RES EARCH
◥ to obesity development in mouse models and
REVIEW SUMMARY
NEUROSCIENCE
Integrative neurocircuits that control metabolism
and food intake
Jens C. Brüning* and Henning Fenselau
BACKGROUND: There is an ever-increasing pop- and neuronal inputs, signaling nutrient avail-
ulation of overweight and obese individuals ability of the organism. The core of this hypo-
who exhibit the predisposition for a plethora thalamic control system comprises two neuronal
of obesity-associated disorders, such as type 2 populations, which exert almost opposite func-
diabetes mellitus, cardiovascular diseases, tions in the regulation of feeding behavior,
certain types of cancers, as well as neuro- energy expenditure, and fuel metabolism.
degenerative disorders. Because both energy Agouti-related peptide (AgRP) neurons are
homeostasis and peripheral metabolism are activated in conditions of energy deficit, are
coordinated through the brain, defining the inhibited by the fuel communication signals
basic neurobiological mechanisms of meta- leptin and insulin, and promote foraging and
bolic regulation and defining how alterations food consumption. Pro-opiomelanocortin
in these pathways promote obesity develop- (POMC) neurons are activated in states of
ment and the onset of obesity-associated meta- positive energy balance and the associated
bolic disorders are urgently needed to devise hormonal changes and reduce food intake
therapeutic interventions for these prevalent and increase energy expenditure. Intense re-
diseases. The arcuate nucleus (ARC) of the search over the past 20 years has revealed that
hypothalamus integrates multiple hormonal alterations in this circuitry are causally linked
Astrocyte
TH
SST Hunger and Satiety
Glucose tolerance
MSH Insulin sensitivity
PNOC POMC
Motivational behaviour
NPY Proteostasis
Oxtr
3V AgRP Vglut2 Lipolysis
Tanycytes Energy expenditure
Blood
vessel Microglia
ARCUATE NUCLEUS
Adipose
Stomach (fat)
Pancreas Sensory Gut Hormonal
cues signal regulation
Small
intestine
Time
Hypothalamic integration of food-related signals in metabolic control. Key hunger- and satiety-
promoting neuronal cell types in the hypothalamus integrate nutrient-related signals across different
timescales: (i) upon sensory perception of food, (ii) post-ingestive gut-derived signals, and (iii) hormonal
signals that communicate the energy state of the organism. In addition to feeding, these neurocircuits also
adapt multiple behaviors and other physiological parameters in peripheral tissues in accordance to the
energy state of the organism.
Brüning et al., Science 381, 1426 (2023) 29 September 2023
humans.
ADVANCES: Recent developments of high-
throughput single-cell and single-nucleus RNA-
sequencing methods have enabled the definition
of cellular subpopulations at unprecedented
molecular resolution. Applying these technol-
ogies has recently led to the identification of
numerous additional food intake and metab-
olism regulatory neuronal and non-neuronal
cell populations in the hypothalamus. In par-
allel, functional molecular systems approaches
have allowed the delineation not only of the
functional role of these newly identified cell
types in metabolism control but also defini-
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tion of the neuronal network organization as
well as assessment of their activity in freely
behaving animals. These experiments revealed
that metabolism regulatory neurons are mod-
ulated across different timescales, including
upon sensory perception of food cues, post-
ingestive signals that originate from the gastro-
intestinal tract, and more long-term hormonal
mediators. The integration of these signals
serves to fine-tune metabolic adaptation and
associated behaviors in an allostatic manner.
These studies have largely advanced our knowl-
edge of the fundamental principles of central
nervous system–dependent control of me-
tabolism. They also allowed the definition of
new strategies to combat metabolic diseases.
These recent advances are highlighted in the
Review.
OUTLOOK: Further expanding on these devel-
opments will allow a more holistic insight
into the conserved metabolism regulatory cell
types and neurocircuits not only in rodent
models but also in humans. This new knowl-
edge will aid the definition of how their de-
regulation is linked to the development of
metabolic disturbances. Moreover, such studies
will help clarify the mode of action of prom-
ising new anti-obesity therapeutics. These in-
clude glucagon-like peptide-1 (GLP-1) receptor
agonists as well as newly developed polyago-
nists for different receptors of gut-derived pep-
tides, for which clinical studies have provided
evidence for promising efficacy in body weight
reduction and metabolic improvement. Fur-
thermore, deeper insights into the molecular
signature of metabolism-regulatory cell types
and into the synaptic mechanisms underlying
CREDIT: (MOUSE IMAGE) N. BURGESS/SCIENCE
their network interaction carry the potential to
nurture the development of alternative ther-
apeutic strategies for metabolic diseases.
▪
The list of author affiliations is available in the full article online.
*Corresponding author. Email: bruening@sf.mpg.de
Cite this article as J. C. Brüning, H. Fenselau, Science 381,
eabl7398 (2023). DOI: 10.1126/science.abl7398
READ THE FULL ARTICLE AT
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RES EARCH

◥ dicted that the receptors of energy state–

REVIEW sensing hormones would be expressed on
key neurons that adapt food intake and energy
NEUROSCIENCE expenditure in a feedback regulatory mecha-
nism. Although it took another three decades
Integrative neurocircuits that control metabolism to identify the fundamental energy-sensing
signal as leptin, the breakthrough discovery of
and food intake this hormone and its receptor mainly in the
CNS has opened a new era in the science of
Jens C. Brüning1,2,3,4* and Henning Fenselau2,3,5 CNS-dependent control of energy balance and
metabolism (4). Defining the underlying neuro-
Systemic metabolism has to be constantly adjusted to the variance of food intake and even be prepared circuitry targeted by leptin and other energy-
for anticipated changes in nutrient availability. Therefore, the brain integrates multiple homeostatic communicating signals—such as insulin, ghrelin,
signals with numerous cues that predict future deviations in energy supply. Recently, our understanding and glucagon-like peptide-1 (GLP-1)—has al-
of the neural pathways underlying these regulatory principles—as well as their convergence in the lowed us to begin unraveling the central mecha-
hypothalamus as the key coordinator of food intake, energy expenditure, and glucose metabolism—have nisms that underlie not only feeding behavior

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been revealed. These advances have changed our view of brain-dependent control of metabolic and energy expenditure but also metabolic sub-
physiology. In this Review, we discuss new concepts about how alterations in these pathways contribute strate utilization in peripheral tissues, which
to the development of prevalent metabolic diseases such as obesity and type 2 diabetes mellitus and ultimately control body weight as well as stable
how this emerging knowledge may provide new targets for their treatment. glucose and lipid metabolism (Fig. 1) (5, 6).
Defining the exact nature of this regulation

O
rganismal survival and health require
the maintenance of energy stores, water,
salt, and temperature within specific
physiological ranges. The basic princi-
ples of homeostasis have been outlined
as early as the late 19th century, when the
physiologist Claude Bernard proposed that
critical physiological parameters have to be
regulated within a defined physiological range
to ensure survival and organismal integrity.
He provided evidence that the central nervous
system (CNS) plays an important role in this
process. In the 1930s, the physiologist Walter
Cannon further specified the formal concept
of homeostasis, which thereafter has been the
conceptual framework for numerous regula-
tory principles in physiology (1). Nevertheless,
the proposed concept of homeostasis—that a
variable parameter in physiology is monitored
and that deviations from its setpoint elicit
counterregulatory responses in control systems—
does not provide ideal regulatory precision
to maintain a constant, steady-state level of a
regulated parameter because it requires devia-
tions to occur before counterregulation sets in.
Thus, to optimize maintenance of a stable
milieu, integrating anticipated changes of the
regulated parameter provides higher physio-
logical stability. Incorporating the parameters
of environmental influences and anticipated
changes has broadened the concept of homeo-
1
Department of Neuronal Control of Metabolism, Max Planck
Institute for Metabolism Research, 50931 Cologne, Germany.
2
Policlinic for Endocrinology, Diabetes, and Preventive
Medicine (PEDP), University Hospital Cologne, 50924
Cologne, Germany. 3Excellence Cluster on Cellular Stress
Responses in Aging Associated Diseases (CECAD) and
Center of Molecular Medicine Cologne (CMMC), University of
Cologne, 50931 Cologne, Germany. 4National Center for
Diabetes Research (DZD), 85764 Neuherberg, Germany.
5
Research Group Synaptic Transmission in Energy
Homeostasis, Max Planck Institute for Metabolism Research,
50931 Cologne, Germany.
*Corresponding author. Email: bruening@sf.mpg.de
has become of utmost societal importance be-
stasis to that of allostasis, which was formal- cause deregulated body weight control is in-
ized more recently by the neuroscientist Peter creasingly affecting global populations. There
Sterling (2). is an ever-increasing population of overweight
The maintenance of stable body weight was and obese individuals, which exhibit predis-
mainly viewed under the assumptions of position for a plethora of obesity-associated
homeostatic regulation. Concepts such as lipo- disorders, such as type 2 diabetes mellitus,
static control of body weight have been put cardiovascular diseases, certain types of can-
forth as early as the 1950s, when the physiol- cers, as well as neurodegenerative disorders
ogist Gilbert Kennedy proposed that energy (7). Therefore, defining the basic neurobio-
homeostasis is regulated through hormonal logical mechanisms of metabolic regulation
feedback (using then unidentified hormones), (Box 1 and Fig. 2) and defining how alterations
which would communicate the energy state of in these pathways promote obesity development
the organism to the CNS (Fig. 1) (3). He pre- and obesity-associated metabolic disorders are
1849 1953 1970s 1994 RECENT YEARS
PVH
Glucose
Blood vessel VMH
ARC
The brain controls glucose
metabolism in the periphery Hypothalamic nuclei are GLP-1
Insulin
body weight and glucose Ghrelin
? Leptin
Periphery
Leptin
Dissection of complex
Hormones from the periphery neurocircuitry in feeding
control feeding states The discovery of leptin and systemic metabolism
Fig. 1. Timeline of discoveries detailing the brain mechanisms that underlie metabolic control. The
timeline shows key conceptual advances in our understanding of CNS-dependent control of body weight and
metabolism. Breakthrough discoveries, such as the identification of leptin and the melanocortin
neurocircuitry, have had implications for many areas of investigations, including the development of
therapeutics for obesity and metabolic diseases.

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projections into hypothalamic and extrahypo-

Box 1. Technical advances that facilitate defining the neurocircuitry of metabolic control. thalamic regions, where they engage down-
stream neural pathways through fast-acting
The tremendous complexity arising from the particularly high level of cellular heterogeneity and synaptic neurotransmitters and neuropeptides for met-
connectivity in neurocircuits that underlie homeostatic control have made functional investigations inherently abolic coordination. Owing to their localiza-
difficult. Advances in Cre/loxP technologies have provided an extended toolbox of approaches that enable tion in the ventral part of the hypothalamus,
anatomical and functional interrogations of defined cell types in the CNS. Although these techniques have AgRP and POMC neurons have the remark-
propelled the identification and detailed characterization of neurocircuits, critical limitations remain; the able ability to precisely detect fluctuations in
techniques are often based on a single, previously identified marker gene. hormone and nutrient levels in the blood-
Recent developments of high-throughput single-cell and single-nucleus sequencing methods have enabled stream (13). It was assumed that this is due
the definition of cellular subpopulations at unprecedented molecular resolution (25, 154). These approaches to a more porous blood-brain barrier, but a
have revealed that numerous transgenes that were previously considered specific to a certain cell exhibit new participant in the relay of hormonal and
more widespread distribution in further types and subtypes of cells, adding caution regarding the previously nutritional signals from circulation to these
assumed specificity of Cre-mediated targeting of neurocircuits on the basis of a single marker gene (Fig. 2). neurons has been revealed: tanycytes (14).
Although these data have provided us with exciting new knowledge, a major task for future functional These are specialized radial glia cells that line
investigations will be to advance bioinformatic tools that enable integration of these multiple emerging the third ventricle and make contact with

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datasets into standardized molecular atlases of brain regions to provide a unified nomenclature and blood vessels in the median eminence (ME)
assignment of cell types. Further, advances in spatial transcriptomic analyses and tools that enable the and nearby neurons in the mediobasal hypo-
integration of this spatial information with single-cell sequencing information will be required. Notably, thalamus. Tanycytes regulate GLP-1 and insu-
because single-nucleus sequencing can be performed on rapidly frozen tissue, it allows the capture of lin access to the ARC, although their role in
state-dependent changes in transcriptional regulation (56). Therefore, single-nucleus sequencing studies leptin transport is still a matter of debate
carry the potential to identify new neural cell types involved in metabolic control in an unbiased manner (15–18). Notably, deleting the insulin receptor
(Fig. 2). Last, recent developments in transgenic technologies that use combinatorial recombinase such as specifically from tanycytes in mice mimicked
Dre/rox– and Flp/frt–dependent recombination together with Cre/loxP–mediated recombination allows the insulin resistance that occurs in obesity
intersectional genetic targeting of specific subtypes of cells that are characterized by multiple molecular mouse models, which in turn altered the ac-
markers (Fig. 2) (47, 155, 156). These emerging developments will further our understanding of the tivity of AgRP neurons to regulate feeding
functional organization of metabolism regulatory neurocircuits at the level of highest cellular granularity. and glucose homeostasis (15). Thus, future re-
search should define the molecular and func-
tional organization of this cell type in humans
to characterize them as potential targets in
urgently needed to devise therapeutic interven- ral tissues in preparation for increasing nu- the treatment of metabolic diseases. In ad-
tions for these prevalent diseases. trient availability. Last, we discuss how this dition to tanycytes, a wide area of research
Additional evidence that obesity originates knowledge has led to the recent development has more recently unraveled a critical role for
through altered signaling in the CNS has of new therapeutics for obesity and metabolic other non-neuronal cell types in the hypo-
arisen from human genetics data, according to diseases. thalamus in control of energy metabolism reg-
which most gene variants in obesity are pre- ulatory neurocircuits. These include astrocytes,
dominantly expressed in the CNS (8). Further, Neural populations that control which themselves sense metabolism regula-
monogenetic defects in human obesity syn- systemic metabolism tory hormones, such as insulin and leptin
dromes also cluster in genes whose products The melanocortin circuitry is a prototypic reg- (19, 20), and their activity regulates neighbor-
act in the highly conserved hypothalamic neu- ulatory pathway in homeostatic control of sys- ing neurons through various mechanisms,
rocircuitry targeted by leptin in mice and rats temic metabolism (9). The core of this system such as neurotransmitter release as well as
(9). Last, defining the neurocircuitry-dependent comprises two neuronal populations, which ensheatment of metabolism-regulator neurons
regulatory principles underlying systemic en- reside in the arcuate nucleus (ARC) of the (21). Similarly, oligodendrocytes and microglia
ergy and glucose homeostasis as well as their hypothalamus and exert almost opposite func- have been identified as regulators of hypothal-
deregulation in obesity prevents the wide- tions in the regulation of feeding behavior, amic neuronal function and their deregulation
spread stigmatization of patients with obesity energy expenditure, and fuel metabolism. Agouti- in obesity (22, 23). However, how non-neuronal
as suffering from a simple lack of will power related peptide (AgRP) neurons are activated cells affect central metabolism-regulatory
to control their food intake and hence body in conditions of energy deficit, are inhibited by neurocircuits has been elegantly reviewed
weight (10). the fuel-communication signals leptin and in- elsewhere and is beyond the scope of this
In this Review, we discuss the recent ad- sulin, and promote foraging and food consump- Review (24).
vances in our understanding of the neurobio- tion. Pro-opiomelanocortin (POMC) neurons Several other neuronal populations in the
logy that underlies the regulation of food intake, are activated in states of positive energy bal- ARC have been identified as additional reg-
energy balance, and systemic glucose metabo- ance and the hormonal changes associated ulators of systemic metabolism. Initial ob-
lism. This includes molecularly distinct neuro- with it, reduce food intake, and increase energy servations of the ARC revealed that it is an
nal populations in energy-regulating neuronal expenditure. The tight interaction of AgRP and exceptionally heterogeneous hypothalamic
centers in mice and new developments in POMC neurons in control of feeding behavior nucleus, which contains phenotypic markers
human genetics to define conserved regula- had already been predicted on the basis of the for various neurotransmitters and neuropep-
tory pathways in metabolic control. These dis- orexigenic (feeding-promoting) effect of neuro- tides. Subsequent single-cell and single-nucleus
coveries have also broadened our understanding peptide Y (NPY) as well as the demonstration of RNA-sequencing approaches have enabled an
of CNS-dependent control of integrative physi- a dense network of NPY-immunoreactive axons in-depth cellular analysis of the ARC in mice
ology beyond the concept of homeostatic reg- and axon terminals in close apposition with and pinpointed new cellular substrates underly-
ulation, highlighted by recent findings that b endorphin–immunoreactive neurons through- ing metabolic control (Fig. 3) (25, 26).
food-predicting cues rapidly engage neurocir- out the medial basal hypothalamus (11, 12). Both g-Aminobutyric acid (GABA) is the most
cuits to adapt metabolic pathways in periphe- of these ARC neurons show a large number of abundant fast-acting neurotransmitter in the

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jects to and synaptically inhibits PVH neurons

A SINGLE-NUCLEUS SEQUENCING
Hypothalamus
B CELL CLUSTERING AND IDENTIFICATION
UMAP of the hypothalamus
C STATE-DEPENDENT SIGNATURE
Energy deprived
through GABA release (25). Chemogenetic
Beads Oil stimulation of SST-ARC neurons potently in-
Nuclei Library preparation creases feeding in mice. However, single-cell
capture and sequencing RNA-sequencing analyses of the ARC revealed
Nuclei that SST-ARC neurons exhibit a transcriptional
profile that is very similar to that of AgRP-ARC
neurons (Fig. 3) (25). Thus, further experiments
will have to define the specific role of AgRP-
negative SST-ARC cells in feeding regulation.
Gene X A third GABAergic population was identi-
fied through an unbiased approach for molec-
Gene Y
ular profiling of activated neurons (34). This
study demonstrated that short-term (3 days)
exposure of mice to a high-fat diet (HFD) ac-
Activation signature tivates ARC neurons that express the neuro-

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Steady state Obese Fos Noct Gem
peptide prepronoceptin (PNOC) (35). Selective
assessment of PNOC-ARC neurons showed
Circadian
that their activation promotes feeding, whereas
their ablation protects from overconsumption
D SPATIAL ALLOCATION (hyperphagia) and body weight gain upon HFD
Alignment and decoding feeding (35). Thus, PNOC-ARC neurons are a
Tissues key population for acutely controlling feed-
Gene X ing behavior and obesity development when
Gene Y
energy-dense, highly palatable food is ac-
Array cessible. Circuit-mapping studies established
that PNOC-ARC neurons synaptically inhibit
E MANIPULATIONS WITH NEUROSCIENCE TOOLS nearby POMC neurons through GABA (35).
Cre
X Gene X This is notable because dynamics in ARC-
Cre Multiple
X Targeted derived GABAergic synaptic input has been
Dre feature
subpopulation implicated in determining POMC neuron ac-
sa2
6 targeting Dre
Ro Gene Y
AAVs and/or Transgenics tivity in response to changes in nutrient avail-
ability (Fig. 3) (36–39). More recently, elegant
loxP loxP rox rox studies have revealed a function of non-AgRP,
Rosa26
NPY-expressing neurons in the ARC to control
promoter Stop Stop Transgene feeding under positive energy balance (40).
loxP loxP FRT FRT Important unsettled questions at present are
Intron
Virus gene Trans to which extent these ARC populations over-
INTERSECT promoter
lap, what central and circulating signals me-
diate the energy state–dependent activity
Fig. 2. Defining a cell’s function in metabolic control. (A) Workflow shows the use of droplet-based single- regulation of these GABAergic neurons, and
nucleus RNA-sequencing to capture and measure the expression levels of genes in discrete cell types. Nuclei can how dysregulation of these circuit mecha-
easily be isolated from either fresh or frozen tissue, and transcriptomic profiles of thousands to millions of nisms could relate to increased susceptibility
individual cells can be obtained. (B) Visualization of cell heterogeneity and expression of marker genes in to metabolic disorders.
annotated cell types is achieved through uniform manifold approximation and projection (UMAP) embedding. For many years, it was assumed that POMC
(C) Nuclei collection in different metabolic states provides a snapshot of transcriptomic profiles of numerous neurons promote meal termination because
genes, including cell-specific markers that reflect activity levels. (D) Measuring and mapping gene activity in the genetic deficiency of POMC or lack of POMC
spatial context with recent transcriptomic approaches allow the identification of a cell’s location. (E) A suite of neurons result in hyperphagia and severe
new viruses and recombinase driver lines expands the ability to target chemo- or optogenetic tools to identified obesity in humans and mice (41–44). How-
cell types on the basis of multiple genetic factors for manipulation studies. ever, acute opto- or chemogenetic manipu-
lations of POMC neurons have repeatedly
been found to have no or minimal effects on
ARC. Consistent with its relevance as a feeding- chronically silencing them attenuates food in- short-term feeding behavior in mice (41, 45–48),
promoting signal released from AgRP neurons take and body weight gain. These effects are pro- which indicates that POMC neurons are more
(27–29), additional orexigenic, GABA-releasing posed to be driven by GABAergic inhibition of important for long-term regulation of energy
ARC populations have been identified. A do- downstream satiety neurons, including those balance, and/or points to the possibility that
paminergic, tyrosine hydroxylase (TH)–expressing located in the paraventricular hypothalamus subsets of POMC neurons may have distinct
population (30) was originally classified as a (PVH) (30). Because GABAergic inhibition of PVH feeding regulatory functions. Given that the
purely neuroendocrine cell type whose dopa- satiety neurons by AgRP neurons also controls fast, feeding promoting action of orexigenic
mine release coordinates the secretion of the feeding behavior (27), these findings suggest ARC neurons is mediated by rapid inhibition
principal lactogenic hormone prolactin from that this inhibitory pathway is a common fea- of downstream satiety neurons (27), a rapidly
the pituitary (31–33). However, when optogenet- ture of orexigenic, GABA-releasing ARC neurons. acting satiety neuron, if it exists, would pre-
ically stimulated in mice, ARC-TH neurons evoke Another orexigenic ARC population is marked sumably release a fast-acting excitatory neu-
a rapid increase in feeding (30). Correspondingly, by somatostatin (SST) expression, which pro- rotransmitter. In this context, a glutamatergic

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trast to what is observed upon chemogenetic

Food-predicting cues Hunger and Satiety stimulation of the entire POMC-ARC popula-
tion, selective activation of Glp-1r–expressing
Hypothalamus
Appetitive and but not Lepr-expressing POMC neurons de-
Sight, smell, and aversive behavioral creased feeding in a more rapid manner, which
taste of food adjustment is consistent with previous studies that revealed
that the food intake–suppressing effect of
ARCUATE GLP-1 is at least in part mediated by POMC
Gastric and PRE- Glucose tolerance
NUCLEUS
intestinal ABSORPTIVE neurons (47, 57). Thus, further definition of
distension functionally relevant subsets of previously con-
Astrocyte Insulin sensitivity
sidered homogenous metabolism regulatory
neurons is warranted, which could also define
Absorbed TH targets for therapeutic intervention (58).
nutrients SST GABA
POST- GABA
INGESTIVE Lipolysis Integration of sensory food cues
Gut hormones MSH
PNOC
POMC In addition to internal feedback regulatory
GABA

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mechanisms communicating systemic energy
NPY Proteostasis
Adipocyte, status to the CNS, integration of signals that
AgRP Oxtr
pancreatic, LONG-TERM 3V Vglut2 predict future nutrient uptake are pivotal to
GABA
and hepatic FEEDBACK maintaining a stable metabolic state. Environ-
hormones Energy expenditure mental cues associated with food consump-
Tanycytes Microglia
tion as well as with seeing, smelling, or tasting
food elicit a myriad of physiological processes,
Fig. 3. ARC-based neurocircuits in control of metabolism. The arcuate nucleus of the hypothalamus
including saliva production, secretion of diges-
(ARC), a small nucleus located at the lower surface of the brain, has emerged as a key regulator of systemic
tive enzymes, and release of hormones such as
metabolism. Intense research over the past two decades has revealed that Agouti-related peptide (AgRP)
insulin (59, 60). These feed-forward, anticipa-
and proopiomelanocortin (POMC) neurons, which constitute key components of the melanocortin circuitry, exert
tory mechanisms, often referred to as cephalic
almost exclusive opposite regulatory functions of various physiological processes. In addition, recent studies
phase responses, ensure that consumed food
have established several additional ARC neurons as regulators of metabolism: dopaminergic, tyrosine hydroxylase
is rapidly digested and absorbed and that nu-
(TH)–expressing, somatostatin (SST)–expressing, prepronoceptin (PNOC)–expressing, and oxytocin receptor
trients are efficiently metabolized and removed
(Oxtr)–expressing ARC neurons. ARC neurons have the ability to sense alterations in circulating levels of hormonal
from circulation (61). In addition, cues that
and nutritive factors, which constantly adjust their neural activity to the internal state of the organism. Recent
anticipate food consumption are linked to ap-
activity recordings have further uncovered that cues predicting future food consumption and nutrient uptake as
petitive and aversive behavioral adjustments,
well as gut-derived, postingestive signals adapt the firing properties of discrete ARC neuron populations.
hunger and satiety regulation, and preferences
for certain food items. In contrast to the slow
population of ARC neurons, marked by ex- afferents emanating from the ARC—and po- feedback signals that primarily arise from
pression of the oxytocin receptor (Oxtr), rap- tentially also other, glutamatergic inputs— changes in circulating levels of hormones,
idly decreases feeding when stimulated (Fig. 3) plays an important role because PVH neurons transmission of feed-forward signals must
(48). Consistent with the above-mentioned sa- efficiently integrate excitatory inputs owing to be fast to initiate the appropriate responses
tiety model, these Oxtr neurons inhibit feeding their expression of the voltage-gated sodium before food consumption—hence, they must
through the PVH, where they release glutamate channel NAV1.7 (53). Notably, genetic deletion be mediated by neuronal pathways.
onto satiety neurons (48). Thus, in contrast to of NAV1.7 from PVH neurons in mice decreases Electrophysiological recordings in rodents
the hunger-promoting system in which rap- their firing owing to diminished summation of and monkeys found that sensory signals that
idly acting (GABA and NPY) and slowly acting excitatory inputs and leads to the development predict future consumption or nutrient uptake
(AgRP) signals are released by one group of of massive obesity (53). rapidly alter neuronal activity in hypothalamic
neurons—AgRP neurons (27, 29, 49, 50)—the In addition to the diversification of a paral- regions (62–64). Interpretation of these find-
satiety-promoting system is functionally diver- lel glutamatergic Oxtr and melanocortin POMC ings and conceptualizing them with the var-
sified and works through two parallel-projecting circuits subserving the PVH, diverse groups of ious, functionally distinct neuronal populations
neurons: ARC-Oxtr neurons, which release the POMC neurons have been identified through of the hypothalamus was, however, difficult
fast-acting neurotransmitter glutamate, and their distinct electrophysiological responses because the molecular identity of the recorded
POMC neurons, which work through melano- to insulin and leptin and molecular profiles neurons was unknown. Optical and electro-
cortin 4 receptor (MC4R) signaling (48). Nota- (54, 55). Acute activation of POMC neurons physiological measurements from genetically
bly, glutamatergic projections from ARC-Oxtr can also increase feeding in mice, which is pre- distinct cell types have offered new insight
neurons predominantly engage MC4R-expressing sumably mediated by preferential processing of into the dynamics of defined neuronal pop-
PVH satiety neurons (51, 52), and this circuit is the POMC precursor to b-endorphin in a subset ulations in awake, freely behaving animals
regulated in strength by MC4R signaling; spe- of these neurons (46). In addition, single-cell (65–67). This led to the discovery that AgRP
cifically, activation of MC4R by the POMC- RNA-sequencing analyses revealed that leptin neurons in energy-deprived mice rapidly re-
derived neuropeptide a-melanocyte-stimulating receptor (Lepr)–expressing and Glp-1 receptor duce their activity within seconds of the ap-
hormone (a-MSH) potentiates transmission (Glp-1r)–expressing POMC neurons represent pearance of food or presentation of sensory
across the glutamatergic ARC→PVH satiety largely distinct subgroups of cells (55, 56). They cues such as those predicting food consump-
synapse (48). These two parallel-projecting exhibit a distinct profile of neuropeptide re- tion (Fig. 4) (68–70). This unexpected rapid
satiety neurons thus interact by means of ceptors that are indicative of distinct regula- reduction in neuron activity was found to
MC4R-mediated synaptic plasticity. The con- tory principles in addition to differential Lepr begin before food ingestion and to be scaled
trol of PVH satiety neurons through excitatory and Glp-1r expression (47). Interestingly, in con- with the energy content of the presented food

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(68–70). Consistent with the opposing activity
regulation of POMC neurons, the appearance
of food induced a rapid increase in their ac-
tivity (69, 70). These compelling data un-
covered that AgRP and POMC neurons can
anticipate the future impact of consumed
nutrients.
Given the wide array of physiological pro-
cesses controlled by AgRP neurons, the dis-
covery of their food cue–evoked inhibition has
brought forward various hypotheses to explain
its function (68–74). The paradoxical observa-
tion that their inhibition occurs before food is
actually consumed, and even persists during
food consumption, implied that increased fir-
ing of AgRP neurons is not required for driv-
crease in food intake requires NPY signaling
(50), indicating that AgRP neuron–derived NPY
sustains hunger during a meal. A primary role
for the rapid activity changes in guiding learned
behavior was based on observations that AgRP
neuron activation is mildly aversive, which sug-
gests that their acute reduction in activity
could act as a teaching signal (68). To test this
directly, one afferent neural pathway respon-
sible for rapid inhibition of AgRP neurons was
recently defined (76). Through this experimen-
tal design, any slow—nutrient- or hormone-
mediated—effects could be bypassed. This
revealed a polysynaptic circuit connecting
the lateral hypothalamus to Lepr-expressing
GABAergic neurons of the dorsal medial hy-
thalamus, and the magnitude of these responses
covaries with nutrient levels in the blood at the
time of the cue-nutrient conditioning (78), which
provides support for the notion of an integration
between external and internal nutritional cues
also in humans.
Because acute stimulation of AgRP neurons
rapidly alters metabolism in peripheral tissues
(49, 79, 80), it is likely that their food cue–
evoked inhibition also contributes to cephalic-
phase responses. This has, however, not been
directly explored and should be the subject of
future studies. Given that AgRP neurons pro-
vide strong inhibitory input to POMC neurons
(27), this local connection may underlie the
rapid activation of POMC neurons that is ob-

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ing feeding behavior. Optogenetic stimulation
of AgRP neurons in the absence of food, and
tens of minutes before food becomes available,
is sufficient to evoke the same voracious feed-
ing response that can be observed when stim-
ulation is performed in the presence of food
(75). Recent work has shown that release of
the neuropeptide NPY bridges the sustained
feeding response by AgRP neurons (50). Spe-
cifically, brief optogenetic stimulation of AgRP
neurons in the absence of food drives vora-
cious feeding after AgRP neuron stimulation
has been terminated (50). This long-lasting in-
Sensory cues that
anticipate food
Insulin
sensitivity
GABA
LepR
Normal feeding
Glutamate
Activity
pothalamus, which synaptically inhibit AgRP
neurons (Fig. 4) (76, 77). Notably, imaging the
different nodes of this circuit demonstrated
that it is rapidly engaged by sensory cues pre-
ceding food ingestion (77). Moreover, its selec-
tive disruption greatly impaired the ability of
mice to learn a specific operant task for acquir-
ing food (77). These findings show that the
acute drop in the activity of AgRP neurons is
critical for behavioral adjustments, probably
by acutely eliminating the negative feeling of
hunger. Interestingly, in humans learned re-
sponses to food cues are observed in the hypo-
Hunger Energy Nucleus of the
Expenditure solitary tract
Glp1R
AgRP Nodose
ganglia
Food
CCK OxtR
served after sensory food perception (69, 70).
There is strong evidence that the acute in-
crease in POMC neuron firing rapidly induces
metabolic changes in the liver after a meal
(postprandial) (81). Specifically, calcium sig-
nal analyses showed that POMC neuron activ-
ation upon sensory food perception correlates
with hepatic activation of the mammalian tar-
get of rapamycin (mTOR), preparing the orga-
nism for the ingestion of food (81). This rapid
signaling in the liver is recapitulated by opto-
genetic stimulation of POMC neurons, whereas
deficiency of the downstream melanocortin
pathways attenuates the hepatic responses to
sensory food perception (81). These findings
are consistent with the emerging concept of
POMC neurons as rapid sensors of food-related
cues to fine tune peripheral metabolism. Ex-
tending the concept of sensory food perception–
dependent POMC neuron regulation, a study
revealed that during fasting, food-odor stimu-
lation is sufficient to increase free fatty acids in
the blood through adipose tissue lipolysis in an
olfactory memory–dependent manner in mice,
which is mediated by the central melanocortin
and sympathetic nervous systems (82).

Collectively, the emerging data indicate that

Glut
utt 5-HT
Hypothalamus sensory perception–dependent but also home-
PYY
ostatic hormone–dependent regulation of mela-
Time
Food Gastric EEC nocortin neurons not only control feeding
perception infusion behavior and energy expenditure but also
Food cue glucose and lipid metabolism, as well as pro-
Activity

Activity

teostasis in peripheral tissues. This supports

Lateral the overarching concept that these multimodal
Dorsal medial energy state–sensing neurons are ideally po-
Time Time
sitioned to adapt the complex regulation of
integrative physiology to the energy state of
Fig. 4. Rapid and sustained regulators of AgRP neuron activity. Energy deprivation activates AgRP the organism. Given that energy sensing, me-
neurons that, once engaged, adapt numerous physiological processes, such as systemic insulin sensitivity, tabolism, and proteostasis represent key reg-
hunger drive, and thermogenesis. The increased activity of AgRP neurons is inhibited upon food consumption, a ulators of longevity and health span, these
process that comprises two distinct components. The first is sensory detection of food, or cues associated with food neurons are also potential regulators of these
delivery. This cue-evoked inhibition of AgRP neurons is astoundingly rapid, mediated by inhibitory GABAergic processes (83). AgRP neurons are required for
neurons of the dorsal medial hypothalamus (DMH) that are marked by expression of the leptin receptors (LepR). the activation of liver autophagy, another key
Recent work uncovered that glutamate release from lateral hypothalamic neurons regulates the activity of this neural pathway in protein quality control and life
pathway, which is required for learning food-acquisition tasks. The second component, which is slow and longer span, upon short-term food restriction in mice.
lasting, is triggered by nutrients that reach the gut. Factors secreted from enteroendocrine cells of the intestine— Of note, AgRP neuron–dependent control of
including cholecystokinin (CCK), peptide YY (PYY), and serotonin (5-HT), as well as gut-innervating, stretch-sensing liver autophagy declines upon aging, thus
vagal afferents—mediate the sustained inhibition of AgRP neurons. opening interesting new avenues for further

Brüning and Fenselau, Science 381, eabl7398 (2023) 29 September 2023 5 of 10

RES EARCH | R E V I E W
investigation. This points to the possibility that
melanocortin neurons represent targets to im-
prove life span and health span (84). Given the
emerging concept of sensory food perception–
dependent regulation of these key metabolism
regulatory neurons, primarily through olfactory
perception, it is notable that olfactory dysfunc-
tion represents a strong predictor of 5-year
mortality (85).
Neuronal basis of gut-brain communication
The rapid activity changes in AgRP and POMC
neurons that are triggered by sensory food
perception remain at a relatively stable level
if mice subsequently obtain and consume food
ad libitum (Fig. 4) (68–70, 86). If food is, how-
ever, not accessible, or provides no or only few
calories, the acute activity changes are readily
reversed (68–70, 86). Thus, after transient,
sensory-driven signals, postingestive signals
eventually reach the ARC and sustain neuro-
nal activity at a new level. Recent studies have
demonstrated that food-derived signals that
arise in the gut play an important role in
mediating these responses (87–89). Specifically,
calcium recordings from AgRP neurons showed
that their inhibition after food consumption
is proportional to the caloric content of the
food (87, 89). This correlative inhibition is re-
capitulated when nutrients are directly delivered
into the stomach or small intestine, bypassing
any sensory and oral cues (Fig. 4) (87, 89). Thus,
AgRP neurons integrate online information
from the gut that precedes assimilation of in-
gested calories and eventually results in changes
of circulating energy state–communicating
hormones. Molecularly distinct vagal sensory
neurons, which bridge the gut and the brain,
are a major afferent pathway of this commu-
nication and mediate various physiological re-
sponses to maintain systemic metabolism.
Sensory neurons of the vagus nerve, com-
monly called vagal afferents, are pseudouni-
polar neurons, whose cell bodies are located
in two nodose ganglia (NG) at the base of the
skull in proximity to the carotid arteries (90, 91).
Their central axons project to the dorsal
hindbrain, where they synaptically activate
neurons in the nucleus of the solitary tract
and in the area postrema (NTS/AP) (Fig. 4)
(90, 91). Their peripheral axons target the organs
of the gastrointestinal (GI) tract, where they
sense mechanical signals, such as stretch or
distension (92). In addition, they sense chem-
ical signals, primarily through hormones
secreted by enteroendocrine cells (EECs),
including cholecystokinin (CCK), GLP-1, pep-
tide YY (PYY), and serotonin [5-hydroxy-
tryptamine (5-HT)] (91, 93, 94). Vagal afferent
activation by these gut hormones is likely to
dominate the sustained inhibition of AgRP
neurons after food consumption. Infusion
of nutrients directly into the small intestine
(87–89, 95), which causes the natural release
Brüning and Fenselau, Science 381, eabl7398 (2023)
of EEC hormones (94), as well as pharmaco-
logical administration of CCK, PYY, and 5-HT
all potently reduce AgRP neuron activity in
the ARC (87–89, 95). Moreover, surgical re-
moval of the vagus nerve blocks the ability of
gut-delivered fat and exogenous CCK to inhibit
AgRP neuron activity (Fig. 4) (88). Elegant ma-
nipulation studies uncovered that vagal afferents
that innervate the stomach and duodenum
mediate the satiating action of CCK and nu-
trient sensing (96). Notably, activation of this
vagal gut-brain pathway was found to be
highly rewarding as assessed by using self-
stimulation and place preference assays, and
to recruit substantia nigra dopaminergic re-
ward neurons (96). Thus, vagal afferents con-
vey gut-derived signals that decrease the
activity of aversive AgRP neurons and that
enhance reward-related signaling through
the dopaminergic pathway.
Vagal afferents are functionally and anato-
mically heterogeneous, and their peripheral
axons also innervate other internal organs in
addition to the stomach and the intestine (90).
RNA-sequencing of NG, including single-cell
RNA-sequencing of retrogradely labeled organ-
specific innervating neurons, recently char-
acterized the population(s) that transmit
gut-derived information to the brain in mice
(97–101). These studies revealed that vagal
afferents express various genetic markers, in-
cluding calcitonin gene-related peptide 1 (Calca),
Glp-1r, the proton-sensing G protein–coupled
receptor Gpr65, vasoactive intestinal peptide
(Vip), and Oxtr. The subtypes marked by
these five genes are particularly noteworthy
because as demonstrated through selective
histological assessment, they show distinct
innervation patterns and morphologies in
GI tract organs (98, 99, 101, 102). Calca and
Glp-1r define subtypes that primarily innervate
the stomach (98, 99, 102, 103), where Calca
terminals form putative chemosensory muco-
sal endings (98, 103). Glp-1r terminals are
enriched in gastric muscular layers and form
intraganglionic laminar endings (IGLE)
(98, 99, 102), which are thought to be me-
chanosensors. By contrast, Gpr65, Vip, and
Oxtr subtypes primarily innervate the small
intestine, where Gpr65 and Vip mucosal
endings are enriched in intestinal villi, and
Oxtr form IGLE, with the highest density
in the muscular layers of the proximal small
intestine (98, 99, 102). Notably, as revealed by
simultaneously monitoring AgRP neuron
activity while chemogenetically manipulating
distinct vagal afferents, stimulation of mecha-
nosensory (Oxtr and Glp-1r) but not chemo-
sensory (Gpr65 and Vip) subtypes were found
to selectively inhibit AgRP neuron activity
(Fig. 4) (98). These observations suggest that
AgRP neuron–based hunger circuits integrate
online mechanical information from the gut.
This pathway has likely far-reaching func-
29 September 2023
tional consequences and explains why gastric
and intestinal distension by non-nutritive sub-
stance reduces feeding owing to their ability to
fill GI tract organs correlates with AgRP neuron
inhibition (98). Moreover, acute chemo- and
optogenetic stimulation of the same mechano-
sensory vagal afferents, but not chemosensory
subtypes, has been shown to potently inhibit
food intake in mice (98, 102).
The molecular mechanisms by which vagal
afferents detect mechanical stimuli in GI tract
organs remain incompletely understood. How-
ever, many of the receptors and ion channels
that are expressed by somatosensory neurons
that detect mechanical stimuli in other periph-
eral organs (104, 105), such as the skin, are also
Downloaded from https://www.science.org at Universidade Estadual de Campinas on October 16, 2023
found in vagal afferents (97, 98). Thus, these
molecular sensors likely account, at least in
part, for the stretch- and distension-induced
activation of vagal afferents whose periph-
eral terminals innervate the muscular layers
of the stomach and intestines (99). In addi-
tion, activation of EECs may contribute to gut-
brain communication by mechanosensory
vagal afferents to inhibit food intake. EECs
can convert mechanical stimuli into the pro-
duction of gut hormones, which in turn acti-
vate vagal afferents (106–108). This could
include CCK release and the activation of
stomach-innervating, stretch-responsive Glp-1r
subtypes. Indeed, selective stimulation of CCK-
expressing EECs suppressed feeding in mice
(109, 110). This was abolished by removal of
vagus nerve innervation of the GI tract or
blocking CCK receptors, which are highly ex-
pressed in Glp-1r vagal afferents (98, 99, 102).
It is likewise unclear what central pathways
downstream of vagal afferents relay gut-
derived information to the ARC and how this
route actually contributes to the regulation of
feeding behavior as well as other aspects of
metabolism. Systemic glucose regulation is
of particular interest in this regard because
neural gut-brain communication and ARC-
based circuits both have long been recognized
as essential for glycemic control, especially in
the postprandial state (13, 111). Vagal afferent
signaling onto distinct neurons in the hind-
brain NTS/AP is believed to be an important
control point for the integration and routing
of gut-derived information (Fig. 4). Molecu-
larly defined NTS/AP neurons are activated
upon selective opto- or chemogenetic stimu-
lation of gut-innervating vagal afferents in
mice (96, 98, 102) and by natural stimuli that
excite them, such as organ stretch, CCK ad-
ministration, meal ingestion, or gastric delivery
of nutrients (112, 113). Further, manipulating
distinct NTS/AP neurons produces effects on
food consumption (114–121), appetitive and
aversive behavior (115, 116), and systemic
glucose homeostasis (120, 122). From the NTS/
AP, gut-derived signals could reach the ARC
through direct projections or relay through
6 of 10
RES EARCH | R E V I E W
other nodes. The lateral parabrachial nucleus
(LPBN) is a strong candidate node for relaying
gut mechano- and chemosensory signals be-
cause it is heavily innervated by the NTS/AP
(123). Moreover, recent calcium imaging stud-
ies have established that anorexigenic neurons
in the LPBN are activated by meal ingestion and
selective stimulation of the stomach (124, 125).
However, neurons in the NTS/AP, and also in
the LPBN, are remarkably heterogeneous, and
further research is needed to fully map their
afferent and efferent connections (114, 118, 126).
Another major obstacle in deciphering the
functionally relevant circuits between vagal
afferents and the ARC has been the technical
difficulties associated with targeting vagal
afferents in NGs, which are extremely small and
located close to delicate structures. Recently,
the metabolic functions of specific vagal affer-
ents have been investigated by using an inter-
sectional approach to facilitate genetic entry
into molecularly defined subtypes (102). This
revealed that stomach-innervating mechano-
sensory Glp-1r vagal afferents relay anorexi-
genic signals (99, 102) and play a crucial role
in controlling glycemia during feeding (102).
By contrast, selective manipulations of Gpr65
vagal afferents, which are activated by intes-
tinal nutrients (99), revealed that their activa-
tion increases hepatic glucose production (102),
but that they are dispensable for food-intake
regulation (98, 102). Future work is required
to map the functional neurocircuits between
these and other gut-innervating vagal afferents,
NTS/AP neurons, and ARC neurons and to
detail the connections between gut mechano-
sensation and chemosensation and their im-
pact on systemic metabolic homeostasis.
Disease-associated circuit alterations
Soon after the discovery of leptin, it was rec-
ognized that obese humans and obese mouse
models exhibit elevated leptin levels and dis-
play an attenuated response to exogenously
applied leptin (127, 128). This led to the foun-
dation for a concept of leptin resistance in
obesity, particularly in the ARC (129). Similarly,
mouse obesity models exhibit resistance to the
regulatory function of the hormones insulin
and ghrelin in the brain (130). These findings
have nurtured research into the molecular
mechanisms of central hormone resistance in
obesity in analogy to the mechanisms under-
lying insulin resistance in peripheral tissues of
humans and mouse models of insulin resist-
ance and type 2 diabetes mellitus. Numerous
mechanisms leading to obesity associated leptin
and insulin resistance mainly in the ARC,
particularly in POMC, and AgRP neurons have
been identified. Such mechanisms include
increased expression of the suppressor of cyto-
kine signaling 3 (SOCS-3), which is a well-
characterized inhibitor of LEPR and insulin
receptor (INSR) signaling (131). Moreover, in-
Brüning and Fenselau, Science 381, eabl7398 (2023)
creased hypothalamic inflammation, in part
from enhanced astrocyte and microglia acti-
vation, has been shown to cause neuronal
leptin and insulin resistance, even preceding
the manifestation of systemic metaflamma-
tion in obesity (132). The complexity of the par-
ticipating CNS cell types in these processes—
microglia, circulating macrophages, and
astrocytes—have been reviewed elsewhere (133).
Exaggerated endoplasmic reticulum (ER)
stress contributes to altered hormone respon-
siveness in critical metabolism regulatory neuro-
circuits such as POMC and AgRP neurons (134).
In addition, ectopic lipid deposition and asso-
ciated lipotoxicity has also been linked to leptin
and insulin resistance in the ARC, and identify-
ing the responsible lipid species accumulating
in the ARC to induce hormone resistance is still
subject to intense research (135). The dynamic
regulation of mitochondrial function and dyna-
mics in metabolism regulatory neurons has
been identified as a key determinant of ARC
neuronal populations, and deregulated balance
of mitochondrial fission and fusion in POMC
and AgRP neurons has been linked to altered
fuel metabolism of these cells and their fine-
tuned, energy state–dependent regulation (136).
To add more complexity, these mechanisms
are closely interconnected because ER stress
and mitochondrial stress responses are inti-
mately linked, and lipotoxic species accumu-
lating in obesity have been found to disrupt
both mitochondrial dynamics and function
as well as to cause ER stress, also in the CNS.
Although most of the present studies have
identified cell-autonomous neuronal changes
in obesity in mice, the effect of HFD-feeding
and obesity on neuronal wiring and commu-
nication remains ill defined. Studies on the
effects of altered maternal metabolism during
pregnancy on the long-term predisposition of
the offspring to the development of obesity
and metabolic disorders have revealed that
deregulated insulin signaling and ER stress
activation inhibit projection formation of
POMC neurons in offspring during critical
developmental periods (137, 138). This effect
then causes altered POMC neuron communi-
cation to downstream effector neurons in the
offspring, leading to increased propensity of
obesity and type 2 diabetes mellitus develop-
ment. Interestingly, mutations in axon guidance
molecules, which are critical for POMC neuron
projection development in mice, have also been
identified in humans with monogenic obesity
(139). Thus, the field of metabolic perinatal
programming of critical feeding circuits clearly
deserves further study.
Therapeutic strategies to control metabolism
The discovery of leptin has provided a paradigm-
shifting molecular correlate that has paved
the way for the functional interrogation of
metabolism regulatory neurocircuits. Accord-
29 September 2023
ingly, hopes were high for leptin treatment of
obesity. However, it was soon realized that
although leptin provided a cure for humans
with rare leptin gene mutations, the majority
of obese humans presented with elevated leptin
levels, which is indicative of leptin resistance.
As such, treating obese humans with leptin
only yielded disappointing outcomes (140).
Nevertheless, recent studies have identified
subtypes of obese humans who exhibit rela-
tively low circulating leptin levels in proportion
to their body-mass index, which is indicative
of relative leptin deficiency, and these individ-
uals exhibit the most profound weight reduc-
tion upon administering recombinant leptin.
Thus, identifying the proper patient class could
Downloaded from https://www.science.org at Universidade Estadual de Campinas on October 16, 2023
make leptin a therapeutic option for a substan-
tial number of obese patients. Given that leptin
resistance may occur in the majority of patients,
strategies to resensitize leptin action in obesity
may provide a promising avenue for new ther-
apeutics. Targeting pathways such as exagger-
ated ER stress and lipotoxicity in hypothalamic
neurons may thus offer new strategies. Appli-
cation of chemical chaperones or improving
leptin action with celastrol, a chemical compound
isolated from the root extracts of Tripterygium
wilfordii, have been shown to enhance leptin
sensitivity and reduce food intake and body
weight in HFD-fed obese mice, which currently
awaits further clinical development (141).
Alternative pathways targeted to improve
weight loss include treatment with long-acting
GLP-1 analogs. These drugs represent one of
the few effective approaches currently in cli-
nical practice. Liraglutide and more recently
semaglutide are approved to treat obesity in
some countries; semaglutide treatment is
capable of reducing body weight by up to 20%
(142). Although the targets of GLP-1 to reduce
food intake have been extensively studied over
recent years—and clearly include POMC neu-
rons in the ARC, as well as through an only
recently identified Lepr/Glp1r–expressing neu-
ron population in the dorsal medial hypo-
thalamus (DMH) (143)—GLP-1R is expressed
in multiple cell types in the central and periph-
eral nervous system, and the weight-reducing
effect of GLP-1 analogs has been shown to
depend on both systems (121). The above-
mentioned NTS/AP region of the hindbrain,
which relays gut-derived information, likely
plays an important role in mediating the
weight loss–promoting effects of GLP-1 ana-
logs. Studies in mice, rats, and nonhuman pri-
mates have revealed that GLP-1–responsive
cells are distributed throughout the NTS/AP
(118, 144–146) and that the activity of these
cells contributes to the observed feeding sup-
pression and body weight loss upon adminis-
tration of GLP-1 analogs (118). Although
further investigations are needed to fully define
the functional cellular and circuit mechanisms,
these data provide support that this hindbrain
7 of 10
RES EARCH | R E V I E W
region is a promising target for the metabolic
benefits of peripherally administered com-
pounds that enable the treatment of obesity.
Another very promising approach for weight
reduction and improvement of metabolism
in obesity builds on the recent development of
polypeptide agonists. This new class of thera-
peutics unifies receptor specificity of two or
more neuropeptides in a single molecule and
among others includes GLP-1-glucagon, GLP-
1–gastric inhibitory polypeptide (GIP), or other
polyagonists (147). These substances exhibit
tremendous efficacy in preclinical models, and
recently, the first GLP-1–GIP agonist provided
superior efficiency as compared with the weight-
reducing effect of semaglutide and has obtained
approval for treatment of type 2 diabetes (148).
Multiple other combined modalities of neuro-
peptide combinations are currently undergoing
advanced clinical testing (149). However, the
molecular targets of these complex drugs still
await detailed elucidation, and approaches such
as single-cell sequencing and cell type–specific
modulation of neuronal activity will aid in the
elucidation of their exact therapeutic mecha-
nism(s) (Box 1 and Fig. 2).
Another important therapeutic challenge is
posed by weight regain after successful weight
reduction, which also holds true after dis-
continuation of long-acting GLP-1 analogs (150).
Further defining the underlying mechanisms,
which include processes of long-term adapta-
tions in the neural pathways that coordinate
the activity of ARC-based feeding circuits, may
lead to the development of molecules that
counteract this well-described yo-yo effect.
Weight loss upon caloric deprivation in mice
leads to a remarkably long-lasting enhance-
ment of the excitatory synaptic input to AgRP
neurons of the ARC, causing their elevated
neural activity and concomitant increase in
hunger drive until lost weight is regained (151).
Identifying the molecular mechanisms respon-
sible for the observed long-term effects will be a
major task for future investigations to advance
targeting strategies that enable inhibiting the
induction, or reversing the maintenance, of this
neuronally induced synaptic plasticity mecha-
nism. Because reorganization of the synaptic
inputs to AgRP and POMC neurons are ob-
served in mouse models of obesity (36), tar-
geting the underlying signaling pathways may
also offer new ways to offset obesity-induced
alterations in their energy state–dependent
activity regulation as well as how these neu-
ronal populations integrate gut-derived and
anticipatory signals when highly palatable
energy-dense food is available in obese indi-
viduals (95).
Conclusions
Further refinement of the molecular-systems
neuroscience approaches described for pre-
clinical research may pave the way for even
Brüning and Fenselau, Science 381, eabl7398 (2023)
more innovative therapeutic approaches. Use
of optogenetics in humans is entering clinical
trials for vision restoration (152). Therefore,
development of improved opto- or chemogenet-
ic tools alongside the more defined identifi-
cation of targetable critical neuronal nodes in
metabolic control may lead to the develop-
ment of gene therapeutic approaches for the
remote control of feeding behavior and sys-
temic metabolism (153). Nonetheless, all of
these developments to treat or even prevent
obesity will critically depend on furthering
our understanding of the detailed regulatory
principles of neurocircuits in metabolism.
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AC KNOWLED GME NTS
We apologize to all colleagues whose contributions to this broad
field of active research could not be covered because of the focus
and space limitations of the present Review. This work has
received funding from the European Research Council (ERC) under
the European Union’s Horizon 2020 research and innovation
program (grant agreement ID 742106 to J.C.B. and ID 851778 to
H.F.) and the BMBF through the German Center for Diabetes
Research (DZD) to J.C.B.; J.C.B. has received research funds
through collaboration agreements with Novo Nordisk, Denmark, and
Sanofi Aventis, Germany, and is founder of Cerapeutix. H.F. has
received research funds through collaboration agreements with
Novo Nordisk, Denmark. We thank members of the Brüning and
Fenselau labs for critical input and discussions. J.C.B. has received
consultancy fees from Eli Lilly and Company and Novo Nordisk.
License information: Copyright © 2023 the authors, some rights
reserved; exclusive licensee American Association for the
Advancement of Science. No claim to original US government
works. https://www.science.org/about/science-licenses-journal-
article-reuse
Submitted 3 April 2023; accepted 31 August 2023
10.1126/science.abl7398
10 of 10
 Integrative neurocircuits that control metabolism and food intake
Jens C. Brüning and Henning Fenselau

Science 381 (6665), eabl7398. DOI: 10.1126/science.abl7398

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Editor’s summary
The maintenance of body weight is regulated through a complex network of neuronal signaling, hormones, and gut-
brain interactions that allow adaptation to food intake and energy expenditure. Defining the nature of the underlying
neurocircuitry and how feedback regulation is achieved are important in understanding the development of obesity
and its attendant pathologies, such as type 2 diabetes mellitus and cardiovascular diseases. In a Review, Brüning and
Fenselau discuss our developing understanding of the neural pathways that underpin food intake, energy expenditure,
and systemic metabolism and discuss how this knowledge provides new therapeutic targets to treat obesity. —Gemma
Alderton

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