melo BF, Guarino MP, Sacramento JF. Insulin
resistance: A new consequence of altered carotid body chemoreflex?
J Physiol 595: 31-41, 2017.
64. Conde SV, Sacramento JF, Guarino MP. Carotid body: A metabolic
sensor implicated in insulin resistance. Physiol Genomics 50: 208-214,
2018.
65. Conde SV, Sacramento JF, Guarino MP, Gonzalez C, Obeso A, Diogo
LN, Monteiro EC, Ribeiro MJ. Carotid body, insulin, and metabolic
diseases: Unraveling the links. Front Physiol 5: 418, 2014.
66. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens
TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL.
Serum immunoreactive-leptin concentrations in normal-weight and
obese humans. N Engl J Med 334: 292-295, 1996.
67. Costa-Silva JH, Zoccal DB, Machado BH. Glutamatergic antagonism
in the NTS decreases post-inspiratory drive and changes phrenic and
1076
Comprehensive Physiology
sympathetic coupling during chemoreflex activation. J Neurophysiol
103: 2095-2106, 2010.
68. Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath
TL, Cone RD, Low MJ. Leptin activates anorexigenic POMC neurons
through a neural network in the arcuate nucleus. Nature 411: 480-484,
2001.
69. Cuhadaroglu C, Utkusavas A, Ozturk L, Salman S, Ece T. Effects of
nasal CPAP treatment on insulin resistance, lipid profile, and plasma
leptin in sleep apnea. Lung 187: 75-81, 2009.
70. Cummings KJ, Li A, Deneris ES, Nattie EE. Bradycardia in serotonin-
deficient Pet-1−/− mice: Influence of respiratory dysfunction and
hyperthermia over the first 2 postnatal weeks. Am J Physiol Regul
Integr Comp Physiol 298: R1333-R1342, 2010.
71. Cundrle I Jr, Somers VK, Singh P, Johnson BD, Scott CG, Olson LJ.
The relationship between leptin and ventilatory control in heart failure.
J Card Fail 19: 756-761, 2013.
72. da Silva AA, Freeman JN, Hall JE, do Carmo JM. Control of appetite,
blood glucose, and blood pressure during melanocortin-4 receptor
activation in normoglycemic and diabetic NPY-deficient mice. Am J
Physiol Regul Integr Comp Physiol 314: R533-R539, 2018.
73. Dadson K, Liu Y, Sweeney G. Adiponectin action: A combination
of endocrine and autocrine/paracrine effects. Front Endocrinol 2: 62,
2011.
74. Daltro C, Gregorio PB, Alves E, Abreu M, Bomfim D, Chicourel MH,
Araujo L, Cotrim HP. Prevalence and severity of sleep apnea in a group
of morbidly obese patients. Obes Surg 17: 809-814, 2007.
75. Darnall RA. The role of CO(2) and central chemoreception in the
control of breathing in the fetus and the neonate. Respir Physiol
Neurobiol 173: 201-212, 2010.
76. Dejours P. Control of respiration by arterial chemoreceptors. Ann N Y
Acad Sci 109: 682-695, 1963.
77. Del Negro CA, Funk GD, Feldman JL. Breathing matters. Nat Rev
Neurosci 19: 351-367, 2018.
78. Deng BS, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki
T. Contribution of orexin in hypercapnic chemoreflex: Evidence from
genetic and pharmacological disruption and supplementation studies
in mice. J Appl Physiol 103: 1772-1779, 2007.
79. Devaskar SU, Ollesch C, Rajakumar RA, Rajakumar PA. Develop-
mental changes in ob gene expression and circulating leptin peptide
concentrations. Biochem Biophys Res Commun 238: 44-47, 1997.
80. Di Fiore JM, Martin RJ, Gauda EB. Apnea of prematurity—perfect
storm. Respir Physiol Neurobiol 189: 213-222, 2013.
81. Dibner C, Gachon F. Circadian dysfunction and obesity: Is leptin the
missing link? Cell Metab 22: 359-360, 2015.
82. Ding W, Cai Y, Wang W, Ji L, Dong Y, Zhang X, Su M, Liu J, Lu G,
Zhang X. Adiponectin protects the kidney against chronic intermit-
tent hypoxia-induced injury through inhibiting endoplasmic reticulum
stress. Sleep Breath 20: 1069-1074, 2016.
83. Ding W, Zhang X, Huang H, Ding N, Zhang S, Hutchinson SZ, Zhang
X. Adiponectin protects rat myocardium against chronic intermittent
hypoxia-induced injury via inhibition of endoplasmic reticulum stress.
PLoS One 9: e94545, 2014.
84. do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE. Con-
trol of blood pressure, appetite, and glucose by leptin in mice lacking
leptin receptors in proopiomelanocortin neurons. Hypertension 57:
918-926, 2011.
85. do Carmo JM, da Silva AA, Moak SP, da Silva FS, Spradley FT,
Hall JE. Role of melanocortin 4 receptor in hypertension induced by
chronic intermittent hypoxia. Acta Physiol 225: e13222, 2019.
86. Doi A, Ramirez JM. Neuromodulation and the orchestration of the
respiratory rhythm. Respir Physiol Neurobiol 164: 96-104, 2008.
87. Doran AC, Meller N, Cutchins A, Deliri H, Slayton RP, Oldham SN,
Kim JB, Keller SR, McNamara CA. The helix-loop-helix factors Id3
and E47 are novel regulators of adiponectin. Circ Res 103: 624-634,
2008.
88. Drummond M, Winck JC, Guimaraes JT, Santos AC, Almeida J, Mar-
ques JA. Autoadjusting-CPAP effect on serum leptin concentrations in
obstructive sleep apnoea patients. BMC Pulm Med 8: 21, 2008.
89. Dubern B, Clement K. Leptin and leptin receptor-related monogenic
obesity. Biochimie 94: 2111-2115, 2012.
90. Dundar NO, Anal O, Dundar B, Ozkan H, Caliskan S, Buyukgebiz
A. Longitudinal investigation of the relationship between breast milk
leptin levels and growth in breast-fed infants. J Pediatr Endocrinol
Metab 18: 181-187, 2005.
91. Edwards BA, Sands SA, Berger PJ. Postnatal maturation of breathing
stability and loop gain: The role of carotid chemoreceptor develop-
ment. Respir Physiol Neurobiol 185: 144-155, 2013.
92. El-Haschimi K, Pierroz DD, Hileman SM, Bjorbaek C, Flier JS. Two
defects contribute to hypothalamic leptin resistance in mice with diet-
induced obesity. J Clin Invest 105: 1827-1832, 2000.
93. Elias CF, Kelly JF, Lee CE, Ahima RS, Drucker DJ, Saper CB,
Elmquist JK. Chemical characterization of leptin-activated neurons in
the rat brain. J Comp Neurol 423: 261-281, 2000.
Volume 10, July 2020
Comprehensive Physiology
94. Elias CF, Lee CE, Kelly JF, Ahima RS, Kuhar M, Saper CB, Elmquist
JK. Characterization of CART neurons in the rat and human hypotha-
lamus. J Comp Neurol 432: 1-19, 2001.
95. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. Unraveling the
central nervous system pathways underlying responses to leptin. Nat
Neurosci 1: 445-450, 1998.
96. Ertl T, Funke S, Sarkany I, Szabo I, Rascher W, Blum WF, Sulyok E.
Postnatal changes of leptin levels in full-term and preterm neonates:
Their relation to intrauterine growth, gender and testosterone. Biol
Neonate 75: 167-176, 1999.
97. Essig DA, Alderson NL, Ferguson MA, Bartoli WP, Durstine JL.
Delayed effects of exercise on the plasma leptin concentration. Metab
Clin Exp 49: 395-399, 2000.
98. Fajas L, Fruchart JC, Auwerx J. Transcriptional control of adipogene-
sis. Curr Opin Cell Biol 10: 165-173, 1998.
99. Famulla S, Horrighs A, Cramer A, Sell H, Eckel J. Hypoxia reduces the
response of human adipocytes towards TNFalpha resulting in reduced
NF-kappaB signaling and MCP-1 secretion. Int J Obes 36: 986-992,
2012.
100. Fang H, Judd RL. Adiponectin regulation and function. Compr Physiol
8: 1031-1063, 2018.
101. Feldman JL, Mitchell GS, Nattie EE. Breathing: Rhythmicity,
plasticity, chemosensitivity. Annu Rev Neurosci 26: 239-266, 2003.
102. Finn PD, Cunningham MJ, Rickard DG, Clifton DK, Steiner RA. Sero-
tonergic neurons are targets for leptin in the monkey. J Clin Endocrinol
Metab 86: 422-426, 2001.
103. Flak JN, Arble D, Pan W, Patterson C, Lanigan T, Goforth PB,
Sacksner J, Joosten M, Morgan DA, Allison MB, Hayes J, Feldman E,
Seeley RJ, Olson DP, Rahmouni K, Myers MG Jr. A leptin-regulated
circuit controls glucose mobilization during noxious stimuli. J Clin
Invest 127: 3103-3113, 2017.
104. Fletcher EC, Lesske J, Qian W, Miller CC 3rd, Unger T. Repetitive,
episodic hypoxia causes diurnal elevation of blood pressure in rats.
Hypertension 19: 555-561, 1992.
105. Fliedner S, Schulz C, Lehnert H. Brain uptake of intranasally applied
radioiodinated leptin in Wistar rats. Endocrinology 147: 2088-2094,
2006.
106. Fortuna MG, Stornetta RL, West GH, Guyenet PG. Activation of the
retrotrapezoid nucleus by posterior hypothalamic stimulation. J Phys-
iol 587: 5121-5138, 2009.
107. Framnes SN, Arble DM. The bidirectional relationship between
obstructive sleep apnea and metabolic disease. Front Endocrinol 9:
440, 2018.
108. Frantz ID 3rd, Adler SM, Thach BT, Taeusch HW Jr. Maturational
effects on respiratory responses to carbon dioxide in premature infants.
J Appl Physiol 41: 41-45, 1976.
109. Frederiksen L, Hojlund K, Hougaard DM, Mosbech TH, Larsen R,
Flyvbjerg A, Frystyk J, Brixen K, Andersen M. Testosterone therapy
decreases subcutaneous fat and adiponectin in aging men. Eur J
Endocrinol 166: 469-476, 2012.
110. Freet CS, Stoner JF, Tang X. Baroreflex and chemoreflex controls of
sympathetic activity following intermittent hypoxia. Auton Neurosci
Basic Clin 174: 8-14, 2013.
111. Fruhbeck G. Intracellular signalling pathways activated by leptin.
Biochem J 393: 7-20, 2006.
112. Fujishima Y, Maeda N, Matsuda K, Masuda S, Mori T, Fukuda S,
Sekimoto R, Yamaoka M, Obata Y, Kita S, Nishizawa H, Funahashi
T, Ranscht B, Shimomura I. Adiponectin association with T-cadherin
protects against neointima proliferation and atherosclerosis. FASEB J
31: 1571-1583, 2017.
113. Fukushi I, Yokota S, Okada Y. The role of the hypothalamus in
modulation of respiration. Respir Physiol Neurobiol 265: 172-179,
2019.
114. Furlong TM, McDowall LM, Horiuchi J, Polson JW, Dampney RA.
The effect of air puff stress on c-Fos expression in rat hypothalamus
and brainstem: Central circuitry mediating sympathoexcitation and
baroreflex resetting. Eur J Neurosci 39: 1429-1438, 2014.
115. Fuster JJ, Ouchi N, Gokce N, Walsh K. Obesity-induced changes in
adipose tissue microenvironment and their impact on cardiovascular
disease. Circ Res 118: 1786-1807, 2016.
116. Gaines J, Vgontzas AN, Fernandez-Mendoza J, Calhoun SL, He F,
Liao D, Sawyer MD, Bixler EO. Inflammation mediates the associa-
tion between visceral adiposity and obstructive sleep apnea in adoles-
cents. Am J Phys Endocrinol Metab 311: E851-E858, 2016.
117. Gamber KM, Huo L, Ha S, Hairston JE, Greeley S, Bjorbaek C.
Over-expression of leptin receptors in hypothalamic POMC neurons
increases susceptibility to diet-induced obesity. PLoS One 7: e30485,
2012.
118. Gao L, Ortega-Saenz P, Garcia-Fernandez M, Gonzalez-Rodriguez P,
Caballero-Eraso C, Lopez-Barneo J. Glucose sensing by carotid body
glomus cells: Potential implications in disease. Front Physiol 5: 398,
2014.
119. Garcia-Rio F, Pino JM, Ramirez T, Alvaro D, Alonso A, Villasante
C, Villamor J. Inspiratory neural drive response to hypoxia adequately
Volume 10, July 2020
Leptin in the Control of Breathing
estimates peripheral chemosensitivity in OSAHS patients. Eur Respir
J 20: 724-732, 2002.
120. Gauda E, Martin R. Control of Breathing. In: Gleason C, Juul S,
editors. Avery’s Diseases of the Newborn. Philadelphia, PA: Elsevier,
2018, p. 600-617.
121. Gauda EB, Carroll JL, Donnelly DF. Developmental maturation
of chemosensitivity to hypoxia of peripheral arterial chemorecep-
tors – invited article. Adv Exp Med Biol 648: 243-255, 2009.
122. Gauda EB, Master Z. Contribution of relative leptin and adiponectin
deficiencies in premature infants to chronic intermittent hypoxia:
Exploring a new hypothesis. Respir Physiol Neurobiol 256: 119-127,
2018.
123. Gauda EB, McLemore GL, Tolosa J, Marston-Nelson J, Kwak D. Mat-
uration of peripheral arterial chemoreceptors in relation to neonatal
apnoea. Semin Neonatol 9: 181-194, 2004.
124. Gerosa-Neto J, Panissa VLG, Monteiro PA, Inoue DS, Ribeiro JPJ,
Figueiredo C, Zagatto AM, Little JP, Lira FS. High- or moderate-
intensity training promotes change in cardiorespiratory fitness, but not
visceral fat, in obese men: A randomised trial of equal energy expen-
diture exercise. Respir Physiol Neurobiol 266: 150-155, 2019.
125. Glavas MM, Kirigiti MA, Xiao XQ, Enriori PJ, Fisher SK, Evans AE,
Grayson BE, Cowley MA, Smith MS, Grove KL. Early overnutrition
results in early-onset arcuate leptin resistance and increased sensitiv-
ity to high-fat diet. Endocrinology 151: 1598-1610, 2010.
126. Gletsu-Miller N, Wright BN. Mineral malnutrition following bariatric
surgery. Adv Nutr 4: 506-517, 2013.
127. Global BMIMC, Di Angelantonio E, Bhupathiraju Sh N, Wormser D,
Gao P, Kaptoge S, Berrington de Gonzalez A, Cairns BJ, Huxley R,
Jackson Ch L, Joshy G, Lewington S, Manson JE, Murphy N, Patel
AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barri-
carte A, Carter B, Cerhan JR, Smith GD, Fang X, Franco OH, Green J,
Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC,
O’Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote
C, Sattar N, Sofianopoulou E, Stevens J, Thun M, Ueshima H, Yang
L, Yun YD, Willeit P, Banks E, Beral V, Chen Z, Gapstur SM, Gunter
MJ, Hartge P, Jee SH, Lam TH, Peto R, Potter JD, Willett WC, Thomp-
son SG, Danesh J, Hu FB. Body-mass index and all-cause mortality:
Individual-participant-data meta-analysis of 239 prospective studies in
four continents. Lancet 388: 776-786, 2016.
128. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ,
Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern
SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kit-
tner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid
DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER
3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK,
Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN,
Virani SS, Wong ND, Woo D, Turner MB, American Heart Associa-
tion Statistics Committee and Stroke Statistics Subcommittee. Heart
disease and stroke statistics—2014 update: A report from the Ameri-
can Heart Association. Circulation 129: e28-e292, 2014.
129. Gonzalez C, Almaraz L, Obeso A, Rigual R. Oxygen and acid
chemoreception in the carotid body chemoreceptors. Trends Neurosci
15: 146-153, 1992.
130. Gonzalez C, Almaraz L, Obeso A, Rigual R. Carotid body chemore-
ceptors: From natural stimuli to sensory discharges. Physiol Rev 74:
829-898, 1994.
131. Gonzalez-Martin MC, Vega-Agapito MV, Conde SV, Castaneda
J, Bustamante R, Olea E, Perez-Vizcaino F, Gonzalez C, Obeso
A. Carotid body function and ventilatory responses in intermittent
hypoxia. Evidence for anomalous brainstem integration of arterial
chemoreceptor input. J Cell Physiol 226: 1961-1969, 2011.
132. Goossens GH, Bizzarri A, Venteclef N, Essers Y, Cleutjens JP,
Konings E, Jocken JW, Cajlakovic M, Ribitsch V, Clement K, Blaak
EE. Increased adipose tissue oxygen tension in obese compared with
lean men is accompanied by insulin resistance, impaired adipose
tissue capillarization, and inflammation. Circulation 124: 67-76,
2011.
133. Gorska E, Popko K, Stelmaszczyk-Emmel A, Ciepiela O, Kucharska
A, Wasik M. Leptin receptors. Eur J Med Res 15 (Suppl 2): 50-54,
2010.
134. Grattan DR, Ladyman SR, Augustine RA. Hormonal induction of lep-
tin resistance during pregnancy. Physiol Behav 91: 366-374, 2007.
135. Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin
DG. Evidence that the caudal brainstem is a target for the inhibitory
effect of leptin on food intake. Endocrinology 143: 239-246, 2002.
136. Groeben H, Meier S, Brown RH, O’Donnell CP, Mitzner W, Tanker-
sley CG. The effect of leptin on the ventilatory responseto hyperoxia.
Exp Lung Res 30: 559-570, 2004.
137. Grove KL, Grayson BE, Glavas MM, Xiao XQ, Smith MS. Develop-
ment of metabolic systems. Physiol Behav 86: 646-660, 2005.
138. Guertzenstein PG, Silver A. Fall in blood pressure produced from
discrete regions of the ventral surface of the medulla by glycine and
lesions. J Physiol 242: 489-503, 1974.
1077
Leptin in the Control of Breathing
139. Guilleminault C, Quo SD. Sleep-disordered breathing. A view at the
beginning of the new Millennium. Dent Clin N Am 45: 643-656, 2001.
140. Guimaraes KSL, de Araujo EV, Aquino JS, Gadelha DA, Balarini CM,
Costa-Silva JH, Magnani M, Vidal H, Braga VA, de Brito Alves JL.
Effect of maternal dyslipidaemia on the cardiorespiratory physiology
and biochemical parameters in male rat offspring. Br J Nutr 118: 930-
941, 2017.
141. Guo R, Zhang Y, Turdi S, Ren J. Adiponectin knockout accentu-
ates high fat diet-induced obesity and cardiac dysfunction: Role of
autophagy. Biochim Biophys Acta 1832: 1136-1148, 2013.
142. Guyenet PG. Regulation of breathing and autonomic outflows by
chemoreceptors. Compr Physiol 4: 1511-1562, 2014.
143. Ha S, Baver S, Huo L, Gata A, Hairston J, Huntoon N, Li W, Zhang T,
Benecchi EJ, Ericsson M, Hentges ST, Bjorbaek C. Somato-dendritic
localization and signaling by leptin receptors in hypothalamic POMC
and AgRP neurons. PLoS One 8: e77622, 2013.
144. Hall JE, da Silva AA, do Carmo JM, Dubinion J, Hamza S, Munusamy
S, Smith G, Stec DE. Obesity-induced hypertension: Role of sympa-
thetic nervous system, leptin, and melanocortins. J Biol Chem 285:
17271-17276, 2010.
145. Hansen CS, Vistisen D, Jorgensen ME, Witte DR, Brunner EJ,
Tabak AG, Kivimaki M, Roden M, Malik M, Herder C. Adiponectin,
biomarkers of inflammation and changes in cardiac autonomic
function: Whitehall II study. Cardiovasc Diabetol 16: 153, 2017.
146. Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour
Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH. Leptin and
ghrelin levels in patients with obstructive sleep apnoea: Effect of CPAP
treatment. Eur Respir J 22: 251-257, 2003.
147. Haselton JR, Guyenet PG. Central respiratory modulation of
medullary sympathoexcitatory neurons in rat. Am J Phys 256:
R739-R750, 1989.
148. Hauck FR, Thompson JM, Tanabe KO, Moon RY, Vennemann MM.
Breastfeeding and reduced risk of sudden infant death syndrome: A
meta-analysis. Pediatrics 128: 103-110, 2011.
149. Haynes WG. Interaction between leptin and sympathetic nervous
system in hypertension. Curr Hypertens Rep 2: 311-318, 2000.
150. Hellgren G, Engstrom E, Smith LE, Lofqvist C, Hellstrom A. Effect of
preterm birth on postnatal apolipoprotein and adipocytokine profiles.
Neonatology 108: 16-22, 2015.
151. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mech-
anisms of hyperglycemia in obese non-insulin-dependent diabetes
mellitus. Diabetes 35: 990-998, 1986.
152. Hilaire G, Viemari JC, Coulon P, Simonneau M, Bevengut M. Modu-
lation of the respiratory rhythm generator by the pontine noradrenergic
A5 and A6 groups in rodents. Respir Physiol Neurobiol 143: 187-197,
2004.
153. Hitzig BM, Perng WC, Burt T, Okunieff P, Johnson DC. 1H-NMR
measurement of fractional dissociation of imidazole in intact animals.
Am J Phys 266: R1008-R1015, 1994.
154. Hodson L, Humphreys SM, Karpe F, Frayn KN. Metabolic signatures
of human adipose tissue hypoxia in obesity. Diabetes 62: 1417-1425,
2013.
155. Hoyda TD, Smith PM, Ferguson AV. Adiponectin acts in the nucleus
of the solitary tract to decrease blood pressure by modulating the
excitability of neuropeptide Y neurons. Brain Res 1256: 76-84, 2009.
156. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific
gene dysregulated in obesity. J Biol Chem 271: 10697-10703, 1996.
157. Huang XF, Han M, South T, Storlien L. Altered levels of POMC,
AgRP and MC4-R mRNA expression in the hypothalamus and other
parts of the limbic system of mice prone or resistant to chronic high-
energy diet-induced obesity. Brain Res 992: 9-19, 2003.
158. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in
the mouse. Science 153: 1127-1128, 1966.
159. Hutter MM, Schirmer BD, Jones DB, Ko CY, Cohen ME, Merkow
RP, Nguyen NT. First report from the American College of Surgeons
Bariatric Surgery Center Network: Laparoscopic sleeve gastrectomy
has morbidity and effectiveness positioned between the band and the
bypass. Ann Surg 254: 410-420; discussion 420-412, 2011.
160. Iftikhar IH, Valentine CW, Bittencourt LR, Cohen DL, Fedson AC,
Gislason T, Penzel T, Phillips CL, Yu-sheng L, Pack AI, Magalang
UJ. Effects of continuous positive airway pressure on blood pressure
in patients with resistant hypertension and obstructive sleep apnea:
A meta-analysis. J Hypertens 32: 2341-2350; discussion 2350, 2014.
161. Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house
mouse. J Hered 41: 317-318, 1950.
162. Inoue DS, Panissa VL, Antunes BM, Oliveira FP, Malta RB, Caldeira
RS, Campos EZ, Pimentel GD, Franchini E, Lira FS. Reduced leptin
level is independent of fat mass changes and hunger scores from high-
intensity intermittent plus strength training. J Sport Med Phys Fit 58:
1045-1051, 2018.
163. Inyushkin AN, Inyushkina EM, Merkulova NA. Respiratory responses
to microinjections of leptin into the solitary tract nucleus. Neurosci
Behav Physiol 39: 231-240, 2009.
1078
Comprehensive Physiology
164. Inyushkina EM, Merkulova NA, Inyushkin AN. Mechanisms of the
respiratory activity of leptin at the level of the solitary tract nucleus.
Neurosci Behav Physiol 40: 707-713, 2010.
165. Ip MS, Lam KS, Ho C, Tsang KW, Lam W. Serum leptin and vascular
risk factors in obstructive sleep apnea. Chest 118: 580-586, 2000.
166. Iturriaga R, Oyarce MP, Dias ACR. Role of carotid body in intermit-
tent hypoxia-related hypertension. Curr Hypertens Rep 19: 38, 2017.
167. Janczewski WA, Feldman JL. Distinct rhythm generators for inspira-
tion and expiration in the juvenile rat. J Physiol 570: 407-420, 2006.
168. Jaquet D, Leger J, Levy-Marchal C, Oury JF, Czernichow P. Ontogeny
of leptin in human fetuses and newborns: Effect of intrauterine growth
retardation on serum leptin concentrations. J Clin Endocrinol Metab
83: 1243-1246, 1998.
169. Jin G, Wang W, Kang J, Wu Y, Hou X, Yu R. Study of serum leptin
level in patients with obstructive sleep apnea. Zhonghua jie he he hu
xi za zhi 25: 204-206, 2002.
170. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep
apnoea. Lancet 383: 736-747, 2014.
171. Kaar JL, Brinton JT, Crume T, Hamman RF, Glueck DH, Dabelea D.
Leptin levels at birth and infant growth: The EPOCH study. J Dev Orig
Health Dis 5: 214-218, 2014.
172. Karvonen MK, Pesonen U, Heinonen P, Laakso M, Rissanen A,
Naukkarinen H, Valve R, Uusitupa MI, Koulu M. Identification of
new sequence variants in the leptin gene. J Clin Endocrinol Metab
83: 3239-3242, 1998.
173. Kelesidis I, Mantzoros CS. Leptin and its emerging role in children
and adolescents. Clin Pediatr Endocrinol 15: 1-14, 2006.
174. Kesavan K, Devaskar SU. Intrauterine growth restriction: Postnatal
monitoring and outcomes. Pediatr Clin N Am 66: 403-423, 2019.
175. Kim DK, Summers BA, Prabhakar NR, Kumar GK. Hypoxia does
not uniformly facilitate the release of multiple transmitters from the
carotid body. Adv Exp Med Biol 536: 291-296, 2003.
176. Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hof-
mann SM, Schraw T, Durand JL, Li H, Li G, Jelicks LA, Mehler MF,
Hui DY, Deshaies Y, Shulman GI, Schwartz GJ, Scherer PE. Obesity-
associated improvements in metabolic profile through expansion of
adipose tissue. J Clin Invest 117: 2621-2637, 2007.
177. Kim S, Whelan J, Claycombe K, Reath DB, Moustaid-Moussa N.
Angiotensin II increases leptin secretion by 3T3-L1 and human
adipocytes via a prostaglandin-independent mechanism. J Nutr 132:
1135-1140, 2002.
178. Kirk SL, Samuelsson AM, Argenton M, Dhonye H, Kalamatianos T,
Poston L, Taylor PD, Coen CW. Maternal obesity induced by diet in
rats permanently influences central processes regulating food intake in
offspring. PLoS One 4: e5870, 2009.
179. Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist
JK. Expression of melanocortin 4 receptor mRNA in the central ner-
vous system of the rat. J Comp Neurol 457: 213-235, 2003.
180. Kokkinos P. Cardiorespiratory fitness, exercise, and blood pressure.
Hypertension 64: 1160-1164, 2014.
181. Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms
of obesity-induced hypertension. Hypertens Res 33: 386-393, 2010.
182. Koyama Y, Coker RH, Denny JC, Lacy DB, Jabbour K, Williams
PE, Wasserman DH. Role of carotid bodies in control of the neuro-
endocrine response to exercise. Am J Phys Endocrinol Metab 281:
E742-E748, 2001.
183. Koyama Y, Coker RH, Stone EE, Lacy DB, Jabbour K, Williams PE,
Wasserman DH. Evidence that carotid bodies play an important role
in glucoregulation in vivo. Diabetes 49: 1434-1442, 2000.
184. Kugananthan S, Lai CT, Gridneva Z, Mark PJ, Geddes DT, Kakulas
F. Leptin levels are higher in whole compared to skim human milk,
supporting a cellular contribution. Nutrients 8: 711, 2016.
185. Kumar P, Prabhakar NR. Peripheral chemoreceptors: Function and
plasticity of the carotid body. Compr Physiol 2: 141-219, 2012.
186. Kuwaki T. Orexinergic modulation of breathing across vigilance
states. Respir Physiol Neurobiol 164: 204-212, 2008.
187. Kwak DJ, Kwak SD, Gauda EB. The effect of hyperoxia on reactive
oxygen species (ROS) in rat petrosal ganglion neurons during devel-
opment using organotypic slices. Pediatr Res 60: 371-376, 2006.
188. Lage M, Baldelli R, Camina JP, Rodriguez-Garci J, Penalva A,
Dieguez C, Casanueva FF. Presence of bovine leptin in edible com-
mercial milk and infant formula. J Endocrinol Investig 25: 670-674,
2002.
189. Lahiri S, DeLaney RG. Relationship between carotid chemorecep-
tor activity and ventilation in the cat. Respir Physiol 24: 267-286,
1975.
190. Lambert E, Straznicky NE, Dawood T, Ika-Sari C, Grima M, Esler
MD, Schlaich MP, Lambert GW. Change in sympathetic nerve firing
pattern associated with dietary weight loss in the metabolic syndrome.
Front Physiol 2: 52, 2011.
191. Lambert EA, Straznicky NE, Dixon JB, Lambert GW. Should the sym-
pathetic nervous system be a target to improve cardiometabolic risk in
obesity? Am J Phys Heart Circ Phys 309: H244-H258, 2015.
Volume 10, July 2020
Comprehensive Physiology
192. Lambert GW, Straznicky NE, Lambert EA, Dixon JB, Schlaich
MP. Sympathetic nervous activation in obesity and the metabolic
syndrome-causes, consequences and therapeutic implications.
Pharmacol Ther 126: 159-172, 2010.
193. Landsberg L. Insulin resistance and the metabolic syndrome.
Diabetologia 48: 1244-1246, 2005.
194. Landt M, Lawson GM, Helgeson JM, Davila-Roman VG, Ladenson
JH, Jaffe AS, Hickner RC. Prolonged exercise decreases serum leptin
concentrations. Metab Clin Exp 46: 1109-1112, 1997.
195. Lecke SB, Morsch DM, Spritzer PM. Leptin and adiponectin in the
female life course. Braz J Med Biol Res 44: 381-387, 2011.
196. Leite RD, Durigan Rde C, de Souza Lino AD, de Souza Campos MV,
Souza M, Selistre-de-Araujo HS, Bouskela E, Kraemer-Aguiar LG.
Resistance training may concomitantly benefit body composition,
blood pressure and muscle MMP-2 activity on the left ventricle of
high-fat fed diet rats. Metab Clin Exp 62: 1477-1484, 2013.
197. Levitzky M. Control of Breathing. In: Michael G. Levitzky, editor.
Pulmonary Physiology; [traduction of the Marcos Ikeda]. 6th ed.
Manole, Barueri: Sao Paulo, 2004.
198. Li A, Nattie E. CO2 dialysis in one chemoreceptor site, the RTN: Stim-
ulus intensity and sensitivity in the awake rat. Respir Physiol Neurobiol
133: 11-22, 2002.
199. Li A, Nattie E. Serotonin transporter knockout mice have a reduced
ventilatory response to hypercapnia (predominantly in males) but not
to hypoxia. J Physiol 586: 2321-2329, 2008.
200. Li P, Cui BP, Zhang LL, Sun HJ, Liu TY, Zhu GQ. Melanocortin 3/4
receptors in paraventricular nucleus modulate sympathetic outflow and
blood pressure. Exp Physiol 98: 435-443, 2013.
201. Li P, Shibata R, Unno K, Shimano M, Furukawa M, Ohashi T, Cheng
X, Nagata K, Ouchi N, Murohara T. Evidence for the importance of
adiponectin in the cardioprotective effects of pioglitazone. Hyperten-
sion 55: 69-75, 2010.
202. Li YL, Schultz HD. Enhanced sensitivity of Kv channels to hypoxia
in the rabbit carotid body in heart failure: Role of angiotensin II.
J Physiol 575: 215-227, 2006.
203. Li YL, Xia XH, Zheng H, Gao L, Li YF, Liu D, Patel KP, Wang W,
Schultz HD. Angiotensin II enhances carotid body chemoreflex con-
trol of sympathetic outflow in chronic heart failure rabbits. Cardiovasc
Res 71: 129-138, 2006.
204. Lin M, Liu R, Gozal D, Wead WB, Chapleau MW, Wurster R, Cheng
ZJ. Chronic intermittent hypoxia impairs baroreflex control of heart
rate but enhances heart rate responses to vagal efferent stimulation
in anesthetized mice. Am J Phys Heart Circ Phys 293: H997-H1006,
2007.
205. Liu M, Liu F. Transcriptional and post-translational regulation of
adiponectin. Biochem J 425: 41-52, 2009.
206. Liu Y, Chewchuk S, Lavigne C, Brule S, Pilon G, Houde V, Xu A,
Marette A, Sweeney G. Functional significance of skeletal muscle
adiponectin production, changes in animal models of obesity and
diabetes, and regulation by rosiglitazone treatment. Am J Phys
Endocrinol Metab 297: E657-E664, 2009.
207. Loredo JS, Clausen JL, Nelesen RA, Ancoli-Israel S, Ziegler MG,
Dimsdale JE. Obstructive sleep apnea and hypertension: Are periph-
eral chemoreceptors involved? Med Hypotheses 56: 17-19, 2001.
208. Lu M, Fang F, Wang Z, Wei P, Hu C, Wei Y. Association between
serum/plasma levels of adiponectin and obstructive sleep apnea
hypopnea syndrome: A meta-analysis. Lipids Health Dis 18: 30,
2019.
209. MacFarlane PM, Vinit S, Mitchell GS. Enhancement of phrenic
long-term facilitation following repetitive acute intermittent hypoxia
is blocked by the glycolytic inhibitor 2-deoxyglucose. Am J Physiol
Regul Integr Comp Physiol 314: R135-R144, 2018.
210. Mack SO, Kc P, Wu M, Coleman BR, Tolentino-Silva FP, Haxhiu MA.
Paraventricular oxytocin neurons are involved in neural modulation of
breathing. J Appl Physiol 92: 826-834, 2002.
211. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Mat-
subara K. cDNA cloning and expression of a novel adipose specific
collagen-like factor, apM1 (adipose most abundant gene transcript 1).
1996. Biochem Biophys Res Commun 425: 556-559, 2012.
212. Makinodan K, Yoshikawa M, Fukuoka A, Tamaki S, Koyama N,
Yamauchi M, Tomoda K, Hamada K, Kimura H. Effect of serum
leptin levels on hypercapnic ventilatory response in obstructive sleep
apnea. Respiration 75: 257-264, 2008.
213. Maki-Nunes C, Toschi-Dias E, Cepeda FX, Rondon MU, Alves
MJ, Fraga RF, Braga AM, Aguilar AM, Amaro AC, Drager LF,
Lorenzi-Filho G, Negrao CE, Trombetta IC. Diet and exercise
improve chemoreflex sensitivity in patients with metabolic syndrome
and obstructive sleep apnea. Obesity 23: 1582-1590, 2015.
214. Malli F, Papaioannou AI, Gourgoulianis KI, Daniil Z. The role of
leptin in the respiratory system: An overview. Respir Res 11: 152,
2010.
215. Mansukhani MP, Kara T, Caples SM, Somers VK. Chemoreflexes,
sleep apnea, and sympathetic dysregulation. Curr Hypertens Rep 16:
476, 2014.
Volume 10, July 2020
Leptin in the Control of Breathing
216. Marchenko V, Koizumi H, Mosher B, Koshiya N, Tariq MF, Bezdud-
naya TG, Zhang R, Molkov YI, Rybak IA, Smith JC. Perturbations of
respiratory rhythm and pattern by disrupting synaptic inhibition within
pre-Botzinger and Botzinger complexes. eNeuro 3: ENEURO.0011-
16.2016, 2016.
217. Marin P, Rebuffe-Scrive M, Smith U, Bjorntorp P. Glucose uptake in
human adipose tissue. Metab Clin Exp 36: 1154-1160, 1987.
218. Marjanovic M, Elliott AC, Dawson MJ. The temperature dependence
of intracellular pH in isolated frog skeletal muscle: Lessons concerning
the Na(+)-H+ exchanger. J Membr Biol 161: 215-225, 1998.
219. Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni
K. Leptin signaling in the nucleus tractus solitarii increases sympa-
thetic nerve activity to the kidney. Hypertension 53: 375-380, 2009.
220. Marshall JM. Peripheral chemoreceptors and cardiovascular regula-
tion. Physiol Rev 74: 543-594, 1994.
221. Martos-Moreno GA, Barrios V, Argente J. Normative data for
adiponectin, resistin, interleukin 6, and leptin/receptor ratio in a
healthy Spanish pediatric population: Relationship with sex steroids.
Eur J Endocrinol 155: 429-434, 2006.
222. Matsuda K, Fujishima Y, Maeda N, Mori T, Hirata A, Sekimoto R,
Tsushima Y, Masuda S, Yamaoka M, Inoue K, Nishizawa H, Kita
S, Ranscht B, Funahashi T, Shimomura I. Positive feedback regula-
tion between adiponectin and T-cadherin impacts adiponectin levels in
tissue and plasma of male mice. Endocrinology 156: 934-946, 2015.
223. McAllen RM. Central respiratory modulation of subretrofacial bul-
bospinal neurones in the cat. J Physiol 388: 533-545, 1987.
224. McDowall LM, Horiuchi J, Dampney RA. Effects of disinhibition of
neurons in the dorsomedial hypothalamus on central respiratory drive.
Am J Physiol Regul Integr Comp Physiol 293: R1728-R1735, 2007.
225. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano
O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee
S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S,
Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Ander-
son CS, SAVE Investigators and Coordinators. CPAP for prevention of
cardiovascular events in obstructive sleep apnea. N Engl J Med 375:
919-931, 2016.
226. Mesarwi OA, Sharma EV, Jun JC, Polotsky VY. Metabolic dysfunc-
tion in obstructive sleep apnea: A critical examination of underlying
mechanisms. Sleep Biol Rhythms 13: 2-17, 2015.
227. Messenger SA, Ciriello J. Effects of intermittent hypoxia on leptin
signalling in the carotid body. Neuroscience 232: 216-225, 2013.
228. Messenger SA, Moreau JM, Ciriello J. Intermittent hypoxia and
systemic leptin administration induces pSTAT3 and Fos/Fra-1 in the
carotid body. Brain Res 1446: 56-70, 2012.
229. Messenger SA, Moreau JM, Ciriello J. Effect of chronic intermittent
hypoxia on leptin and leptin receptor protein expression in the carotid
body. Brain Res 1513: 51-60, 2013.
230. Mistry AM, Swick A, Romsos DR. Leptin alters metabolic rates before
acquisition of its anorectic effect in developing neonatal mice. Am J
Phys 277: R742-R747, 1999.
231. Miyawaki T, Pilowsky P, Sun QJ, Minson J, Suzuki S, Arnolda L,
Llewellyn-Smith I, Chalmers J. Central inspiration increases barosen-
sitivity of neurons in rat rostral ventrolateral medulla. Am J Phys 268:
R909-R918, 1995.
232. Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA,
Mobbs CV. Hypothalamic pro-opiomelanocortin mRNA is reduced
by fasting and [corrected] in ob/ob and db/db mice, but is stimulated
by leptin. Diabetes 47: 294-297, 1998.
233. Mizuno TM, Makimura H, Silverstein J, Roberts JL, Lopingco
T, Mobbs CV. Fasting regulates hypothalamic neuropeptide Y,
agouti-related peptide, and proopiomelanocortin in diabetic mice
independent of changes in leptin or insulin. Endocrinology 140:
4551-4557, 1999.
234. Mizuno TM, Mobbs CV. Hypothalamic agouti-related protein mes-
senger ribonucleic acid is inhibited by leptin and stimulated by fasting.
Endocrinology 140: 814-817, 1999.
235. Mohr MA, Fairchild KD, Patel M, Sinkin RA, Clark MT, Moorman
JR, Lake DE, Kattwinkel J, Delos JB. Quantification of periodic
breathing in premature infants. Physiol Meas 36: 1415-1427, 2015.
236. Moller DE. Potential role of TNF-alpha in the pathogenesis of insulin
resistance and type 2 diabetes. Trends Endocrinol Metab 11: 212-217,
2000.
237. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham
NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH,
Earley AR, Barnett AH, Prins JB, O’Rahilly S. Congenital leptin defi-
ciency is associated with severe early-onset obesity in humans. Nature
387: 903-908, 1997.
238. Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of
continuous positive airway pressure treatment on blood pressure: A
systematic review and meta-analysis of randomized controlled trials.
J Clin Sleep Med 8: 587-596, 2012.
239. Moraes DJ, Zoccal DB, Machado BH. Medullary respiratory network
drives sympathetic overactivity and hypertension in rats submitted
to chronic intermittent hypoxia. Hypertension 60: 1374-1380, 2012.
1079
Leptin in the Control of Breathing
240. Moreau JM, Ciriello J. Effects of acute intermittent hypoxia on energy
balance and hypothalamic feeding pathways. Neuroscience 253: 350-
360, 2013.
241. Moreau JM, Messenger SA, Ciriello J. Effects of angiotensin II on
leptin and downstream leptin signaling in the carotid body during acute
intermittent hypoxia. Neuroscience 310: 430-441, 2015.
242. Moreira TS, Takakura AC, Colombari E, Guyenet PG. Central
chemoreceptors and sympathetic vasomotor outflow. J Physiol 577:
369-386, 2006.
243. Morton GJ, Schwartz MW. Leptin and the central nervous system con-
trol of glucose metabolism. Physiol Rev 91: 389-411, 2011.
244. Munzberg H, Morrison CD. Structure, production and signaling of
leptin. Metab Clin Exp 64: 13-23, 2015.
245. Murphy AM, Thomas A, Crinion SJ, Kent BD, Tambuwala MM, Fabre
A, Pepin JL, Roche HM, Arnaud C, Ryan S. Intermittent hypoxia in
obstructive sleep apnoea mediates insulin resistance through adipose
tissue inflammation. Eur Respir J 49 (4): 1601731, 2017.
246. Myers MG, Cowley MA, Munzberg H. Mechanisms of leptin action
and leptin resistance. Annu Rev Physiol 70: 537-556, 2008.
247. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation
and characterization of GBP28, a novel gelatin-binding protein puri-
fied from human plasma. J Biochem 120: 803-812, 1996.
248. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto
K. Distribution of orexin neurons in the adult rat brain. Brain Res 827:
243-260, 1999.
249. Narkiewicz K, Somers VK. Cardiovascular variability characteristics
in obstructive sleep apnea. Auton Neurosci Basic Clin 90: 89-94, 2001.
250. Narkiewicz K, van de Borne PJ, Pesek CA, Dyken ME, Montano N,
Somers VK. Selective potentiation of peripheral chemoreflex sensitiv-
ity in obstructive sleep apnea. Circulation 99: 1183-1189, 1999.
251. Nattie E. CO2 , brainstem chemoreceptors and breathing. Prog Neuro-
biol 59: 299-331, 1999.
252. Nattie E, Li A. Respiration and autonomic regulation and orexin. Prog
Brain Res 198: 25-46, 2012.
253. Nattie EE, Li A. Retrotrapezoid nucleus lesions decrease phrenic activ-
ity and CO2 sensitivity in rats. Respir Physiol 97: 63-77, 1994.
254. Nattie EE, Li A. Central chemoreception in the region of the ventral
respiratory group in the rat. J Appl Physiol 81: 1987-1995, 1996.
255. Newhouse LP, Joyner MJ, Curry TB, Laurenti MC, Man CD, Cobelli
C, Vella A, Limberg JK. Three hours of intermittent hypoxia increases
circulating glucose levels in healthy adults. Phys Rep 5 (1): e13106,
2017.
256. Newton AJ, Hess S, Paeger L, Vogt MC, Fleming Lascano J, Nillni EA,
Bruning JC, Kloppenburg P, Xu AW. AgRP innervation onto POMC
neurons increases with age and is accelerated with chronic high-fat
feeding in male mice. Endocrinology 154: 172-183, 2013.
257. Nindl BC, Kraemer WJ, Arciero PJ, Samatallee N, Leone CD, Mayo
MF, Hafeman DL. Leptin concentrations experience a delayed reduc-
tion after resistance exercise in men. Med Sci Sports Exerc 34: 608-
613, 2002.
258. Nunes M, da Silva CH, Bosa VL, Bernardi JR, Werlang ICR, Goldani
MZ, NESCA Group. Could a remarkable decrease in leptin and insulin
levels from colostrum to mature milk contribute to early growth catch-
up of SGA infants? BMC Pregnancy Childbirth 17: 410, 2017.
259. Nurse CA, Leonard EM, Salman S. Role of glial-like type II cells
as paracrine modulators of carotid body chemoreception. Physiol
Genomics 50: 255-262, 2018.
260. O’Donnell CP, Schaub CD, Haines AS, Berkowitz DE, Tankersley
CG, Schwartz AR, Smith PL. Leptin prevents respiratory depression
in obesity. Am J Respir Crit Care Med 159: 1477-1484, 1999.
261. Ogden CL, Carroll MD, Fryar CD, Flegal KM. Prevalence of obesity
among adults and youth: United States, 2011-2014. NCHS data brief,
no 219. Hyattsville, MD: National Center for Health Statistics, 2015.
262. Olea E, Ribeiro MJ, Gallego-Martin T, Yubero S, Rigual R, Masa JF,
Obeso A, Conde SV, Gonzalez C. The carotid body does not mediate
the acute ventilatory effects of leptin. Adv Exp Med Biol 860: 379-385,
2015.
263. Olive JL, Miller GD. Differential effects of maximal- and moderate-
intensity runs on plasma leptin in healthy trained subjects. Nutrition
17: 365-369, 2001.
264. Oyamada Y, Ballantyne D, Muckenhoff K, Scheid P. Respiration-
modulated membrane potential and chemosensitivity of locus
coeruleus neurones in the in vitro brainstem-spinal cord of the
neonatal rat. J Physiol 513 (Pt 2): 381-398, 1998.
265. Ozturk L, Unal M, Tamer L, Celikoglu F. The association of the sever-
ity of obstructive sleep apnea with plasma leptin levels. Arch Otolaryn-
gol Head Neck Surg 129: 538-540, 2003.
266. Pan WW, Myers MG Jr. Leptin and the maintenance of elevated body
weight. Nat Rev Neurosci 19: 95-105, 2018.
267. Papp RS, Palkovits M. Brainstem projections of neurons located in var-
ious subdivisions of the dorsolateral hypothalamic area-an anterograde
tract-tracing study. Front Neuroanat 8: 34, 2014.
268. Parameswaran K, Todd DC, Soth M. Altered respiratory physiology
in obesity. Can Respir J 13: 203-210, 2006.
1080
Comprehensive Physiology
269. Pardal R, Lopez-Barneo J. Low glucose-sensing cells in the carotid
body. Nat Neurosci 5: 197-198, 2002.
270. Pardal R, Ortega-Saenz P, Duran R, Lopez-Barneo J. Glia-like stem
cells sustain physiologic neurogenesis in the adult mammalian carotid
body. Cell 131: 364-377, 2007.
271. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan
LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygena-
tion in human obesity: Evidence for rarefaction, macrophage chemo-
taxis, and inflammation without an angiogenic response. Diabetes 58:
718-725, 2009.
272. Patel SR, Palmer LJ, Larkin EK, Jenny NS, White DP, Redline S. Rela-
tionship between obstructive sleep apnea and diurnal leptin rhythms.
Sleep 27: 235-239, 2004.
273. Patel SR, White DP, Malhotra A, Stanchina ML, Ayas NT. Continuous
positive airway pressure therapy for treating sleepiness in a diverse
population with obstructive sleep apnea: Results of a meta-analysis.
Arch Intern Med 163: 565-571, 2003.
274. Paz-Filho G, Mastronardi C, Delibasi T, Wong ML, Licinio J. Con-
genital leptin deficiency: Diagnosis and effects of leptin replacement
therapy. Arquivos brasileiros de endocrinologia e metabologia 54:
690-697, 2010.
275. Peng YJ, Overholt JL, Kline D, Kumar GK, Prabhakar NR. Induction
of sensory long-term facilitation in the carotid body by intermittent
hypoxia: Implications for recurrent apneas. Proc Natl Acad Sci U S A
100: 10073-10078, 2003.
276. Peng YJ, Prabhakar NR. Effect of two paradigms of chronic inter-
mittent hypoxia on carotid body sensory activity. J Appl Physiol 96:
1236-1242; discussion 1196, 2004.
277. Penumarti A, Abdel-Rahman AA. Neuronal nitric oxide synthase-
dependent elevation in adiponectin in the rostral ventrolateral medulla
underlies g protein-coupled receptor 18-mediated hypotension in
conscious rats. J Pharmacol Exp Ther 351: 44-53, 2014.
278. Peppard PE, Young T, Palta M, Dempsey J, Skatrud J. Longitudi-
nal study of moderate weight change and sleep-disordered breathing.
JAMA 284: 3015-3021, 2000.
279. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe
JG, Kilduff TS. Neurons containing hypocretin (orexin) project to mul-
tiple neuronal systems. J Neurosci Off J Soc Neurosci 18: 9996-10015,
1998.
280. Phillips BG, Kato M, Narkiewicz K, Choe I, Somers VK. Increases in
leptin levels, sympathetic drive, and weight gain in obstructive sleep
apnea. Am J Phys Heart Circ Phys 279: H234-H237, 2000.
281. Phillips SA, Ciaraldi TP, Oh DK, Savu MK, Henry RR. Adiponectin
secretion and response to pioglitazone is depot dependent in cultured
human adipose tissue. Am J Phys Endocrinol Metab 295: E842-E850,
2008.
282. Pierard M, Tassin A, Conotte S, Zouaoui Boudjeltia K, Legrand A.
Sustained intermittent hypoxemia induces adiponectin oligomers
redistribution and a tissue-specific modulation of adiponectin receptor
in mice. Front Physiol 10: 68, 2019.
283. Pinheiro AR, Cunha AR, Aguila MB, Mandarim-de-Lacerda CA. Ben-
eficial effects of physical exercise on hypertension and cardiovascular
adverse remodeling of diet-induced obese rats. Nutr Metab Cardiovasc
Dis 17: 365-375, 2007.
284. Piskuric NA, Nurse CA. Expanding role of ATP as a versatile messen-
ger at carotid and aortic body chemoreceptors. J Physiol 591: 415-422,
2013.
285. Platero-Luengo A, Gonzalez-Granero S, Duran R, Diaz-Castro B,
Piruat JI, Garcia-Verdugo JM, Pardal R, Lopez-Barneo J. An O2-
sensitive glomus cell-stem cell synapse induces carotid body growth
in chronic hypoxia. Cell 156: 291-303, 2014.
286. Polak J, Shimoda LA, Drager LF, Undem C, McHugh H, Polotsky
VY, Punjabi NM. Intermittent hypoxia impairs glucose homeostasis in
C57BL6/J mice: Partial improvement with cessation of the exposure.
Sleep 36: 1483-1490; 1490A-1490B, 2013.
287. Polotsky VY, Wilson JA, Smaldone MC, Haines AS, Hurn PD,
Tankersley CG, Smith PL, Schwartz AR, O’Donnell CP. Female
gender exacerbates respiratory depression in leptin-deficient obesity.
Am J Respir Crit Care Med 164: 1470-1475, 2001.
288. Porzionato A, Rucinski M, Macchi V, Stecco C, Castagliuolo I, Mal-
endowicz LK, De Caro R. Expression of leptin and leptin receptor
isoforms in the rat and human carotid body. Brain Res 1385: 56-67,
2011.
289. Prabhakar NR, Dick TE, Nanduri J, Kumar GK. Systemic, cellular
and molecular analysis of chemoreflex-mediated sympathoexcitation
by chronic intermittent hypoxia. Exp Physiol 92: 39-44, 2007.
290. Prabhakar NR, Peng YJ, Kumar GK, Pawar A. Altered carotid body
function by intermittent hypoxia in neonates and adults: Relevance to
recurrent apneas. Respir Physiol Neurobiol 157: 148-153, 2007.
291. Pye RL, Dunn EJ, Ricker EM, Jurcsisn JG, Barr BL, Wyatt CN.
Acutely administered leptin increases [Ca2+] I and BK Ca currents
but does not alter chemosensory behavior in rat carotid body type I
cells. Adv Exp Med Biol 860: 61-67, 2015.
Volume 10, July 2020
Comprehensive Physiology
292. Qiao L, Maclean PS, Schaack J, Orlicky DJ, Darimont C, Pagliassotti
M, Friedman JE, Shao J. C/EBPalpha regulates human adiponectin
gene transcription through an intronic enhancer. Diabetes 54: 1744-
1754, 2005.
293. Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through
Foxo1-C/enhancer-binding protein alpha transcriptional complex.
J Biol Chem 281: 39915-39924, 2006.
294. Rahmouni K. Leptin-induced sympathetic nerve activation: Signaling
mechanisms and cardiovascular consequences in obesity. Curr Hyper-
tens Rev 6: 104-209, 2010.
295. Rahmouni K, Correia ML, Haynes WG, Mark AL. Obesity-associated
hypertension: New insights into mechanisms. Hypertension 45: 9-14,
2005.
296. Rakoczy RJ, Pye RL, Fayyad TH, Santin JM, Barr BL, Wyatt CN.
High fat feeding in rats alters respiratory parameters by a mechanism
that is unlikely to be mediated by carotid body type I cells. Adv Exp
Med Biol 1071: 137-142, 2018.
297. Rakoczy RJ, Wyatt CN. Acute oxygen sensing by the carotid body:
A rattlebag of molecular mechanisms. J Physiol 596: 2969-2976,
2018.
298. Ramadan W, Dewasmes G, Petitjean M, Wiernsperger N, Delanaud
S, Geloen A, Libert JP. Sleep apnea is induced by a high-fat diet and
reversed and prevented by metformin in non-obese rats. Obesity 15:
1409-1418, 2007.
299. Ramirez JM, Garcia AJ 3rd, Anderson TM, Koschnitzky JE, Peng YJ,
Kumar GK, Prabhakar NR. Central and peripheral factors contributing
to obstructive sleep apneas. Respir Physiol Neurobiol 189: 344-353,
2013.
300. Reaven GM. Banting lecture 1988. Role of insulin resistance in human
disease. Diabetes 37: 1595-1607, 1988.
301. Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra
I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-
Peraldi S. Hypoxia decreases insulin signaling pathways in adipocytes.
Diabetes 58: 95-103, 2009.
302. Resto M, O’Connor D, Leef K, Funanage V, Spear M, Locke R. Lep-
tin levels in preterm human breast milk and infant formula. Pediatrics
108: E15, 2001.
303. Rey S, Del Rio R, Alcayaga J, Iturriaga R. Chronic intermittent
hypoxia enhances cat chemosensory and ventilatory responses to
hypoxia. J Physiol 560: 577-586, 2004.
304. Ribeiro MJ, Guimarães JP, Sacramento JF, Conde S. Contribution
of carotid body to leptin effects on ventilation and blood pressure in
control and obese rats. ERJ Open Res 5 (Suppl 3): P77, 2019.
305. Ribeiro MJ, Sacramento JF, Gallego-Martin T, Olea E, Melo BF,
Guarino MP, Yubero S, Obeso A, Conde SV. High fat diet blunts the
effects of leptin on ventilation and on carotid body activity. J Physiol
596: 3187-3199, 2018.
306. Ribeiro MJ, Sacramento JF, Gonzalez C, Guarino MP, Monteiro EC,
Conde SV. Carotid body denervation prevents the development of
insulin resistance and hypertension induced by hypercaloric diets.
Diabetes 62: 2905-2916, 2013.
307. Richter DW, Smith JC. Respiratory rhythm generation in vivo. Physi-
ology 29: 58-71, 2014.
308. Richter DW, Spyer KM. Studying rhythmogenesis of breathing:
Comparison of in vivo and in vitro models. Trends Neurosci 24:
464-472, 2001.
309. Rigatto H, Brady JP, de la Torre Verduzco R. Chemoreceptor reflexes
in preterm infants: II. The effect of gestational and postnatal age on
the ventilatory response to inhaled carbon dioxide. Pediatrics 55: 614-
620, 1975.
310. Roberts BL, Bennett CM, Carroll JM, Lindsley SR, Kievit P. Early
overnutrition alters synaptic signaling and induces leptin resistance
in arcuate proopiomelanocortin neurons. Physiol Behav 206: 166-174,
2019.
311. Ross CA, Ruggiero DA, Joh TH, Park DH, Reis DJ. Rostral ventro-
lateral medulla: Selective projections to the thoracic autonomic cell
column from the region containing C1 adrenaline neurons. J Comp
Neurol 228: 168-185, 1984.
312. Rubinsztajn R, Kumor M, Byskiniewicz K, Bielicki P, Chazan R.
Serum leptin concentration and sympathetic activation estimated on
the adrenaline and noradrenaline serum concentration in patients with
obstructive sleep apnea. Pol Arch Med Wewn 113: 544-551, 2005.
313. Sacramento JF, Chew DJ, Melo BF, Donega M, Dopson W, Guarino
MP, Robinson A, Prieto-Lloret J, Patel S, Holinski BJ, Ramnarain N,
Pikov V, Famm K, Conde SV. Bioelectronic modulation of carotid
sinus nerve activity in the rat: A potential therapeutic approach for
type 2 diabetes. Diabetologia 61: 700-710, 2018.
314. Sacramento JF, Ribeiro MJ, Rodrigues T, Guarino MP, Diogo LN,
Seica R, Monteiro EC, Matafome P, Conde SV. Insulin resistance
is associated with tissue-specific regulation of HIF-1alpha and
HIF-2alpha during mild chronic intermittent hypoxia. Respir Physiol
Neurobiol 228: 30-38, 2016.
315. Sacramento JF, Ribeiro MJ, Rodrigues T, Olea E, Melo BF, Guar-
ino MP, Fonseca-Pinto R, Ferreira CR, Coelho J, Obeso A, Seica R,
Volume 10, July 2020
Leptin in the Control of Breathing
Matafome P, Conde SV. Functional abolition of carotid body activ-
ity restores insulin action and glucose homeostasis in rats: Key roles
for visceral adipose tissue and the liver. Diabetologia 60: 158-168,
2017.
316. Sainz N, Barrenetxe J, Moreno-Aliaga MJ, Martinez JA. Leptin
resistance and diet-induced obesity: Central and peripheral actions of
leptin. Metab Clin Exp 64: 35-46, 2015.
317. Sakurai T. The neural circuit of orexin (hypocretin): Maintaining sleep
and wakefulness. Nat Rev Neurosci 8: 171-181, 2007.
318. Sakurai T. The role of orexin in motivated behaviours. Nat Rev Neu-
rosci 15: 719-731, 2014.
319. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka
H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR,
Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu
WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. Orex-
ins and orexin receptors: A family of hypothalamic neuropeptides and
G protein-coupled receptors that regulate feeding behavior. Cell 92: 1
page following 696, 1998.
320. Samuelsson AM, Clark J, Rudyk O, Shattock MJ, Bae SE, South
T, Pombo J, Redington K, Uppal E, Coen CW, Poston L, Taylor
PD. Experimental hyperleptinemia in neonatal rats leads to selective
leptin responsiveness, hypertension, and altered myocardial function.
Hypertension 62: 627-633, 2013.
321. Samuelsson AM, Morris A, Igosheva N, Kirk SL, Pombo JM, Coen
CW, Poston L, Taylor PD. Evidence for sympathetic origins of hyper-
tension in juvenile offspring of obese rats. Hypertension 55: 76-82,
2010.
322. Samuelsson AS, Mullier A, Maicas N, Oosterhuis NR, Eun Bae S,
Novoselova TV, Chan LF, Pombo JM, Taylor PD, Joles JA, Coen CW,
Balthasar N, Poston L. Central role for melanocortin-4 receptors in
offspring hypertension arising from maternal obesity. Proc Natl Acad
Sci U S A 113: 12298-12303, 2016.
323. Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A. Leptin
orally supplied to neonate rats is directly uptaken by the immature
stomach and may regulate short-term feeding. Endocrinology 146:
2575-2582, 2005.
324. Sandoval D. Bariatric surgeries: Beyond restriction and malabsorption.
Int J Obes 35 (Suppl 3): S45-S49, 2011.
325. Sanner BM, Kollhosser P, Buechner N, Zidek W, Tepel M. Influence
of treatment on leptin levels in patients with obstructive sleep apnoea.
Eur Respir J 23: 601-604, 2004.
326. Savino F, Nanni GE, Maccario S, Costamagna M, Oggero R, Silve-
stro L. Breast-fed infants have higher leptin values than formula-fed
infants in the first four months of life. J Pediatr Endocrinol Metab 17:
1527-1532, 2004.
327. Savransky V, Bevans S, Nanayakkara A, Li J, Smith PL, Torbenson
MS, Polotsky VY. Chronic intermittent hypoxia causes hepatitis in a
mouse model of diet-induced fatty liver. Am J Physiol Gastrointest
Liver Physiol 293: G871-G877, 2007.
328. Schafer H, Pauleit D, Sudhop T, Gouni-Berthold I, Ewig S, Berthold
HK. Body fat distribution, serum leptin, and cardiovascular risk factors
in men with obstructive sleep apnea. Chest 122: 829-839, 2002.
329. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel
serum protein similar to C1q, produced exclusively in adipocytes.
J Biol Chem 270: 26746-26749, 1995.
330. Schultz HD. Angiotensin and carotid body chemoreception in heart
failure. Curr Opin Pharmacol 11: 144-149, 2011.
331. Schulz C, Paulus K, Johren O, Lehnert H. Intranasal leptin reduces
appetite and induces weight loss in rats with diet-induced obesity
(DIO). Endocrinology 153: 143-153, 2012.
332. Schulz C, Paulus K, Lehnert H. Central nervous and metabolic effects
of intranasally applied leptin. Endocrinology 145: 2696-2701, 2004.
333. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central
nervous system control of food intake. Nature 404: 661-671, 2000.
334. Semenza GL, Prabhakar NR. Neural regulation of hypoxia-inducible
factors and redox state drives the pathogenesis of hypertension in a
rodent model of sleep apnea. J Appl Physiol 119: 1152-1156, 2015.
335. Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Con-
sidine RV, Dieguez C, Casanueva FF. Synthesis of leptin in human
placenta. Endocrinology 138: 4501-4504, 1997.
336. Servantes DM, Javaheri S, Kravchychyn ACP, Storti LJ, Almeida DR,
de Mello MT, Cintra FD, Tufik S, Bittencourt L. Effects of exercise
training and CPAP in patients with heart failure and OSA: A prelimi-
nary study. Chest 154: 808-817, 2018.
337. Sharma SK, Agrawal S, Damodaran D, Sreenivas V, Kadhiravan T,
Lakshmy R, Jagia P, Kumar A. CPAP for the metabolic syndrome in
patients with obstructive sleep apnea. N Engl J Med 365: 2277-2286,
2011.
338. Shechter A. Effects of continuous positive airway pressure on energy
balance regulation: A systematic review. Eur Respir J 48: 1640-1657,
2016.
339. Shimizu K, Chin K, Nakamura T, Masuzaki H, Ogawa Y, Hosokawa
R, Niimi A, Hattori N, Nohara R, Sasayama S, Nakao K, Mishima
M, Nakamura T, Ohi M. Plasma leptin levels and cardiac sympathetic
1081
Leptin in the Control of Breathing
function in patients with obstructive sleep apnoea-hypopnoea
syndrome. Thorax 57: 429-434, 2002.
340. Shin MK, Yao Q, Jun JC, Bevans-Fonti S, Yoo DY, Han W, Mesarwi
O, Richardson R, Fu YY, Pasricha PJ, Schwartz AR, Shirahata
M, Polotsky VY. Carotid body denervation prevents fasting hyper-
glycemia during chronic intermittent hypoxia. J Appl Physiol 117:
765-776, 2014.
341. Shinohara E, Kihara S, Yamashita S, Yamane M, Nishida M, Arai
T, Kotani K, Nakamura T, Takemura K, Matsuzawa Y. Visceral fat
accumulation as an important risk factor for obstructive sleep apnoea
syndrome in obese subjects. J Intern Med 241: 11-18, 1997.
342. Shirahata M, Tang WY, Shin MK, Polotsky VY. Is the carotid body a
metabolic monitor? Adv Exp Med Biol 860: 153-159, 2015.
343. Skurk T, van Harmelen V, Blum WF, Hauner H. Angiotensin
II promotes leptin production in cultured human fat cells by an
ERK1/2-dependent pathway. Obes Res 13: 969-973, 2005.
344. Smith HR, Leibold NK, Rappoport DA, Ginapp CM, Purnell BS,
Bode NM, Alberico SL, Kim YC, Audero E, Gross CT, Buchanan
GF. Dorsal raphe serotonin neurons mediate CO2 -induced arousal
from sleep. J Neurosci Off J Soc Neurosci 38: 1915-1925, 2018.
345. Smith JC, Abdala AP, Koizumi H, Rybak IA, Paton JF. Spatial and
functional architecture of the mammalian brain stem respiratory
network: A hierarchy of three oscillatory mechanisms. J Neurophysiol
98: 3370-3387, 2007.
346. Smith JC, Ellenberger HH, Ballanyi K, Richter DW, Feldman JL. Pre-
Botzinger complex: A brainstem region that may generate respiratory
rhythm in mammals. Science 254: 726-729, 1991.
347. Smith-Kirwin SM, O’Connor DM, De Johnston J, Lancey ED, Hassink
SG, Funanage VL. Leptin expression in human mammary epithelial
cells and breast milk. J Clin Endocrinol Metab 83: 1810-1813, 1998.
348. Sobhani I, Bado A, Vissuzaine C, Buyse M, Kermorgant S, Laigneau
JP, Attoub S, Lehy T, Henin D, Mignon M, Lewin MJ. Leptin secretion
and leptin receptor in the human stomach. Gut 47: 178-183, 2000.
349. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural
mechanisms in obstructive sleep apnea. J Clin Invest 96: 1897-1904,
1995.
350. Speretta GF, Lemes EV, Vendramini RC, Menani JV, Zoccal DB,
Colombari E, Colombari DSA, Bassi M. High-fat diet increases
respiratory frequency and abdominal expiratory motor activity during
hypercapnia. Respir Physiol Neurobiol 258: 32-39, 2018.
351. Speretta GF, Silva AA, Vendramini RC, Zanesco A, Delbin MA,
Menani JV, Bassi M, Colombari E, Colombari DS. Resistance training
prevents the cardiovascular changes caused by high-fat diet. Life Sci
146: 154-162, 2016.
352. Stasche N. Selective indication for positive airway pressure (PAP)
in sleep-related breathing disorders with obstruction. GMS Curr Top
Otorhinolaryngol Head Neck Surg 5: Doc06, 2006.
353. Stefater MA, Perez-Tilve D, Chambers AP, Wilson-Perez HE,
Sandoval DA, Berger J, Toure M, Tschop M, Woods SC, Seeley RJ.
Sleeve gastrectomy induces loss of weight and fat mass in obese
rats, but does not affect leptin sensitivity. Gastroenterology 138:
2426-2436, 2436 e2421-2423, 2010.
354. Steinbrekera B, Roghair R. Modeling the impact of growth and leptin
deficits on the neuronal regulation of blood pressure. J Endocrinol 231:
R47-R60, 2016.
355. Stunden CE, Filosa JA, Garcia AJ, Dean JB, Putnam RW. Devel-
opment of in vivo ventilatory and single chemosensitive neuron
responses to hypercapnia in rats. Respir Physiol 127: 135-155, 2001.
356. Sugerman HJ, Baron PL, Fairman RP, Evans CR, Vetrovec GW.
Hemodynamic dysfunction in obesity hypoventilation syndrome and
the effects of treatment with surgically induced weight loss. Ann Surg
207: 604-613, 1988.
357. Sugerman HJ, Fairman RP, Sood RK, Engle K, Wolfe L, Kellum JM.
Long-term effects of gastric surgery for treating respiratory insuffi-
ciency of obesity. Am J Clin Nutr 55: 597S-601S, 1992.
358. Sullivan CE, Berthon-Jones M, Issa FG. Nocturnal nasal-airway pres-
sure for sleep apnea. N Engl J Med 309: 112, 1983.
359. Summer R, Walsh K, Medoff BD. Obesity and pulmonary arte-
rial hypertension: Is adiponectin the molecular link between these
conditions? Pulm Circ 1: 440-447, 2011.
360. Takemura Y, Ouchi N, Shibata R, Aprahamian T, Kirber MT, Summer
RS, Kihara S, Walsh K. Adiponectin modulates inflammatory reac-
tions via calreticulin receptor-dependent clearance of early apoptotic
bodies. J Clin Invest 117: 375-386, 2007.
361. Tan W, Janczewski WA, Yang P, Shao XM, Callaway EM, Feldman
JL. Silencing preBotzinger complex somatostatin-expressing neurons
induces persistent apnea in awake rat. Nat Neurosci 11: 538-540, 2008.
362. Tankersley C, Kleeberger S, Russ B, Schwartz A, Smith P. Modified
control of breathing in genetically obese (ob/ob) mice. J Appl Physiol
81: 716-723, 1996.
363. Tankersley CG, O’Donnell C, Daood MJ, Watchko JF, Mitzner W,
Schwartz A, Smith P. Leptin attenuates respiratory complications
associated with the obese phenotype. J Appl Physiol 85: 2261-2269,
1998.
1082
Comprehensive Physiology
364. Taylor PD, Samuelsson AM, Poston L. Maternal obesity and the devel-
opmental programming of hypertension: A role for leptin. Acta Physiol
210: 508-523, 2014.
365. Thorp AA, Schlaich MP. Relevance of sympathetic nervous system
activation in obesity and metabolic syndrome. J Diabetes Res 2015:
341583, 2015.
366. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in
obesity. Physiol Rev 93: 1-21, 2013.
367. Trayhurn P, Wood IS. Adipokines: Inflammation and the pleiotropic
role of white adipose tissue. Br J Nutr 92: 347-355, 2004.
368. Trombetta IC, Batalha LT, Rondon MU, Laterza MC, Kuniyoshi FH,
Gowdak MM, Barretto AC, Halpern A, Villares SM, Negrao CE.
Weight loss improves neurovascular and muscle metaboreflex control
in obesity. Am J Phys Heart Circ Phys 285: H974-H982, 2003.
369. Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T,
Kadowaki T. Peroxisome proliferator-activated receptor (PPAR)alpha
activation increases adiponectin receptors and reduces obesity-related
inflammation in adipose tissue: Comparison of activation of PPARal-
pha, PPARgamma, and their combination. Diabetes 54: 3358-3370,
2005.
370. Ueno LM, Drager LF, Rodrigues AC, Rondon MU, Braga AM, Math-
ias W Jr, Krieger EM, Barretto AC, Middlekauff HR, Lorenzi-Filho G,
Negrao CE. Effects of exercise training in patients with chronic heart
failure and sleep apnea. Sleep 32: 637-647, 2009.
371. Valuniene M, Verkauskiene R, Boguszewski M, Dahlgren J, Lasiene
D, Lasas L, Wikland KA. Leptin levels at birth and in early postnatal
life in small- and appropriate-for-gestational-age infants. Medicina 43:
784-791, 2007.
372. Van De Wielle R, Michels N. Longitudinal associations of leptin and
adiponectin with heart rate variability in children. Front Physiol 8: 498,
2017.
373. Van Eyck A, Van Hoorenbeeck K, De Winter BY, Van Gaal L, De
Backer W, Verhulst SL. Sleep disordered breathing and autonomic
function in overweight and obese children and adolescents. ERJ Open
Res 2, 2016.
374. Varela L, Horvath TL. Leptin and insulin pathways in POMC and
AgRP neurons that modulate energy balance and glucose homeostasis.
EMBO Rep 13: 1079-1086, 2012.
375. Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A,
Lin HM, Kales A, Chrousos GP. Sleep apnea and daytime sleepiness
and fatigue: Relation to visceral obesity, insulin resistance, and hyper-
cytokinemia. J Clin Endocrinol Metab 85: 1151-1158, 2000.
376. Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin
KM, Vatter P, Gierschik P, Moepps B, Fischer-Posovszky P. Biolog-
ically inactive leptin and early-onset extreme obesity. N Engl J Med
372: 48-54, 2015.
377. Wang B, Wood IS, Trayhurn P. Hypoxia induces leptin gene expres-
sion and secretion in human preadipocytes: Differential effects of
hypoxia on adipokine expression by preadipocytes. J Endocrinol 198:
127-134, 2008.
378. Wang T, Hartzell DL, Rose BS, Flatt WP, Hulsey MG, Menon NK,
Makula RA, Baile CA. Metabolic responses to intracerebroventricular
leptin and restricted feeding. Physiol Behav 65: 839-848, 1999.
379. Wang ZV, Scherer PE. Adiponectin, the past two decades. J Mol Cell
Biol 8: 93-100, 2016.
380. Wauman J, Zabeau L, Tavernier J. The leptin receptor complex: Heav-
ier than expected? Front Endocrinol 8: 30, 2017.
381. Wehrwein EA, Basu R, Basu A, Curry TB, Rizza RA, Joyner
MJ. Hyperoxia blunts counterregulation during hypoglycaemia
in humans: Possible role for the carotid bodies? J Physiol 588:
4593-4601, 2010.
382. Weiszenstein M, Shimoda LA, Koc M, Seda O, Polak J. Inhibition of
lipolysis ameliorates diabetic phenotype in a mouse model of obstruc-
tive sleep apnea. Am J Respir Cell Mol Biol 55: 299-307, 2016.
383. Weltman A, Pritzlaff CJ, Wideman L, Considine RV, Fryburg DA,
Gutgesell ME, Hartman ML, Veldhuis JD. Intensity of acute exercise
does not affect serum leptin concentrations in young men. Med Sci
Sports Exerc 32: 1556-1561, 2000.
384. Wewege M, van den Berg R, Ward RE, Keech A. The effects of high-
intensity interval training vs. moderate-intensity continuous training
on body composition in overweight and obese adults: A systematic
review and meta-analysis. Obes Rev 18: 635-646, 2017.
385. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB.
Adiponectin—a key adipokine in the metabolic syndrome. Diabetes
Obes Metab 8: 264-280, 2006.
386. WHO. World Health Organization Obesity and Overweight. 2018.
https://www.who.int/news-room/fact-sheets/detail/obesity-and-
overweight (accessed 31 Jan 2020).
387. Wolf J, Hering D, Narkiewicz K. Non-dipping pattern of hypertension
and obstructive sleep apnea syndrome. Hypertens Res 33: 867-871,
2010.
388. Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T. Adiponectin
receptors: A review of their structure, function and how they work.
Best Pract Res Clin Endocrinol Metab 28: 15-23, 2014.
Volume 10, July 2020
Comprehensive Physiology
389. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S,
Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki
T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi
Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T,
Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate
antidiabetic metabolic effects. Nature 423: 762-769, 2003.
390. Yang Y, Yang S, Jiao X, Li J, Wu H, Sun H, Yang Y, Zhang M, Wei
Y, Qin Y. Targeted sequencing analysis of the adiponectin gene iden-
tifies variants associated with obstructive sleep apnoea in Chinese Han
population. Medicine 98: e15219, 2019.
391. Yao Q, Pho H, Kirkness J, Ladenheim EE, Bi S, Moran TH, Fuller DD,
Schwartz AR, Polotsky VY. Localizing effects of leptin on upper air-
way and respiratory control during sleep. Sleep 39: 1097-1106, 2016.
392. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin
resistance. Int J Obes 33: 54-66, 2009.
393. Ye J, Gao Z, Yin J, He Q. Hypoxia is a potential risk factor for chronic
inflammation and adiponectin reduction in adipose tissue of ob/ob and
dietary obese mice. Am J Phys Endocrinol Metab 293: E1118-E1128,
2007.
394. Yeh ER, Erokwu B, LaManna JC, Haxhiu MA. The paraventricular
nucleus of the hypothalamus influences respiratory timing and activity
in the rat. Neurosci Lett 232: 63-66, 1997.
395. Yilmaz MI, Sonmez A, Caglar K, Gok DE, Eyileten T, Yenicesu
M, Acikel C, Bingol N, Kilic S, Oguz Y, Vural A. Peroxisome
proliferator-activated receptor gamma (PPAR-gamma) agonist
increases plasma adiponectin levels in type 2 diabetic patients with
proteinuria. Endocrine 25: 207-214, 2004.
396. Yoshikawa M, Yamauchi M, Fujita Y, Koyama N, Fukuoka A, Tamaki
S, Yamamoto Y, Tomoda K, Kimura H. The impact of obstructive
sleep apnea and nasal CPAP on circulating adiponectin levels. Lung
192: 289-295, 2014.
397. Yosunkaya S, Okur HK, Can U, Zamani A, Kutlu R. Impact of con-
tinuous positive airway pressure treatment on leptin levels in patients
with obstructive sleep apnea syndrome. Metab Syndr Relat Disord 13:
272-277, 2015.
Volume 10, July 2020
Leptin in the Control of Breathing
398. Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto
FJ, Stubbs R, Hla KM. Sleep disordered breathing and mortality:
Eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 31:
1071-1078, 2008.
399. Yuan F, Wang H, Feng J, Wei Z, Yu H, Zhang X, Zhang Y, Wang S.
Leptin signaling in the carotid body regulates a hypoxic ventilatory
response through altering TASK channel expression. Front Physiol 9:
249, 2018.
400. Zhang W, Fukuda Y, Kuwaki T. Respiratory and cardiovascular
actions of orexin-A in mice. Neurosci Lett 385: 131-136, 2005.
401. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.
Positional cloning of the mouse obese gene and its human homologue.
Nature 372: 425-432, 1994.
402. Zhou SY, Gilbey MP. Respiratory-related activity of lower thoracic
and upper lumbar sympathetic preganglionic neurones in the rat.
J Physiol 451: 631-642, 1992.
403. Zoccal DB, Bonagamba LG, Paton JF, Machado BH. Sympathetic-
mediated hypertension of awake juvenile rats submitted to chronic
intermittent hypoxia is not linked to baroreflex dysfunction. Exp Phys-
iol 94: 972-983, 2009.
404. Zoccal DB, Furuya WI, Bassi M, Colombari DS, Colombari E. The
nucleus of the solitary tract and the coordination of respiratory and
sympathetic activities. Front Physiol 5: 238, 2014.
405. Zoccal DB, Silva JN, Barnett WH, Lemes EV, Falquetto B, Colom-
bari E, Molkov YI, Moreira TS, Takakura AC. Interaction between the
retrotrapezoid nucleus and the parafacial respiratory group to regulate
active expiration and sympathetic activity in rats. Am J Physiol Lung
Cell Mol Physiol 315: L891-L909, 2018.
406. Zoccal DB, Simms AE, Bonagamba LG, Braga VA, Pickering AE,
Paton JF, Machado BH. Increased sympathetic outflow in juvenile rats
submitted to chronic intermittent hypoxia correlates with enhanced
expiratory activity. J Physiol 586: 3253-3265, 2008.
1083