Leptin and the Blood-Brain Barrier:

Curiosities and Controversies

William A. Banks*1,2

ABSTRACT
Leptin for over 25 years has been a central theme in the study of appetite, obesity, and starvation.
As the major site of leptin production is peripheral, and the site of action of greatest interest is the
hypothalamus, how leptin accesses the central nervous system (CNS) and crosses the blood-brain
barrier (BBB) has been of great interest. We review here the ongoing research that addresses
fundamental questions such as the sites of leptin resistances in obesity and other conditions, the
causes of resistances and their relations to one another, the three barrier sites of entry into the
CNS, why recent studies using suprapharmacological doses cannot address these questions but
give insight into nonsaturable entry of leptin into the CNS, and how that might be useful in using
leptin therapeutically. The current status of the controversy of whether the short form of the leptin
receptor acts as the BBB leptin transporter and how obesity may transform leptin transport is
reviewed. Review of these and other topics summarizes in a new appreciation of what leptin
may have actually evolved to do and what physiological role leptin resistance may play. © 2021
American Physiological Society. Compr Physiol 11:2351-2369, 2021.

Didactic Synopsis • Leptin resistance occurs in conditions other than obesity,

Major teaching points
• Leptin transport is by a saturable system located at the
vascular blood-brain barrier, choroid plexus, and tanycytic
barrier.
• Leptin deficiency results in extreme obesity; typical obe-
sity in humans is characterized by leptin resistance.
• Resistance occurs when the target tissue is unresponsive
or partially responsive to the effector hormone. Resistance
is characterized by an elevation in the effector hormone
with normal or subnormal target tissue activity.
• Best evidence is that in diet-induced obesity (DIO) in
humans and animals, leptin resistance at the arcuate
nucleus receptor drives obesity and the saturable nature
of the BBB impedes the ability of rising blood levels of
leptin to address receptor resistance.
• Modeling of these dual resistances in DIO shows that
together they cause a hyperbolic increase in blood levels
of leptin and hence the levels of adiposity needed to
produce those levels.
• Modeling shows that resistance at the arcuate nucleus
occurs first, but that the greatest percent of resistance is at
the BBB.
• The leptin transporter and receptor are modifiable by
events and substances that can either increase or inhibit
transport capacity. Modifiers include a high-fat diet,
triglycerides, and leptin itself.
such as pregnancy and seasonal shifts, and may involve
resistance only at the BBB or the arcuate nucleus. These
reversible conditions demonstrate a physiological role for
leptin resistance.
• Suprapharmacologic studies cannot address questions
related to saturable transport as they produce blood levels
10 to 30 times greater than that needed to totally saturate
the BBB transporter but do show that blood leptin can
enter the CNS through the extracellular pathways.
• Leptin has effects other than those related to body weight,
and these remain understudied.
Introduction
The discovery of leptin embodied new ways of thinking
in several fields of study. In most cases, these were shifts
in thinking that had been simmering for a long time, but
it was leptin that finally crystallized the thinking for many
of us. Obesity, considered by many health care workers at
*Correspondence to wabanks1@uw.edu
1 Geriatric
Research Education and Clinical Center, Veterans Affairs
Puget Sound Health Care System, Seattle, Washington, USA
2 Division
of Gerontology and Geriatric Medicine, Department of
Medicine, University of Washington School of Medicine, Seattle,
Washington, USA
Published online, October 2021 (comprehensivephysiology.com)
DOI:10.1002/cphy.c200017
Copyright © American Physiological Society.

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Leptin and the BBB
the time to be evidence of a weakness in resolve, was given
a biological basis. Furthermore, that biology was based
in endocrinology and neuroscience. It established fat as a
hormonally active, endocrine tissue and not just a depot for
calories. It was the first regulatory protein with actions in the
central nervous system (CNS) after peripheral administration
for which it was widely assumed that it must cross the blood-
brain barrier (BBB), as opposed to the assumption that it did
not. It was the harbinger of the discovery of a series of other
appetite-related and endocrine-like substances, derived from
the periphery and acting in the brain, such as ghrelin, and
heralded a reexamination of older ones, such as insulin.
Early discoveries regarding leptin’s actions were made
rapidly and the findings dramatic. Very soon after the gene
and protein sequencing of leptin, the protein itself became
widely available as well as other tools, such as a radioim-
munoassay for its measurement. These tools greatly increased
the number of laboratories that could investigate leptin.
Many labs under many physiological and disease conditions
showed a strong statistical relation between serum leptin
levels and measures of adiposity (35). An absence of its
biological activity either because of a lack of the protein
or a lack of the functional receptor resulted in profound
obesity (33, 75). For example, the original publication by
Ingalls et al. (75) describing the ob/ob mouse showed that at
10 months of age the mice lacking leptin weighed three times
more than the mice that expressed leptin. Essentially, all of
this excess body weight is attributable to fat; in other words,
while normal mice might be about 80% nonadipose tissue,
those lacking leptin were only about 25% nonadipose tissue.
Leptin replacement in the ob/ob mouse that lacks leptin
induced profound weight loss by both decreasing appetite
and increasing caloric expenditure.
These early discoveries led to the hope that leptin would
be a dramatic treatment for human obesity. However, obesity
in humans is associated with high levels of leptin, not a
deficiency (32, 35). Figure 1 shows the average body mass
index (BMI), which we assume in this article as a measure
of adiposity, paired with its average blood leptin levels from
six classic studies that evaluated cerebrospinal fluid (CSF)
and blood leptin relationships (4, 32, 85, 100, 143, 163).
They show not a linear but an asymptotic rise in serum
blood levels of leptin as a function of BMI. But the effects
of leptin treatment in obese humans have been interpreted
by most as disappointing, even ineffectual, compared to the
dramatic effects in leptin deficiency. This has led to long
discourses on the basis of leptin resistance and whether it can
be overcome.
Leptin’s site of action for appetite regulation is primarily
in the hypothalamus at the arcuate nucleus (45, 57, 144),
but its site of secretion is primarily from fat (67, 171).
Between blood (a proxy for the site of production) and
brain interstitial fluid (the milieu for the receptors) lies the
BBB. Of the various possible causes of leptin resistance
(molecular alterations, altered clearance, blocking antibod-
ies, etc.), all were quickly eliminated but two: the BBB and
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BMI vs Serum leptin
50
Serum leptin (ng/mL)
40
30
20
10
0
0 10 20 30 40
BMI
Figure 1 Relation of mean levels of serum leptin and BMI from six
classic studies. Data is fitted to an exponential growth curve: Serum
leptin = Y0k(BMI) , where Y = 0.0195 and k = 0.238 (n = 10, r2 = 0.847).
Reused, with permission, from Arnulf I, et al., 2006 (4); Caro JF, et al.,
1996 (32); Koistinen HA, et al., 1998 (85); Mantzoros C, et al., 1997
(100); Schwartz MW, et al., 1996 (143); Wiedenhoft A, et al., 1999
(163).
receptor/postreceptor deficits (32, 66, 157). A quarter century
of research has resolved many old issues but raised new ones.
Important, fresh discoveries have sometimes added to the
confusion when they might have resolved issues, because
they were neglectful of a comprehensive physiology. This
article discusses the outstanding controversies in the field,
primarily those related to the lingering questions of why
obese humans are resistant to treatment with leptin, where
that resistance resides, whether leptin resistance should be
viewed as physiology or disease, and what the roles of leptin
really are.
Early Evidence for Leptin Resistance
The introduction of the concept of hormonal resistance is
attributed to Albright et al. (2). They described a condition
that seemed to be caused by an absence of parathyroid
hormone but in which levels of that hormone were actually
elevated. A condition in which a target tissue is unresponsive
or underresponsive despite adequate levels of the effector
hormone is termed resistance.
To understand hormonal resistance, one must first under-
stand the concept of a negative feedback loop as it applies to
physiology. Negative feedback loops are found throughout
nature, engineering, computer technology, and other fields
where self-regulating systems are important. As applied to
physiology, a classic negative feedback loop in its simplest
form has four components that have a specific relation to one
another: (i) an effector tissue that secretes (ii) a stimulus or
effector hormone, (iii) an end organ or target tissue on which
the effector hormone acts, and (iv) the controlled substance
that is secreted by the target tissue in response to the effector
hormone AND that acts on the effector tissue to inhibit the
release of the effector hormone (Figure 2). Although cause
and effect is not unidirectional (that is, which tissue is labeled
Volume 11, October 2021
Comprehensive Physiology Leptin and the BBB

(A) (B) Pituitary

TRH
Effector hormone
TSH

Controlled substance
Effector Thyroid hormones Hypothalamus
Target tissue Thyroid
tissue

Peripheral tissues

(C) PTH (D)

Insulin

Calcium Glucose Pancreas

Muscle, fat,
Parathyroid liver
GI tract and
kidney

(E) (F) CSF

Leptin Serum BBB leptin
leptin (–)

CSF leptin
(–)

Dec caloric use

Feeding
Leptin secretion Serum leptin
Feeding
Hypothalamus Adipose tissue

Caloric expenditure Excess calories (+)

Brain
Fat

Figure 2 Classic negative feedback loops. (A) The classic negative feedback loop is illustrated. Effector hormone
released from the effector tissue stimulates the target tissue to secrete the controlled substance. The controlled substance
suppresses release of the effector hormone. Thus, the system is self-regulated at a steady-state value. (B) The negative
feedback controlling thyroid hormone levels. (C) The negative feedback loop controlling calcium levels. (D) The negative
feedback loop controlling glucose levels. (E) The leptin-adipose tissue feedback loop as an adipostat. (F) The leptin
negative feedback loop with two points of resistance in series: the BBB and the arcuate nucleus.

as effector and which target tissue is usually arbitrary as
is which is labeled effector hormone and which controlled
substance), traditionally negative feedback loops are drawn
with reference to the stimulating substance being the effector
hormone.
There are many classic examples of effector hormone/
controlled substance pairings: thyroid-stimulating hormone/
thyroid hormones; parathyroid hormone/calcium; and
insulin/glucose. Interestingly, none of these examples repli-
cate the classic negative feedback loop but are some variant
of it. The thyroid axis (Figure 2B) has not two but three tis-
sues and three secreted substances (hypothalamus secreting
thyroid-releasing hormone that stimulates the pituitary to
secrete thyroid-stimulating hormone that stimulates the thy-
roid to secrete primarily thyroxine that feeds back primarily
at the pituitary to inhibit TSH release). The target tissues
for parathyroid hormone do not “secrete” calcium, but PTH
acts at multiple tissues and by a variety of mechanisms to
elevate calcium levels (Figure 2C). Likewise, insulin does
not induce glucose secretion, but glucose uptake by the target
tissues, resulting in glucose lowering (Figure 2D). To make
the insulin/glucose negative feedback loop appear more like
the classic model, glucose would need to be considered the
effector “hormone,” and insulin the controlled substance.
Negative feedback loops can become quite complex with
internal positive feedback loops or external modulators being
especially common. Rasmussen (128) uses glyconeogen-
esis and blood clotting as examples of complex negative
feedback loops that are generally inactive at physiological
levels, but when stimulated react dramatically. In other
words, negative or positive subfeedback loops or other mod-
ulating factors can make a system active under one set of
physiological conditions but not others.
As originally envisioned by the early work on leptin with
ob/ob mice, the negative feedback loop would pair leptin
levels and feeding behavior/thermogenesis with adipose
tissue as the effector tissue and brain as the target tissue
(Figure 2E). Already, the leptin negative feedback loop is not
classic, with behaviors and physiological responses taking the
place of a blood-borne substance. Additionally, the negative
feedback loop can be drawn in different ways, for example,
with brain as the effector tissue or with starvation rather than

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Leptin and the BBB
feeding as the effector behavior. Given that cause and effect
in loop systems are not assignable, drawing the negative
feedback loop for leptin in different ways may at first seem
akin to semantics. But as discussed later, the drawing reflects
whether one sees leptin as having evolved to inform the brain
about caloric excesses (an adipostat) versus caloric deficits
(a signal of starvation).
As originally defined by the work of Albright et al., resis-
tance is caused by some defect in the end-organ receptor
(158). It was previously known that low calcium levels in
blood could occur because of an absence of parathyroid
hormone, a condition called hypoparathyroidism. Albright
et al. discovered a condition in which calcium levels were
low despite high levels of parathyroid hormone, a condition
termed pseudohypoparathyroidism. Since then, the con-
cept of hormonal resistance has been broadened to include
any cause resulting in an impaired end-organ response.
For example, excess binding of the hormone by blocking
antibodies or increased or abnormal binding proteins is
also termed resistance (130, 165). Thus, resistance is func-
tionally defined as an elevation in the effector hormone in
the presence of a subresponsive target tissue, and although
a defect at the target tissue’s receptor is the most com-
mon example given as to its cause, there can be pre- and
postreceptor causes as well.
In most cases, resistance to the effector hormone is only
partial; that is, the end-organ receptor still responds to
some degree to the effector hormone. Partial resistance can
often be overcome by an increased secretion of the effector
hormone, resulting in the controlled substance remaining
at a normal level. For example, if resistance to insulin’s
glucose lowering effect is partial, insulin levels rise until
euglycemia is reestablished (hyperinsulinemic euglycemia).
As a first estimate, an end-organ resistance of 50% can
be overcome by a doubling in effector hormone level. At
some point, this compensation becomes inadequate, either
because of effector tissue exhaustion or because of high
levels of resistance. Thus, insulin resistance can result
either in hyperinsulinemic euglycemia or diabetes mellitus
(22). Often, these compensations result in the hypertrophy
of the effector tissue. For example, an enlarged thyroid
is a classic finding in some types of thyroid resistance
syndromes (130).
The negative feedback loop with partial resistance is useful
to explain some aspects of the relation between leptin and
body weight regulation. Obesity can be viewed as hyper-
trophy of the effector tissue (adipose tissue) in the face of
target tissue resistance (the brain). Partial resistance can be
overcome by elevating levels of the effector hormone (leptin).
Because the amount of leptin secreted per gram of adipose
tissue is rather fixed, the only way to increase leptin levels
is for hypertrophy of the effector tissue. Thus, the degree of
target tissue resistance is reflected not only in the level of
leptin but also in the level of adiposity.
An important question is whether leptin resistance in diet-
induced obesity (DIO) remains partial or is absolute? That
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Comprehensive Physiology
is, could further increases in leptin, perhaps those beyond
what the body can produce, reduce body weight. That leptin
resistance is not absolute is supported by work by Ottaway
et al. (115), which demonstrated that a powerful leptin
antagonist could induce further body weight gain in DIO
mice. This suggests that endogenous leptin in DIO-induced
leptin resistance is still exerting some effect on appetite
suppression and if removed, results in further weight gain.
An interesting question is what would happen if adipose
tissue could more widely modulate its leptin production
by altering efficiency, that is by increasing or decreasing
the amount of leptin secreted per gram of fat tissue? In the
study of Begriche et al. (25), the adipose tissue of mice
heterozygous for leptin loss (ob/+) produced about half the
amount of leptin per gram of fat as wild-type mice. Leptin
levels were similar between the two groups on standard
chow with the slightly higher fat mass of the heterozygotes
being nonsignificant. On a high-calorie diet, leptin levels
increased in both groups to about the same level and were
not statistically different between the two groups. The het-
erozygotes, however, gained approximately twice as much
weight. Viewed from the perspective of the negative feedback
loop, one would conclude that the high-fat diet induced a
similar level of leptin resistance (because leptin levels were
similar) and that increasing adiposity is simply the mecha-
nism needed to raise leptin to the level needed to overcome
resistance.
Another interesting question is what would happen if leptin
sensitivity were preserved despite being placed on a high-
calorie diet? A paper by Zhao et al. (172) partially addresses
this issue. Although designed to study another aspect of
leptin and resistance, one consistent finding was that all of
their experimental groups had lower leptin levels at baseline.
According to the negative feedback loop model, a lower
leptin level at baseline equates to increased leptin sensitivity.
Accordingly, these mice maintained lower leptin levels,
gained less total body weight, and gained less fat mass on a
high-calorie diet than did the wild type (WT) and were more
sensitive to exogenous leptin.
Although the negative feedback model works well in leptin
deficiency, it works increasing less well as animals that can
normally secrete leptin become obese (Figure 2F). In either
leptin deficient or resistant animals, the brain does not per-
ceive the hormonal signal that reduces feeding and increases
caloric expenditure, and so animals become obese. When
leptin signaling is restored in leptin deficiency, hunger is
abated, and caloric expenditure is increased, reducing excess
calories, fat mass, and leptin levels. Based on the work with
leptin-deficient rodents and humans, the negative feedback
loop between the brain and adipose tissue as mediated by
leptin is a potent one. But based on the work with rodents
and humans that can secrete leptin normally, the negative
feedback loop is far from robust. Interestingly, normal body
weight animals seem to be much more responsive to leptin
loss as induced by administration of a leptin antagonist,
quickly increasing food intake and weight gain, than they
Volume 11, October 2021
Comprehensive Physiology Leptin and the BBB

are responsive to administration of additional leptin, often (A) 400

showing minimal reductions in eating and weight (83, 115).
This dichotomous potency of leptin, very effective in defi- 300

CSF (pg/mL)
ciency and weakly so in resistance, is one of the mysteries
Obese Male Boys
of how leptin works and raises questions about what its true 200
Lean Female Girls
function is. It suggests that leptin has a complex negative
feedback loop, but unlike those examples given by Ras- 100 A Nervosa No-narcolepsy
mussen, the activity occurs at low levels and is increasingly No A Nervosa Narcolepsy
deactivated as levels of leptin and obesity increase. Before 0
0 10 20 30 40 50
discussing what this may imply about the functions of leptin,
Vascular leptin (ng/mL)
we first discuss the potential of dual sites mediating leptin 3.74
resistance and why that duality can be so powerful in inducing (B)

(CSF/Serum ratio) x 100

a resistance. 10

Relation Between CNS and Blood Levels
of Leptin
Early studies indicated that leptin resistance in diet-induced
obese mice occurred at two separate sites (66, 157). Animals
went through a phase when they were responsive to leptin
given directly into the brain, but not to leptin given peripher-
ally. Thus, there was at lower levels of obesity a resistance
to peripherally administered leptin (termed peripheral resis-
tance), but not to leptin given into the CNS (termed central
resistance). It was proposed that peripheral resistance was
caused by a defect in the ability of leptin to cross the BBB.
One way to evaluate this possibility is to consider the relation
between leptin levels in the CNS and blood.
Numerous studies have measured CSF and blood levels
of leptin and reported their relation. Figure 3A shows the
mean values reported from six studies in humans (4, 32,
85, 100, 143, 163) and includes populations with anorexia
nervosa and obesity, males and females, and adults and
children. Blood levels of leptin in these six studies, totaling
more than 200 subjects, seldom exceeded 50 ng/mL; only
two patients are reported to have levels of about 80 ng/mL.
CSF leptin levels seldom exceeded 350 pg/mL. In these six
studies, the means for blood leptin levels range from 1.75
to 40.2 ng/mL, and the means for CSF leptin levels range
from 98 to 360 pg/mL. Thus, while the increase from lowest
to highest is over 20-fold for serum, it is less than fourfold
for CSF. Both CSF and serum leptin levels correlated with
measures of obesity, including BMI. For all six studies
combined, there was a nonlinear relation for both CSF versus
blood levels of leptin (Figure 3A) and for the CSF/blood
ratio versus blood leptin levels (Figure 3B). These nonlinear
relations suggested that leptin crossed the BBB by a saturable
mechanism.
Although CSF leptin levels in the six studies were regressed
against log values of serum leptin, this data actually fits the
hyperbolic model better (Figure 3A) with an r2 of 0.514
(hyperbola) versus 0.268 (logarithmic). A hyperbolic model
is consistent with leptin transport being saturable and can
be used to calculate at which point leptin resistance occurs.
There are two striking findings regarding this hyperbolic
6
4
2
0.5
0
0 10 20 30 40 50
Leptin (vasc)
Figure 3 Blood and CSF leptin levels from six classic leptin studies.
(A) Relation of mean leptin levels for CSF vs. blood fitted to a one-
site hyperbolic model. These six studies evaluated levels in several
categories besides obese and lean, including children, anorexia ner-
vosa, and narcolepsy. The Kd of the hyperbola (the x value at which
50% of the maximum Y value is achieved) is shown by the vertical
dashed line and is 3.74 ng/mL. (B) The CSF/serum ratios from these
six studies plotted against their respective values for blood leptin lev-
els. The horizontal dashed line is at the ratio of 0.005 (or 0.5%), the
approximate brain/serum ratio for albumin in young healthy individu-
als. Reused, with permission, from Arnulf I, et al., 2006 (4); Caro JF,
et al., 1996 (32); Koistinen HA, et al., 1998 (85); Mantzoros C, et al.,
1997 (100); Schwartz MW, et al., 1996 (143); Wiedenhoft A, et al.,
1999 (163).
curve. The first is that the Kd, the blood value at which
CSF levels have reached 50% of their maximum value, is
3.74 ng/mL (see dashed vertical line in Figure 3A). This value
is well below the typical blood level for nonobese individ-
uals; in fact, it is below the mean of most groups. That is,
leptin resistance at the BBB is significant even at low blood
levels of leptin. The second is that there is no point at which
the relation of CSF levels to blood is truly linear nor when
CSF/serum ratios to blood are flat. In other words, BBB
resistance is demonstrable to some degree throughout the
range of leptin blood levels. How quickly the hyperbolic
relation attenuates increases in CSF in response to rising
blood levels/obesity can be illustrated with these calculations
made from the hyperbolic curve shown in Figure 3A: With
a doubling of leptin blood levels from 2 to 4 ng/mL, CSF
levels increase by 49%, but with the doubling from 20 to
40 ng/mL, CSF levels increase by only 8%. At leptin blood
levels of 50 ng/mL, CSF levels are at 93% of their theoretical
maximum value.

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Leptin and the BBB
The CSF/serum ratios show even more strikingly the
effects of a saturable transport system (Figure 3B). If the
movement of leptin across the BBB were nonsaturable, then
the CSF/serum ratio would not change but be a constant.
The ratios for the data in Figure 3 show a dramatic change
from relatively high CSF/serum ratios at low leptin levels
to very low values with increasing blood leptin levels. In
their subjects with very low leptin levels, Suzuki et al. (149)
and Koistinen et al. (85) each report CSF leptin values that
are greater than 20% of the matched blood leptin values,
and Wiedenhoft et al. (163) report a single value in excess
of 30%. However, as Figure 3B shows, CSF/serum ratios
of leptin quickly decline as serum levels of leptin increase.
Figure 3B shows a horizontal dashed line for the CSF/blood
value of 0.5% (154). This is a typical value for the CSF/serum
level for the vascular marker albumin, a molecule that is not
transported into the CNS but enters through the extracellular
pathways and with CSF production (7, 27). As such, the
CSF/serum ratio can be used as a marker of vascular space
or of BBB leakiness (55, 80, 159). Of the classic vascular
markers used in BBB studies, albumin is the most appropriate
as its radius is closest in size to that of leptin, being about
twice as large. Any substance with sustained levels in blood,
an absence of a brain-to-blood efflux system, and a lack of
CNS degradation can achieve this CSF/serum ratio.
The question arises as to what degree does CSF physiology
reflect what is happening in the brain tissue. The predomi-
nant movement of fluid and molecules is in the direction of
brain interstitial fluid to CSF, with CSF often thought of as
being a sink for materials being eliminated from the brain.
Figure 4 shows the data from Figure 3 plus the data previ-
ously published in which the brain was perfused with known
concentrations of leptin, corrected for a nonsaturable compo-
nent, and fitted to a hyperbolic curve (11). With this method,
vascular levels were achieved up to 129 ng/mL, much higher
than that reported in any of the six studies. A similar hyper-
bolic pattern is produced, although the Kd is shifted to the
right and higher at 15.6 ng/mL.
Where Does Leptin Resistance Occur:
BBB Transport versus CNS Receptor?
The question has often been posed in the literature whether
obesity results from a defect in BBB transport or at the CNS
leptin receptor/postreceptor. Arguments have been made for
either receptor or transporter being the sole cause of leptin
resistance in obesity. Based on what is discussed above
regarding classic hormone resistance, the hormone level
will rise in the fluid proximal to the site of resistance. We
can characterize what resistance at the BBB only or at the
receptor only would look like. For resistance at the receptor
only, CSF and blood levels would increase as BMI increases,
but CSF/blood levels would remain constant. For resistance
at the BBB only, blood levels would rise, CSF levels would
remain constant, and CSF/blood levels would decrease as
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Comprehensive Physiology
CSF Brain
400 1.5
300
Brain (ng/mL)
CSF (pg/mL)
1.0
200
0.5
100
0 0.0
0 50 100 150
Vascular leptin (ng/mL)
Figure 4 Comparison of brain vs. blood and CSF vs. blood relations.
CSF data from the six studies of Figure 3 plotted with a perfusion study
done in mice correlating vascular leptin levels with brain levels of leptin.
Both fit a hyperbolic pattern although the curve for CSF is shifted to the
left, indicating saturation at a lower vascular level of leptin. Reused,
with permission, from Banks WA, et al., 2000 (11).
BMI increases. Resistance at both sites would produce the
pattern seen: CSF and serum levels both increase, and the
CSF/serum ratio decreases as BMI increases. It is evident,
therefore, that in DIO, resistance occurs at both sites. As
discussed below, this pattern is not universal, and resistance
can occur at only the BBB or receptor level.
That resistance occurs at both the BBB and receptor levels
is borne out experimentally as well. Resistance at the leptin
arcuate nucleus receptor begins as early as day 6 of a high-
fat diet (109). Experimental data make it clear that animals
that have only an inhibition in BBB transport of leptin or only
a receptor/postreceptor defect become obese. For example,
blockade of leptin transport into brain causes an immediate
increase in body weight (46). In a model that combines genetic
susceptibility with DIO, it was shown that the sole lesion at
birth was at the level of the receptor. But as obesity progressed,
the BBB also became a source of resistance (93). Thus, an inti-
mate “chicken and egg” interaction occurs between the BBB
and the arcuate nucleus receptor during the development and
progression of obesity.
Based on the above modeling, the answer to the question
of where leptin resistance in DIO is clear: it is at both the
BBB and the receptor. This raises another question: Which
site of resistance drives obesity? The answer to this question
is shown in Figure 5. This figure shows that as adiposity (mea-
sured as BMI) goes up, so does CSF leptin. Indeed, there is
in Figure 5 a strong relation between BMI and CSF, and just
as in the classic literature, that relation is linear: CSF lev-
els = 15.6(BMI) − 124, r2 = 0.680, P = 0.003. CSF, if consid-
ered as a proxy for brain interstitial fluid (and the close parallel
between brain tissue and CSF curves noted in Figure 4 argues
that it could be in this case), reflects the leptin levels seen by
the receptor. That the relation between BMI and CSF is linear
is important for two reasons. First, if resistance were only at
the BBB and the receptor free of resistance, then CSF lev-
els would not change as a function of BMI and so would be
Volume 11, October 2021
Comprehensive Physiology
400
CSF leptin (pg/mL) 300
200
100
0 One site
10 20 30 40
BMI
Figure 5 A strong correlation exists between the mean CSF levels
of the six classic studies and BMI (r2 = 0.685, P = 0.003). Modeling
demonstrates that an elevation in CSF levels of leptin is consistent with
resistance at the leptin receptor. This is both because CSF is proximal to
the receptor and so reflects resistance at the receptor and also because
resistance at only the BBB would result in normal CSF leptin levels (but
elevated blood and decreased CSF/serum ratios of leptin).
a flat line. Second and as discussed below, the linear relation
between CSF and BMI supports a one-site model of resistance
at this level, whereas the asymptotic relation between serum
and BMI is consistent with a two-site model of resistance.
An elevated CSF level, therefore, indicates both that there
is a resistance at the receptor and also the degree of that resis-
tance. As noted above, the degree of resistance to the effec-
tor hormone is reflected in the degree to which the effector
hormone is elevated. For example, the equation gives for a
BMI of 15 a CSF value of 110 pg/mL and at a BMI of 30 a
CSF value of 344. Therefore, it takes in the latter case more
leptin at the receptor to satisfy brain needs, a clear indicator of
resistance. The CSF leptin level for the BMI of 15 is 32% of
the CSF value for the BMI of 30, so a rough estimate is that,
in comparison to a BMI of 15, the leptin receptor is working
at about 32% of efficiency (110/344 = 0.32).
In comparison, the relation between serum leptin levels
and BMI is nonlinear (Figure 1). Data in Figure 1 as well as
typically in the literature can be fitted to an exponential
growth curve (Y0 = 0.0195, k = 0.238, n = 10, r2 = 0.847, and
P = 0.00016). In serum, leptin levels are about 0.7 ng/mL at
BMI 15 and 24.9 ng/mL at BMI 30. Hence, (0.7/24.9) gives a
value of 2.8% of capacity. This is substantially lower than the
32% efficiency of the receptor and shows that between blood
and CSF there is an additional loss of efficiency. Modeling
that compares a system with one point of resistance to that of
a system with two points of resistance can help explain the
differences in the curves in Figures 1 and 5.
Table 1 compares the effects of resistance or decreased
efficiency when there is a one site of resistance versus two
sites of resistance. No resistance (100% active) is defined
as 1.0 of efficiency in Table 1. The fold increase needed
to overcome a given level of resistance at one site can be
calculated by the remaining efficiency; for example, for 0.5
efficacy: 1/0.5 = 2.0; that is, when the system is working at
50% of maximum, it would take a doubling of the effector
hormone to bring the target tissue back to the physiological
level of function. If serum leptin levels were 2 ng/mL at
Volume 11, October 2021
Leptin and the BBB
One vs Two site
20 impairment models
Fold increase
15
Two site
10
5
0
0 20 40 60 80 100
Percent impairment
Figure 6 Modeling of one vs. two sites of impairment. Although both
are nonlinear, the two-site model is obviously much more so. This
explains the apparent linearity of CSF leptin levels vs. BMI, which
reflects resistance at one site vs. the hyperbolic increase in serum leptin
levels at the same range of BMI’s as serum reflects resistance at two
sites: the BBB and the CNS receptor.
a no resistance level, then at 50% efficiency at one site of
impairment, the leptin level would need to be 4 ng/mL to
compensate.
The decrease in total efficiency when there are two sites
of impairment is calculated by multiplying the two efficacy
values together:
Total Efficiency = (Site 1 efficiency) × (Site 2 efficiency)
(1)
Table 1 shows that if two impaired sites in series each
have an efficacy of 0.5, then the total system is working at
0.5 × 0.5 = 0.25, or 25% of the unimpaired level. Figure 6
compares the fold increase needed to overcome a given level
of impairment when there is either one site of impairment or
two sites in series. Both models show an exponential increase,
but that of the two-site impairment model is obviously so at
much lower levels of impairment.
The value of 2.8% above derived from the relation bet-
ween serum and BMI corresponds to total efficiency, since
serum must overcome resistance at both the BBB and the
receptor. The value of 32% derived from the relation between
CSF and BMI corresponds to one of the sites of resistance,
that at the receptor. Thus, Eq. (1) can be used to calculate the
efficiency of passage at the BBB:
0.028 = (BBB efficiency) × (0.32).
Solving the equation for BBB efficiency yields a value of
0.0875. In other words, the BBB transporter at a BMI of 30
is working at only 8.75% of the efficiency as at a BMI of 15.
In this case, then resistance is greater at the BBB than at the
receptors. This answers a third question: at which site is resis-
tance greater? Analysis at most blood and CSF combinations
is consistent with the resistance being greater at the BBB than
the receptor (5).
This modeling affects interpretation of an often-observed
phenomenon: that of obese animals still responding to icv lep-
tin but no longer to peripheral leptin administration (67, 127,
157). This does not prove that resistance is only at the level of
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Leptin and the BBB Comprehensive Physiology

Table 1 Modeling of Impairment at One Site vs. Two Sites

%Impairment Remaining efficiency: Remaining efficiency: Fold increase: Fold increase: *Leptin level: *Leptin level:
at each site one site two site one site two site one site two site

0 1.0 1.0 1.0 1.0 2 2

10 0.90 0.81 1.11 1.23 2.2 2.46
20 0.80 0.64 1.25 1.56 2.5 3.12
50 0.50 0.25 2 4 4 8
75 0.25 0.0625 4 16 8 32

Modeling assumes that impairment is equal at two sites that are in series. Leptin level at full efficiency arbitrarily set at 2 ng/mL.

the BBB or even that the BBB is the main site of resistance. Endogenous
A better interpretation is that peripheral doses must overcome
10 1 mg/kg

(CSF/Serum ratio) x 100

two sites of resistance (BBB and receptor), whereas central
administration must only overcome a single site (receptor).
Thus, modeling is consistent with resistance at both the
BBB and the receptor-postreceptor level with the driving
resistance being that of the receptor, but the greater resistance
usually occurring at the BBB (Figure 2F). In short, receptor
resistance demands an elevation in leptin levels. The nonlin-
ear nature of BBB transport means that the BBB acts as a
choke point for the entry of leptin into the CNS so that blood
levels must rise to overcome both this choke point and the
receptor/postreceptor resistance.
Suprapharmalogic Leptin Injections
Most of the studies regarding the relations between peripheral
and CNS leptin or BBB kinetics have relied on measuring
immunoreactive leptin or using radioactively labeled leptin.
Each of these approaches has its strengths. Radioactivity,
for example, allows quantitation of kinetics and transport
rates at doses of radioactive hormone that do not influence
the physiology or pathology of the state being studied.
Anatomical studies with radioactivity, although possible,
are cumbersome and time consuming. Fluorescent dyes are
usually superior for such qualitative work (139). However,
their detection level is much lower than that of radioactivity
and so often require very high dose levels to be given that can
influence the system being studied.
Several recent studies have given very high doses of lep-
tin (1–5 mg/kg) that have elevated blood levels into the high
ng/mL to low μg/mL range (56, 68, 82). As shown in Figure 7,
these doses produce blood levels 100 to 300 times greater
than those seen in nonobese individuals and 10 to 30 times
those seen in obesity. At this level, the leptin transporter is
long ago saturated. The CSF/blood ratio has decreased to
below 0.5%. At this level, substances as large as leptin enter
the CNS through those routes used by molecules such as
albumin. Albumin, which does not cross the vascular BBB
but enters the CNS through the extracellular pathways, has a
2.5 mg/kg
5 Obese control
(from 1 mg/kg study)
0.5
0.5
0.0
0 25 50 500 1000 1500
Leptin (vasc) (ng/mL)
Figure 7 Comparison of leptin vascular levels and CSF/serum levels
achieved by suprapharmacological leptin doses. The left hand portion
of the graph shows the values measured in the six classic studies plus
the controls from the 1 mg/kg study. All values in the left-hand portion
have vascular levels less than 50 ng/mL (the vertical dashed line) and
CSF/serum ratios greater than 0.005 (or 0.5%). The right-hand portion
of the figure shows values in animals treated with 1 or 2.5 mg/kg. Blood
values are typically 10 to 30 times greater than those seen in obesity,
and CSF/serum rations less than 0.005. At the suprapharmacological
levels, entry into the CNS is likely by way of the nonsaturable extracel-
lular pathways as the transporters across the barriers are saturated.
CSF/blood ratio of 0.5% to 0.7% in healthy individuals, being
slightly higher in older than younger adults (21, 55, 76, 154).
Why the CSF/blood ratio for leptin is even lower than that
for albumin is unclear but may reflect a greater catabolism of
leptin than of albumin within the CNS. Otherwise, the results
of the suprapharmacological studies look very similar to
those found for albumin, filling the circumventricular organs
and the choroid plexus.
Although these studies giving such high levels of leptin are
not able to address aspects of the saturable transport system,
they do address other important issues. First, they show no
leakage from the median eminence into the arcuate nucleus
(68), a route that has been repeatedly claimed for leptin. These
studies also show (56, 82) that suprapharmacological doses
of leptin can greatly elevate CSF levels of leptin, but do so
independently of the leptin transporter.

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Comprehensive Physiology
Does Obesity Accentuate BBB
Resistances?
The nature of the saturable systems is the cause of decreasing
CSF/blood ratios of leptin with increasing obesity. Although
leptin levels in CSF increase as blood leptin levels rise, the
fraction of leptin crossing decreases. When maximal satura-
tion has occurred, no more leptin is able to enter the CNS
by this route. There could, however, be other, confounding
reasons for decreased leptin transport across the BBB. It is
possible that factors in obesity could shift the CSF versus
blood leptin curve to the right or left, altering the efficiency
of transport. One way this would be evidenced is an alteration
in the Kd, the level at which the leptin transporter is 50%
saturated. In Figure 4, for example, the CSF/blood curve is
shifted to the left of the brain/blood curve with Kds of 3.8
and 15.6, respectively. It is true that the CSF versus blood
curve was derived from studies that studied humans, whereas
the brain versus blood curve was derived from mice receiving
perfusions. Thus, the higher levels in humans are produced
by obesity, whereas the higher levels in the mice were pro-
duced by exogenous infusions. Among the reasons for the
differences in Kds is the possibility that a circulating factor
in obesity alters the leptin BBB transporter. Additionally, in
studies that use the brain perfusion method that negates the
acute influences of circulating substances, there is sometimes
a lower transport rate of leptin in obese animals, suggesting
factors that affect leptin transport other than circulating leptin
levels (13).
One such modulating factor that impairs leptin transport
across the BBB is triglycerides (12). Hypertriglyceridemia
is the classic dyslipidemia of obesity and the metabolic
syndrome. Therefore, the question arises as to whether
triglycerides acting at the BBB worsen peripheral resistance.
If so, then dyslipidemia represents a therapeutic target for the
treatment of obesity. Preclinical studies show improved leptin
transport when triglycerides are lowered below 100 mg/dL
with gemfibrozil (12).
The tanycytic barrier is modified by 24 h of fasting by
its extending up the wall of the third ventricle. At the same
time, a population of capillaries in the ventromedial region
of the arcuate nucleus becomes leaky (124). It is currently
unclear how these changes affect leptin transport or leptin
resistance.
There is also evidence that in some cases of obesity,
endogenous blood levels of leptin must be taken into account
when interpreting BBB transport rates of radioactive leptin.
This is definitely true for most conditions, such as DIO,
the Koletsky obese model, and the effects of LPS on leptin
secretin and transport. This thinking would predict that trans-
port of radioactive leptin in the ob/ob mouse would be very
high because there is no blood leptin to compete with it and
that in the db/db mouse transport would be low because of
the high levels of blood leptin (about 90 ng/mL) that are there
to compete with the radioactive leptin (87). But in both of
these cases, the transport rate of radioactive leptin is similar
Volume 11, October 2021
Leptin and the BBB
to that of the transport rate in the nonobese heterozygotes
(97). Furthermore, dose-response inhibitions do not differ
substantially between obese homozygotes and nonobese
heterozygotes, showing similar inhibition patterns. It seems
that in these groups the BBB transporter has been readjusted
to the endogenous leptin blood level by unknown factors.
Where Does Blood-borne Leptin Enter the
CNS to Reach the Arcuate Nucleus?
Leptin has been proposed to enter the CNS by crossing the
capillary bed including that of the arcuate nucleus, at the
choroid plexus, at tanycytes by a transporter, and by leakage
into the arcuate nucleus (9).
In vivo and in vitro evidence shows transport of leptin
across the capillary bed of the brain and brain endothelial
cells (19, 102). Early evidence showed that radioactive leptin
appeared throughout the brain and that leptin receptors are
located in deep brain tissue (17). Because of limits in diffusion
through brain tissue, only by crossing local capillary beds
could leptin reach these deeper locations. In vitro transport
has been shown using primary mouse brain endothelial cells
and immortalized human brain endothelial cells (12, 102).
Early studies showed that the choroid plexus-bound lep-
tin (39) expressed both long and short forms of the leptin
receptor (106). The presence of leptin in the CSF is presump-
tive evidence of passage across the choroid plexus, but leptin
diffusing from brain interstitial fluid could also contribute to
CSF levels. Studies that show leptin filling the choroid plexus
are not proof of leptin transport as the vessels in the plexus
are leaky. To demonstrate passage, transport must be shown
to occur across the ependymal cell lining and into CSF, not
across the capillary plexus.
Several studies have clearly shown leptin crossing at the
choroid plexus. The multiple-time regression analysis method
and other similar methods relying on intravenous injection
have been used by us and others to study the entry of radioac-
tive leptin into the brain (153, 174). Study times can be kept
short so that it is unlikely that CSF contributes to brain tissue
levels or that brain interstitial fluid contributes to CSF lev-
els. Thus, these methods have been used to study entry into
both the brain tissue and CSF. Zlokovic et al. (174) showed
in rats that leptin transport across the choroid plexus was very
rapid, similar to that of the transport rate at the hypothala-
mus. In mice, the rate was found to be closer to that of the
whole brain (111). Thus, species differences may exist as to
the rate of transport across the choroid plexus. An interest-
ing feature of leptin passage across the choroid plexus is that
it has both a saturable and nonsaturable component (153).
The nonsaturable component likely represents the extracellu-
lar pathways (7, 27) and could account for the very high levels
of leptin that can be achieved in the CNS with suprapharma-
cological dosing as discussed above (56, 82).
One traditional argument against hormones in the CSF
having an influence on brain nuclei is that the CSF-to-brain
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Leptin and the BBB
tissue diffusion distances are extremely small (98, 99). Pen-
etration from CSF into brain tissue falls off logarithmically.
Two counterarguments are typically advanced to counter the
diffusional limitations argument. One is that neuronal pro-
jections and neuronal bodies make contact with ventricular
CSF and so can be activated by CSF hormones (96). Another
counterargument is that although diffusional distances are
limited, periventricular tissues can still be influenced. The
diffusional distance for leptin has been measured by Maness
et al. and found to be 0.3 mm (in other words, the leptin
concentration 0.3 mm from the CSF is 50% of that of the CSF
itself; at 0.6 mm, 25%; at 0.9 mm, 12.5%, etc.). Modeling
has previously shown that the arcuate nucleus lies within the
diffusional area of the third ventricle CSF (99).
Many have assumed leptin leaks into the arcuate nucleus
after entering the median eminence. The capillary bed of the
median eminence is leaky and does not form a BBB (162).
However, a layer of tanycytes separates the median eminence
from the arcuate nucleus, and a layer of ependymal cells
with barrier function separates the median eminence from
the CSF of the third ventricle (123). Furthermore, the vessels
of the arcuate nucleus do form a barrier (123, 132, 136).
Hence, substances are not able to leak from the interstitial
fluid of the median eminence into either the CSF or the
interstitial fluid of the arcuate nucleus. Leakage would also
not be able to explain one of the fundamental aspects of leptin
resistance, that of peripheral resistance in the face of central
sensitivity, or the ability to respond to leptin given into the
CNS but not given peripherally. Leakage is an unregulated
phenomenon, and the amount of leptin entering by such a
mechanism would always be a constant fraction of blood
levels. Thus, leakage does not explain another fundamental
aspect of leptin physiology: that of the nonlinear relation
between CNS and the blood levels of leptin (Figures 3, 4,
and 7). Direct evidence that leakage from the median emi-
nence is not a major source for CNS leptin was provided
by Kastin et al. (78). They found no difference in the influx
rates between the cortex and subcortical areas, thus ruling
out simple diffusion from either the median eminence or
the choroid plexus as a predominant route. They also found
that leptin entry into the brain greatly exceeded that of albu-
min and inulin, markers of leakage. Others have found that
tanycyte conditional ablation does not change body weight
or leptin-induced pSTAT activation but does increase body
fat content and accelerate body weight increases when on a
high-fat diet (167). Thus, ironically, leakage paradoxically
enhances leptin resistance. Additionally, because of the poor
diffusion rates in CNS tissue, leakage from the median emi-
nence would not be able to provide leptin to distal or deep
brain regions. Finally, the supraphysiologic studies found no
dye in the arcuate nucleus, even though blood leptin levels
were exceedingly high.
The above arguments, however, are against a role for leak-
age and not against a role for the median eminence. Several
other mechanisms exist by which the median eminence and
other circumventricular tissues communicate with the regions
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Comprehensive Physiology
of the brain having BBBs (146). One of these is by neuronal
projections into and out of the median eminence. Another
would be if the tanycytic barrier were, like the vascular BBB
and the blood-CSF barrier, more than just a barrier but also a
regulatory interface. Such seems to be the case as tanycytes
that face the arcuate nucleus and the third ventricle CSF are
capable of transporting leptin out of the median eminence
(92, 124). A saturable transport system for leptin at the tany-
cytic barrier would be consistent with the saturable nature of
leptin’s entry into the CNS and the simultaneous occurrence
of peripheral leptin resistance and central sensitivity.
Is the Leptin Short Receptor the Leptin
Transporter?
When a substance is known to cross the BBB, it has often
been assumed that the same protein that acts as its receptor
will also act as its transporter. Why this assumption should
have so much appeal is unclear. Many substances have
multiple receptors; if such variety exists among receptors, it
seems illogical that one of them would perform a dual role
as a receptor and transporter. It would seem equally logical
that the evolutionary pressures that dictate multiple recep-
tors would also dictate evolution of a separate transporter.
Additionally, some BBB transporters transfer a variety of
substances that have different receptors. For example, peptide
transport system-1 has an equal affinity for the opiate peptide
Met-enkephalin and the tetrapeptide Tyr-MIF-1 (18). But
Met-enkephalin binds to the delta opiate receptor, whereas
Tyr-MIF-1 does not. In such cases, at best, only one ligand
could be using its receptor as a transporter (101). In this case,
the delta opiate receptor is clearly not the transporter as it
does not bind and therefore could not transport Tyr-MIF-1.
There are a few cases in which the transporter versus recep-
tor question has been answered definitively. The receptors
for tumor necrosis factor alpha (TNF) also act as transporters
across the BBB (121) and their upregulation increases TNF
transport from blood to brain (117). Knockout studies of
these proteins completely abolish TNF transport across the
BBB. But most other cases have shown that the transporter
and receptor are not the same protein. The brain-to-blood
transporter for pituitary adenylate activating polypeptide 27,
which has been isolated from brain endothelial cells and
identified, is not related to any of its receptors (43). Using
knockouts, receptor inhibitors, shared ligands, and other
strategies, ligand and transporter have been shown to differ-
ent epidermal growth factor, insulin, ghrelin, and prolactin
(28, 119, 134, 135).
It was assumed early on that the short form of the leptin
receptor (Ob-Ra) would be the leptin transporter. However,
very solid research has given different answers. Early on,
it was shown that Ob-Ra is expressed by brain endothelial
cells (72) and that Ob-Ra can act as a soluble receptor,
“transporting” leptin in the blood stream in pregnancy (91).
However, expression levels of Ob-Ra do not correlate with
Volume 11, October 2021
Comprehensive Physiology
transport rates: neonatal mice express all leptin receptors,
including Ob-Ra, at higher levels in brain endothelial cells
than adults but transport radioactive leptin at a lower rate than
adults (118). The Koletsky rat and the Ob receptor knockout
mouse, both of which lack all functional forms of the leptin
receptor, were noted to not transport radioactive leptin after
its intravenous administration or to transport it at a reduced
rate (72, 79). However, these mice are obese, and transport of
radioactive leptin is reduced across the BBB in most models
of obesity because of competition with the higher levels of
leptin in the blood. When leptin transport was tested using
a brain perfusion method that negates the effects of blood
leptin levels on BBB transport, the Koletsky rat was found to
have a normal rate of leptin transport across the BBB (20).
Interestingly, the Koletsky rat may actually not have resis-
tance at the level of the BBB as it has a constant CSF level in
the face of increasing obesity (166). When the ObR receptor
knockout mice were fasted, reducing both body weight and
blood leptin levels, leptin transport increased. In an in vitro
model of the BBB, a blocking antibody to the leptin receptors
did not prevent leptin from crossing, although it did block
signal transduction (59). These studies would seem to make
it clear that there is a leptin transporter that is unrelated to
the leptin receptor. However, other evidence argues in favor
of the short form of the leptin receptor being the transporter.
Madin-Darby canine kidney cells stably expressing leptin
receptors transport leptin across in a polarized fashion; cells
not expressing leptin receptors do not (73). Di Spiezio et al.
(40) found that mice with a selective knockout of the leptin
receptors in brain endothelial and epithelial cells, but not
tanycytes, had no transport of radioactive leptin across the
BBB. These mice were obese, but this study used the brain
perfusion method and so overcame the issue of leptin self-
saturation. Thus, solidly performed studies have given clear
answers to the question, but unfortunately that answer has not
been uniform. Whether the short form of the leptin receptor
is also the transporter at the BBB seems to be currently
unresolved.
Megalin, a multiligand scavenger receptor that transports
leptin at the renal proximal tubule and is also known as low-
density lipoprotein receptor-related protein-2 (LRP-2), has
been proposed as the transporter responsible for leptin trans-
port across the choroid plexus (42). Mice that are deficient
in brain endothelial megalin also develop obesity, metabolic
syndrome, cognitive impairments, and neuroinflammation
on regular chow diet (24). Paradoxically, these mice are
protected from developing obesity, glucose intolerance, or
hepatic steatosis when placed on a high-fat diet (24).
Modulators of Leptin Transport and
Sensitivity
The question of modulation of leptin sensitivity is important
for at least three reasons. First, as discussed above, inhibitors
of transport would decrease leptin levels in the brain, thus
Volume 11, October 2021
Leptin and the BBB
Chronic alcohol
Fasting
Glucose
Insulin
Cholecystokinin
Alpha1 agonists
Blood leptin CSF Leptin Arcuate
BBB nucleus
and its receptor
Leptin
Triglycerides
Starvation
Prolactin
Chronic ovarian
Dysfunction
Figure 8 Substances and conditions that modulate the transport of
leptin at the BBB. Conditions that increase leptin transport across the
BBB are shown in the green trapezoid, and substances in the green
rectangle. Conditions that inhibit leptin transport across the BBB are
shown in the red trapezoid. Triglycerides and leptin inhibit BBB transport
of leptin and also cross the BBB to induce resistance at the leptin receptor
in the arcuate nucleus.
accentuating peripheral resistance and obesity. Second, such
modulators could be important physiological regulators of
appetite. Third, the ability to increase leptin transport would
increase leptin levels in the brain and could aid in treating
obesity. Modulation implies that obesity and leptin resis-
tance are both acquired and reversible conditions and that
an environmental factor or factors directly or indirectly lead
to obesity and leptin resistance. The proximal mediators of
leptin resistance would be viable therapeutic candidates.
The BBB transport of leptin is modulated by several fac-
tors. Besides obesity (13, 15, 29, 93), other factors associated
with reduced leptin transport are starvation, triglycerides,
prolactin, and chronic loss of ovarian function (8, 12, 156),
whereas chronic alcohol consumption, fasting, glucose,
insulin, cholecystokinin 8, and alpha1 adrenergics are asso-
ciated with increased transport (6, 30, 77, 116). Alpha
adrenergics work at the BBB, whereas triglycerides work at
both the BBB and the arcuate nucleus receptors (Figure 8).
There are also diurnal variations in the rate of leptin transport
across the BBB (120).
The most obvious environmental cause of obesity is the
ingestion of excess calories. However, the ingestion or even
the absorption of a substance does not mean that the sub-
stance needs to be proportionately retained. In the case of
water, as an example, it is excretion, not retention, that is pro-
portionate to absorption under normal conditions. In disease
states such as renal failure and congestive heart failure where
negative feedback loops regulating excretion fail, retention
must then be modulated through control of ingestion. Evolu-
tion designed very different systems for dealing with these two
2361
Leptin and the BBB
commodities essential for life that have resulted in hording of
calories but not water.
High calorie ingestion is a potent inducer of leptin resis-
tance. In a study by Knight et al. (83), ob/ob mice at 4 weeks
of age were already about 50% heavier than WT mice, but an
infusion that produced blood leptin levels of about 5 ng/mL
normalized weight as long as mice were on a low-fat diet.
However, the ob/ob infused mice that were on a high-fat diet
gained weight at the same rate as WT mice. Thus, while a
level of 5 ng/mL of leptin was able to prevent obesity in the
face of a low-fat diet, a high-fat diet overcame the anorec-
tic effect of leptin at this level and also at the much higher
blood levels of leptin in the WT mice. In another study, ob/ob
mice responded to leptin while on a low-fat diet but not when
placed on a high-fat diet (84), even though the dose given
(1.25 mg/kg) could be expected to raise blood leptin levels
to over 500 ng/mL. Likewise, Tg mice that overexpress leptin
have lower body weights than WT mice while on normal chow
(114) but once placed on high-fat chow gain more weight or
fat mass than the WT mice (114, 173).
Leptin is involved in the induction of its own resistance.
Mice whose leptin levels were about 5 ng/mL lost weight
when their leptin levels were increased by an additional
15 ng/mL, even when the mice were obese, but mice who
were obese and also had high leptin levels of 30 to 150 ng/mL
did not respond when their leptin levels were raised by an
additional 15 ng/mL (83). Likewise, STAT3 levels in the
hypothalamus increased after an ip bolus of 2 mg/kg of leptin
in mice on normal chow and obese mice with low leptin levels
but not in obese mice with high leptin levels. Zhao et al. (173)
have shown that reducing leptin levels not only will restore
leptin sensitivity to exogenous leptin but that mice whose
fat cells produce more leptin gain more fat on a high-calorie
diet and that lowering leptin levels can result in weight loss.
Perhaps the most obvious example of leptin-induced leptin
resistance is that an animal on normal chow with a given
level of obesity responds to leptin when it is leptin deficient
(ob/ob) but not when it can secrete leptin.
Some causes of leptin-induced leptin resistance are known.
The self-inhibiting nature of leptin transport at the BBB
means that increasing CNS levels of leptin becomes progres-
sively less efficient as blood levels of leptin rise. Likewise,
leptin inhibits its own signaling by activating SOCS-3,
inducing resistance at a postreceptor level (110). Downreg-
ulation of receptor or transporter levels by their ligands is
common and one of the causes of hormonal resistance and
is a possible mechanism of leptin resistance. Interestingly,
leptin is not the cause of the resistance that results from being
on a high-fat diet. Koch et al. (84) showed that ob/ob mice
placed on a high-fat diet lost their sensitivity to a high dose of
leptin within 4 days of starting the diet. As these mice do not
produce leptin, the high-fat diet must be inducing resistance
independently of leptin levels.
At first, the work of Ottaway et al. (115) showing that
antagonism of leptin activity in DIO mice increases body
weight seems to contradict with that of Zhao et al. (173),
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Comprehensive Physiology
who showed that reducing leptin levels in DIO reduced body
weight. However, these are reconcilable as they likely work
through different mechanisms. With potent antagonist treat-
ment, the level of remaining leptin activity is immediately
reduced, resulting in a relative, acute leptin deficiency and so
stimulating feeding. With a significant reduction in endoge-
nous leptin levels (172), body weight also increases, but with
a modest reduction in leptin levels, weight paradoxically
recovers. Thus, modest reductions in leptin levels produce
the paradoxic effect, whereas larger reductions produce the
expected increase in weight gain. Given this, it would be
interesting to determine the effect of a weak antagonist on
weight gain. Interestingly, the time course of these effects
were different as well, with the antagonist studies producing
a significant effect within a week, but modest leptin reduction
requiring about 7 weeks.
Three other factors have been considered in the literature
that could be the cues linking environment and leptin resis-
tances: inflammation, triglycerides, and angiotensin II. Being
placed on a high-fat diet induces hypothalamic inflammation
and results in postreceptor resistance (152). What the exact
mechanism is by which fat in the diet translates to inflamma-
tion in the hypothalamus is not clear, but there is no shortage
of candidates. Leptin itself has immunomodulatory actions in
the periphery and the CNS (95, 103, 107), including at its
own receptor (110). The brain endothelial cells that comprise
the BBB are able both to transport into brain and to secrete
cytokines and other immune-related substances (16, 74, 133).
Zhao et al. (173) found that reducing leptin levels reduced
hypothalamic inflammation.
A second factor is triglycerides, which have been shown to
cross the BBB and to induce leptin receptor resistance (14).
Thus, elevated triglycerides, the classic dyslipidemia of the
metabolic syndrome, produce leptin resistance at both the
BBB and the arcuate nucleus. Interestingly, triglycerides have
the opposite effect on the orexigenic ghrelin, stimulating its
transport across the BBB (10).
Angiotensin II is implicated as a third factor as blockade of
the AT1 receptor prevents DIO (164). Although angiotensin
II through the AT1 receptor modulates BBB transcytosis (49,
62, 63), its blockade with telmisartan has no direct effect on
leptin BBB transport, but it seems that its protective effects on
DIO are mediated through actions on the receptor (142).
It should be noted that these three factors are not mutually
exclusive. Triglycerides and free fatty acids, both of which
cross the BBB (14, 38, 151, 161), induce neuroinflammation
(90, 155). Telmisartan normalizes peripheral and hypothala-
mic triglyceride levels and reduces hypothalamic inflamma-
tion from DIO and stroke (86, 129).
Thus, there are many modulators of leptin and leptin resis-
tance. Although it is unclear which of these are the dominate
causes of leptin resistances in DIO, it is clear that leptin
resistance is multifactorial. Why leptin resistance should
occur is currently a bigger mystery than how. The following
section considers some aspects of this by looking at the
functions of leptin outside of obesity.
Volume 11, October 2021
Comprehensive Physiology
Beyond Obesity: Other Roles of Leptin
and Leptin Resistance
Nearly all the literature on leptin takes the perspective that
the crucial interaction is that of leptin’s effect on body weight
as mediated through receptors at the arcuate nucleus. Given
the phenomenal obesity of leptin-deficient animals and the
miraculous effect of leptin in those animals, it is hard to think
of leptin in other terms. Yet, typical obesity is not caused
by leptin deficiency but is hallmarked by leptin resistance.
Indeed, leptin resistance increasingly occurs as body weight
is gained at any level, not just obesity. Leptin resistance,
then, seems not pathological, but physiological; in short, it
seems built-in as part of the well-fed state. It is necessary,
therefore, to look at other roles of leptin beyond that of weight
control and at receptors engaged in activities other than those
involved in feeding, asking what other roles does leptin play
and does resistance occur for those conditions as well. Here,
we consider three aspects of these alternative lives of leptin:
in what conditions other than obesity does leptin resistance
occur; what other functions other than feeding does leptin
affect; does leptin resistance occur at receptors other than
those of the arcuate nucleus? After these considerations, we
return to revisit the role of leptin and body weight control.
Leptin resistance occurs in conditions other than obesity.
Pregnancy is associated with a loss of appetite suppression
to both peripherally administered and centrally administered
leptin. Evidence shows that both leptin transport across
the BBB and hypothalamic response to leptin are impaired
(64, 145, 156). Leptin blood levels are increased in preg-
nancy in both rats and sheep by about 1.8-fold. However,
the increased leptin does not arise from adipose tissue but
by secretion from the placenta in primates and because of
increases in the circulating short form of the receptor in mice
(70, 91). Thus, the negative feedback loop between food
storage and regulation of feeding may be supplanted by a
loop between energy demands of pregnancy and regulation
of feeding. Consistent with this is that in sheep, the increase
in leptin levels corresponds with the number of fetuses and
thus the energy demands of pregnancy (89).
Leptin resistance also occurs seasonally in some animals
(150), such as Siberian hamsters and sheep. In general, resis-
tance occurs during the long days of summer when animals
are eating more and gaining body weight. During the long
days, plasma and CSF levels of leptin increase, but animals
are not responsive to icv-administered leptin, demonstrating
central leptin resistance. Interestingly, CSF/plasma ratios do
not decrease as a function of leptin blood levels in sheep,
suggesting that there is no resistance at the BBB. During short
days, animals decrease food intake after icv-administered
leptin, demonstrating that CNS resistance has abated. But
CSF levels are constant rather than increasing as plasma
levels increase. As noted in the models section above, this is
the pattern expected when a partial resistance is only at the
level of the BBB and not involving the receptor.
Volume 11, October 2021
Leptin and the BBB
Leptin receptors are found throughout the brain (61) and
in many peripheral tissues. With receptors in such a diverse
number or CNS and non-CNS locations, it is not surprising
that leptin has many actions other than decreasing feeding
and increasing thermogenesis. Leptin may have effects on
heat dissipation and the defense of core body temperature
(48). Many of the actions of leptin, such as stimulation of
the reproductive and immune systems, are intense users of
calories and are a large part of the reason that calories are
consumed. Leptin is a pro-inflammatory hormone, affecting
both the innate and adaptive immune systems. Blood lev-
els of leptin increase two to threefold in mice treated with
lipopolysaccharide, a fragment of Gram-negative bacteria
that stimulates the innate immune system (53, 104, 105).
Nearly all immune cells express the long form of the leptin
receptor. Leptin induces B cells to secrete cytokines (37).
B cell development and B cell-driven humoral immunity are
impaired in DIO. However, this effect of obesity may be
more driven by insulin resistance than leptin resistance (37).
In vitro, B cells from lean and obese individuals were equally
stimulated (54).
Leptin, as do seemingly all hormones related to metabolism
and the gastrointestinal tract, has impressive effects on
cognition (36, 41, 60). These are mediated in part at the hip-
pocampus. Bone density, breathing, and hepatic triglyceride
secretion are all modulated by leptin. Leptin restores the
integrity of the glycocalyx at the BBB in the BTBR ob/ob
mouse model of obesity (69). Many of leptin’s effects on
peripheral tissues are not mediated through local peripheral
receptors but controlled by the CNS through vagal efferent
nerves. These include the effects on bone density, breathing,
and hepatic triglyceride secretion (44, 65, 138). As already
noted, many of these actions are actually stimulated by
increasing leptin levels, although more properly the evidence
indicates that the presence of leptin is often permissive,
relieving a block imposed by starvation and its absence of
leptin. However, leptin’s stimulation of breathing, which is
mediated through the CNS, does seem to show resistance in
obesity (138). This raises the question of whether sleep apnea
as seen in obesity is a form of leptin resistance or is treatable
with leptin. Peripheral infusions of leptin reversed respiratory
depression in ob/ob mice and at high infusion levels in diet-
induced obese mice (113). Intranasal administration (a route
of administration that bypasses the BBB) of leptin, but not
peripheral administration of leptin, increased ventilation and
decreased the number of desaturation events during REM
sleep in diet-induced obese animals (26). Leptin’s effects
on cognition are impaired in obesity and show evidence
of being mediated through triglycerides. In contrast to the
cases above, at least some of the actions of leptin are directly
mediated at immune cell receptors, and leptin relieves the
immunosuppression of starvation (81, 95). In brief, leptin
has many actions that are at best only tangentially related to
feeding and in some cases do not show resistance in obesity.
Given that the leptin receptor is found in many locations
mediating a diverse number of functions, the question this
2363
Leptin and the BBB
raises is whether resistance to leptin occurs in those tissues
as a function of either obesity or other conditions. Within
the hypothalamus, leptin receptors at locations other than
the arcuate nucleus remain sensitive to leptin after 16 weeks
of high-fat diet, a time at which arcuate nucleus receptors
are leptin resistant (109). In agouti obese mice no longer
responding to inhibition of food intake, icv leptin continues
to stimulate in a dose-response manner renal sympathetic
nerve activity (126). Likewise, in a rat model with a genetic
propensity to obesity, the degree of leptin resistance at an
early period of life varied among hypothalamic receptors
from 21% to 64%, while hindbrain receptors stimulating
sympathetic outflow were normal (93).
Stucchi et al. (148) examined the ability of leptin to stim-
ulate STAT3 phosphorylation in healthy mice between the
ages of 3 and 10 months. They found that heart remained
responsive throughout these ages, whereas adipose tissue was
not responsive at ages 5 and 10 months and liver at the age
of 10 months. These results show that leptin sensitivity is
independently regulated among tissues, at least as effected by
age. Cardiomyocytes respond to leptin and that response is
impaired in DIO mice, suggesting leptin receptor resistance
in this model (131). Leptin receptors (or at least its mRNA)
are also found on immune cells (103), the antral mucosa that
controls gastric secretions (58), the testis and ovary, (168),
and adrenal medulla (31).
The above review shows that leptin resistance occurs in
states other than obesity, that leptin has functions not imme-
diately related to control of body weight, and that leptin resis-
tance can occur for some of these other functions, but not for
others. These areas together suggest a nontraditional view of
leptin resistance.
Traditionally, many authors starting soon after the discov-
ery that human obesity represented a leptin resistant state
have pointed out that leptin makes a poor anorectic signal.
Although its correlation with adiposity is strong, its brake on
further inhibition of feeding as adiposity increases becomes
ever weaker because of its peripheral and central resistances.
Schwartz and others have pointed out that leptin, or rather the
absence of leptin, serves much better as a starvation signal
(1, 12, 51, 147). Just as the absence of gas in a car or the
absence of money in a bank account can skew behavior toward
conservation of the resource, the absence of leptin defaults
toward increased feeding behavior and the conservation of
calories, even when saving those calories means lowering
immune defenses, body temperature, and reproduction of
the species (23, 34, 47, 95, 108). Elevated triglycerides,
which can cause both peripheral and central resistance and
also impair leptin’s actions on cognition, are found not just
in obesity but also in starvation. Triglycerides could have
evolved as an indirect signal of starvation by inhibiting leptin
action. This view is not of leptin as a regulator of body fat, but
its absence of function from the brain as a sign of starvation.
These two views of leptin function, that of leptin as an adi-
postat and that of the absence or reduction of leptin levels as
a signal of starvation, have dominated thinking about leptin.
2364
Comprehensive Physiology
The rapid reduction in body weight when leptin is given
to leptin-deficient mice and the huge increase in adiposity
whenever leptin signaling to the hypothalamus does not occur
because of deficiency, receptor or postreceptor defects, or
blockade by leptin antagonists favor the adipostat view. Lep-
tin as a permissive switch, allowing the expenditure of energy
on calorically expensive activities such as reproduction and
support of the immune system, makes the starvation view
appealing. In the starvation view, evolution has pressured the
leptin negative feedback system toward preventing a caloric
deficiency, thus avoiding death from starvation, the inability
to fight off infections, or the lack of resources to reproduce.
But with excess caloric states being so rare, no evolutionary
pressure was exerted on forming that end of the leptin-body
weight spectrum.
However, the instances of leptin resistance in pregnancy,
with seasonality in sheep, and with hibernation as well as the
modulatory state of leptin resistance suggest a third view of
leptin. In this view, leptin resistance serves a physiological
purpose as well. In all these cases, a common theme could
be to acquire the calories while one can, either because of
an immediate increased demand for calories (pregnancy) or
because of a future in which caloric intake will be decreased.
In summary, leptin has many actions at many different
tissues. Some are stimulated and others inhibited in the face
of starvation or obesity, while others (23, 47, 95) may be
independent of feeding state. Some are mediated through
the CNS and others directly at the peripheral tissue. Many
can be fit into the theme of leptin as related to caloric use or
storage. Finally, leptin resistance may play a physiological
role in modulation of caloric intake outside the realm of
obesity/starvation.
Can Leptin Be Used to Treat Human
Obesity?
In comparison to the dramatic results seen in leptin-deficient
individuals, leptin’s actions in typical human obesity are
not impressive. In leptin-deficient individuals, 0.02 to
0.04 mg/kg/day, or about 4.1 mg/day, resulted in an average
weight losses of 42.3 kg of fat, 14.8 kg of lean body mass,
and 57.1 kg of total body weight in 18 months (122). This
translates to 0.03 mg/kg/day of leptin inducing about 0.73 kg
of weight loss per week.
In comparison, Heymsfield et al. (71) found that about
0.30 mg/kg/day induced a weight loss of 7.1 kg in 24 weeks,
or 0.3 kg/week. Roughly speaking, 10 times as much leptin
as used in deficient patients produced 40% of the effect.
Fogteloo et al. (52) found a 7.9 kg weight loss using about
0.22 mg/kg/day, or about 0.65 kg/week, whereas Zelissen
et al. (170) using a dose also of about 0.22 mg/kg/day for 12
weeks found weight loss that was not statistically different
from that lost by the no-leptin group. Based on these three
studies, it seems that leptin replacement can be effective but
is variable.
Volume 11, October 2021
Comprehensive Physiology
Would higher doses of leptin be more effective in treat-
ing obesity? At first, the answer would seem to be no. These
clinical trials giving 0.22 to 0.3 mg/kg/day elevated serum lep-
tin levels to about 180 to 480 ng/mL. As this is well above
the level at which maximal saturation of the BBB transporter
occurs, little or no additional leptin would enter the brain by
this mechanism. However, there is a nonsaturable component
to leptin passage across the choroid plexus (153) which likely
is the extracellular pathway (27). This pathway has therapeu-
tic potential for substances that have sustained levels in blood
(7). Indeed, the studies discussed under the suprapharmaco-
logical section produced CSF levels in the range of 360 to
5,400 pg/mL. This is about 10 times more than the theoretical
maximum of leptin that can be achieved in CSF by saturable
mechanisms. Thus, suprapharmacological dosing can over-
come the leptin resistance at the BBB, not by reversing periph-
eral resistance but using the alternative route of the extracel-
lular pathways. The work of Ottaway et al. (115) with a leptin
antagonist suggests that the brain could respond to such addi-
tional leptin. However, the work of Koch et al. (84) showed
that a dose of leptin expected to increase blood leptin lev-
els to greater than 500 ng/mL was without effect even in the
leptin-deficient ob/ob mouse when the mice were on a high-fat
diet. Therefore, leptin resistance seems particularly difficult to
overcome when animals are on a high-fat diet.
Reversal of leptin resistance at either the receptor or the
BBB should greatly improve leptin’s therapeutic effect. As
the modeling shows, having resistance at two sites in series
decreases leptin’s effectiveness logarithmically. For example,
a level of resistance at two sites, each of which would require
4 times as much leptin to overcome the individual resis-
tance, in tandem would require 16 times as much leptin.
Furthermore, as obesity decreases, it is likely that the level of
resistance will also decrease. This is certainly true of resis-
tance at the BBB, where the nonlinear relation between serum
leptin levels and transport rate means that the leptin trans-
porter works much more efficiently at low levels of serum
leptin. Because of this “chicken-and-egg” phenomenon, that
each resistance accentuates the impairment of the other, it
can be very difficult to determine the site of action of an
effective therapeutic. An agent working at the arcuate nucleus
to reduce body weight, for example, would also appear to
relieve BBB resistance simply because transport would be
occurring at lower serum levels of leptin. This seems to be
the case with the angiotensin receptor blocker telmisartan
which increases leptin sensitivity, including in models of DIO
(86, 108, 129). Recent work has shown that telmisartan acts
centrally with its effects at the BBB occurring secondarily
from the decrease in saturating levels of leptin (142).
The resistance at the BBB transporter may be overcome in
other ways as well. As noted above, leptin BBB transport can
be modulated by several conditions and agents. For example,
decreasing triglycerides in the circulation below about
100 mg/dL relieves resistance both at the leptin transporter
and at the leptin arcuate nucleus receptor (12, 14). Treatment
with alpha1 adrenergic agents should also increase leptin
Volume 11, October 2021
Leptin and the BBB
transport (6). Some analogs of leptin have been constructed
that can cross the BBB but do so independently of the leptin
transporter. These include small peptides, a glycosylated
leptin peptide, and pluronic leptin (3, 88, 112, 125, 137, 160).
Each of these has been demonstrated to cross the BBB and
to induce weight loss to varying degrees in mice on high-fat
diets.
Another way to overcome BBB resistance is by delivery
by the nasal route. Some substances when placed at the level
of the cribriform plate are able to enter the brain (94, 169).
Leptin is one of the substances shown to be capable of enter-
ing the brain by this route. A 0.2 mg/kg dose increased brain
levels by fivefold and doubled levels in the hypothalamus
(50). Brain distribution did not rely on either CSF flow
or blood-to-brain transport. Furthermore, intranasal leptin
reduced body weight in both normal weight mice and in DIO
mice (26, 140, 141).
Conclusions
Leptin is a regulatory protein that continues to be intriguing.
Many of its effects depend on the relation between produc-
tion in the periphery and sites of action within the CNS and
the BBBs that modulate that relation. In this article, we dis-
cussed several of the curiosities and controversies relating to
leptin and the BBB and came to conclusions about many of
them: Leptin crosses three BBBs (vascular BBB, blood-CSF
barrier at the choroid plexus, and tanycytic barrier) by sat-
urable regulated processes. The vascular barrier distributes
leptin throughout the brain, the choroid plexus to periventric-
ular tissue, and all barriers likely contribute to leptin at the
arcuate nucleus. The ability of leptin to dramatically reverse
obesity in leptin-deficient animals supports the first model for
leptin, that of an adipostat. The viability of the adipostat model
at only low levels of leptin with the development of resis-
tance at higher levels supports the second model proposed
for leptin, that of a starvation signal. In most cases of obe-
sity, resistance to leptin develops at both the BBB and the
arcuate nucleus receptor. Modeling shows resistance as a con-
tinuum and demonstrable to some degree at low leptin levels.
Modeling suggests that in DIO it is the arcuate nucleus that
is the original and driving cause of obesity and that the BBB
plays a secondary role by limiting the amount of leptin that can
reach the CSF/brain interstitial space to overcome receptor
resistance. However, modeling further suggests that it is the
BBB that accounts for a higher percent of total resistance than
does the receptor. This may be in part because BBB resistance
may not only occur because of saturation by high endogenous
levels of blood leptin but also because of factors in obesity
that directly act on the BBB transporter, making it less effi-
cient. There are some conditions where resistance occurs at
only a single site, that is, at the BBB transporter or at the arcu-
ate nucleus receptor. These are often conditions that are short
term or reversible, such as pregnancy, seasonal feeding, or in
preparation for hibernation. These conditions suggest a third
2365
Leptin and the BBB
model for leptin that complements the adipostat and starvation
models, that of leptin resistance as physiologically purposive.
The short-term nature of these conditions illustrates that leptin
resistance is inducible by environmental and dietary factors.
Among these conditions are a high-fat diet, which can induce
resistance even in mice that do not secrete leptin and so is
not dependent on leptin or leptin resistance. Triglycerides can
induce resistance at the BBB and can cross the BBB to induce
resistance at the receptor itself. Leptin induces self-resistance
both at the BBB and at its receptor in the arcuate nucleus. The
protein that acts as the leptin transporter at the vascular BBB
is unknown with good evidence that it is the short form of
the leptin receptor and good evidence that it is not. It may be
that transport/receptors interact in undefined ways to modu-
late transport function. Megalin is the candidate for the leptin
transporter at the choroid plexus, but evidence for it being
the transporter at the vascular BBB is mixed. Recent stud-
ies using suprapharmacological doses of leptin have achieved
blood levels of over 1000 ng/mL; since the leptin transporter is
nearly fully saturated at blood levels of about 50 ng/mL, these
studies give no insight into leptin-saturable transport. They do,
however, show that leakage of leptin does not occur from the
median eminence to the arcuate nucleus and that these large
doses of leptin achieve high levels of leptin in the CSF with a
rate of entry consistent with the extracellular pathways. This
raises the possibility that BBB resistance can be negated by
peripheral administration of leptin, and CSF levels achieved
that would be capable of stimulating arcuate nucleus receptors
to any remaining capacity. Analogs of leptin or its antagonists
that can cross the BBB, intranasal delivery of leptin, or using
modulators of the leptin transporter or receptor may also aid
in treating leptin resistance. In the end, use of leptin to treat
obesity should be taken in the context that leptin likely did
not evolve as a brake on obesity but more probably as a sig-
nal to the brain regarding starvation and that leptin resistance
in some cases plays a physiological role that is important in
preparing animals for immediate or future caloric demands.
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Central Nervous System Control of Nutrient Homeostasis
CNS Targets of Adipokines
Pathogenesis of Hyperthyroidism
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Hypothalamic–Pituitary–Adrenal Axis–Feedback Control
Leptin Function and Regulation
Mathematical Modeling in Neuroendocrinology
Hypothalamus as an Endocrine Organ
2366
Comprehensive Physiology
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