Cells 12 01801
Cells 12 01801
Cells 12 01801
Review
Neurochemical Basis of Inter-Organ Crosstalk in Health and
Obesity: Focus on the Hypothalamus and the Brainstem
Dhanush Haspula 1, * and Zhenzhong Cui 2
1 Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive
and Kidney Diseases, Bethesda, MD 20892, USA
2 Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, MD 20892, USA; [email protected]
* Correspondence: [email protected]
Abstract: Precise neural regulation is required for maintenance of energy homeostasis. Essential to
this are the hypothalamic and brainstem nuclei which are located adjacent and supra-adjacent to the
circumventricular organs. They comprise multiple distinct neuronal populations which receive inputs
not only from other brain regions, but also from circulating signals such as hormones, nutrients,
metabolites and postprandial signals. Hence, they are ideally placed to exert a multi-tier control
over metabolism. The neuronal sub-populations present in these key metabolically relevant nuclei
regulate various facets of energy balance which includes appetite/satiety control, substrate utilization
by peripheral organs and glucose homeostasis. In situations of heightened energy demand or excess,
they maintain energy homeostasis by restoring the balance between energy intake and expenditure.
While research on the metabolic role of the central nervous system has progressed rapidly, the neural
circuitry and molecular mechanisms involved in regulating distinct metabolic functions have only
gained traction in the last few decades. The focus of this review is to provide an updated summary of
the mechanisms by which the various neuronal subpopulations, mainly located in the hypothalamus
and the brainstem, regulate key metabolic functions.
Keywords: obesity; hypothalamus; appetite; glucose homeostasis; weight-loss drugs; AGRP; POMC;
NTS; incretins
2. Hypothalamic and Brainstem Nuclei Involved in Appetite Control and Energy Balance
The hypothalamus and brainstem are critical components of the homeostatic system
that regulates appetite and energy balance. These key brain regions have distinct neuronal
populations and nuclei, having both complimentary and contrasting roles, exert tremen-
dous control over several facets of energy balance. This occurs both at the level of energy
intake and energy expenditure. This section serves to introduce the distinct hypothalamic
and brainstem nuclei, and its primary role in the regulation of energy balance. More
detailed mechanisms involving the regulation of glycemia and lipid metabolism will be
discussed in the next section.
2.1. Hypothalamus
The hypothalamus is one of the most well-studied brain regions in metabolism. Apart
from regulating a broad range of thermoregulatory, reproductive, and cardiovascular
functions, it also exerts tremendous influence on several aspects of energy balance. The
hypothalamus is composed of multiple nuclei located adjacent to the third ventricle. These
nuclei comprise a distinct subpopulation of neurons, capable of altering energy intake
and/or energy expenditure via anabolic or catabolic functions. The complex nexus of
hypothalamic neuronal interconnections can integrate responses from peripheral signals
(hormones, nutrients, and metabolites), to modulate appetite centrally, and to influence lipid
and glucose metabolism, peripherally. Additionally, they also have reciprocal projections
to and from extrahypothalamic nuclei located in the brainstem, midbrain, and forebrain
which can also alter synaptic activity in the hypothalamic metabolic circuits. Consequently,
via integration and coordination of responses from the brain and periphery, hypothalamic
nuclei are key regulators of energy homeostasis.
on the other hand inhibits it [60,61]. For more information on the role of the melanocortin
system in regulating the HPT axis, readers can refer to other reviews on this topic [62].
Another key aspect of the ARC neurons, especially POMC, is that they exhibit sex-
ual dimorphism. Higher number of POMC neurons and increased neural activity were
observed in female animals when compared to their male counterparts [63]. Disruption of
key genes in POMC neurons in female mice resulted in the development of obesity [63–66].
More recently, POMC-specific alteration of certain highly expressed CNS genes, resulted in
changes in glucoregulation and energy balance in female mice only [67–69].
ARC is highly susceptible to synaptic plasticity in response to the hormonal milieu.
Both AGRP and POMC neurons have been described as exhibiting some level of synaptic
rewiring under periods of food deprivation and overfeeding conditions [70]. Particularly,
the melanocortin system has been reported to exhibit synaptic remodeling under both
extreme metabolic changes, such as starvation and overfeeding, but also under physio-
logical feeding states which results in modest metabolic changes [71–73]. Plasticity of the
ARC has important implications in obesity, as diet-induced obesity has been demonstrated
to suppress hypothalamic remodeling and neurogenesis resulting in reduced neuronal
turnover [74]. It was also demonstrated to result in reactive gliosis in the ARC with altered
synaptic architecture of the NPY and POMC neurons [75]. High fat diet (HFD)-induced
neurogenesis is not restricted to the neuronal populations alone in the ARC. HFD activated
neurogenesis in the median eminence however leads to energy storage, while prevention
of it results in a reduction in weight gain [76]. Stimulation of neurogenesis in response to
HFD is observed in female mice and not in males, suggesting a sexual dimorphic nature of
hypothalamic neurogenesis [77].
penditure [95–98]. Interestingly, PVH not only comprises MC4R neurons, but also contains
other neuronal populations such as prodynorphin-expressing neurons, which lack MC4R.
These neuronal populations have comparable effects to the PVH-MC4R expressing neurons
on regulating satiety [99]. Several such anatomically distinct neuronal populations have
been identified in the PVH as having appetite-regulatory roles, which further highlights the
complexity of this nucleus [100–103]. For a more detailed review on the pathophysiological
roles of MC4R neurons, readers can refer to excellent reviews on this topic [104,105].
2.2. Brainstem
The brainstem exerts significant control over autonomous biological functions. The
medulla is a key brainstem structure which has prominent cardioregulatory and metabolic
functions, via specialized cardiovascular and satiety centers, respectively. The medullary
cardiovascular centers have well-established roles in the homeostatic regulation of blood
pressure via the baroreflex [128]. Although the brainstem is not as well-investigated as
its counterpart, the hypothalamus, in metabolism, studies dating back to the 1970s high-
Cells 2023, 12, 1801 6 of 28
lighted the importance of the caudal brainstem in mediating satiety and glucoregulatory
responses [129,130]. Importantly, specialized medullary regions serve as crucial integration
points between the CNS and the digestive tract. They receive visceral afferent input from
gastrointestinal sensory neurons, the latter conveying satiety signals in response to a meal.
Additionally, the brainstem also comprises a circumventricular organ, area postrema (AP),
which allows access to satiety signals. These signals in turn can modulate adjacent and
supra-adjacent neuronal populations located in the brainstem. These proximally located
neuronal populations in the caudal brainstem, in conjunction with the AP, are key structures
in mediating postprandial satiety [131,132].
populations are able to exert both short- and long-term effects on energy homeostasis in
Cells 2023, 12, 1801 8 of 28
response to energy demands.
Figure
Figure 1. Key
1. Key hypothalamic
hypothalamic nuclei
nuclei involvedininthe
involved theregulation
regulation of of appetite
appetiteandandenergy
energy balance.
balance. ARC,
ARC,
comprising
comprising AGRP AGRP andand POMCneurons,
POMC neurons, isislocated
located next
nextto the median
to the medianeminence. This region
eminence. This comprises
region com-
permeable
prises permeable capillaries, thereby
capillaries, therebyallowing access
allowing to circulating
access signals.
to circulating These These
signals. signalssignals
can modulate
can mod-
ulateARC
ARCneuronal
neuronal populations,
populations, whichwhich
thenthen
havehave extensive
extensive projections
projections to PVH toand
PVH andhypothalamic
other other hypotha-
lamic nuclei.PVH
nuclei. PVHisisthethemajor
majorhypothalamic
hypothalamic satiety
satiety center.
center. POMC
POMC neurons
neurons activate
activate MC4R
MC4R neurons
neurons
in the
in PVH to decrease
the PVH to decreaseappetite, while
appetite, AGRP
while AGRP neurons
neurons inhibit PVH-MC4R
inhibit PVH-MC4Rneuronsneuronstotoincrease
increaseap-
petite. Additionally,
appetite. AGRPAGRP
Additionally, neurons also inhibit
neurons POMC
also inhibit POMC neurons
neuronsvia via
stimulation
stimulationof of
inhibitory
inhibitoryGA-
BAergic input to
GABAergic POMC
input neurons.
to POMC Anorexigenic
neurons. Anorexigenicsignals such
signals as leptin
such and
as leptin andGLP1
GLP1increase
increasesatiety
satiety by
acting
byon POMC
acting neurons,
on POMC whereas
neurons, orexigenic
whereas signals
orexigenic such such
signals as ghrelin can increase
as ghrelin appetite
can increase by acting
appetite by
on AGRP neurons. Other hypothalamic neuronal populations have extensive
acting on AGRP neurons. Other hypothalamic neuronal populations have extensive projections projections to and
fromtoadjacent
and from nuclei.
adjacentWhile DMH
nuclei. has DMH
While predominantly inhibitory
has predominantly projections
inhibitory to PVH to
projections and PVHPOMC,
and it
also POMC,
has been shown
it also to also
has been have
shown to activate
also haveinhibitory GABAergic
activate inhibitory neurons
GABAergic projecting
neurons to the
projecting to AGRP
the
neurons
AGRP inneurons
the ARC. VMH
in the ARC.mainly
VMHhas excitatory
mainly projections
has excitatory to the to
projections POMC neurons,
the POMC while
neurons, AGRP
while
neurons
AGRP has inhibitory
neurons projections
has inhibitory to VMH.
projections Additionally,
to VMH. postprandial
Additionally, postprandialsatiety signals
satiety signalsfrom
fromthe
theen-
teroendocrine cells of the GIT can also act on DVC located in the brainstem
enteroendocrine cells of the GIT can also act on DVC located in the brainstem to suppress appetite.to suppress appetite.
AGRP:AGRP:Agouti-related
Agouti-related protein;
protein;POMC:
POMC:Pro-opiomelanocortin;
Pro-opiomelanocortin; ARC: ARC:Arcuate
Arcuatenucleus;
nucleus; ME:ME: median
median
eminence; VMH: Ventromedial nucleus of the hypothalamus; DMH:
eminence; VMH: Ventromedial nucleus of the hypothalamus; DMH: Dorsomedial hypothalamus; Dorsomedial hypothalamus;
PVH: Paraventricular
PVH: Paraventricular nucleus;
nucleus;3V:3V: Third ventricle;
Third ventricle; DVC:
DVC: Dorsal
Dorsal vagal vagal complex;
complex; CCK: cholecysto-
CCK: cholecystokinin;
kinin; GIP: Glucose-dependent insulinotropic polypeptide; GLP1: Glucagon-like
GIP: Glucose-dependent insulinotropic polypeptide; GLP1: Glucagon-like peptide-1; WAT: White
peptide-1; WAT:
White adipose tissue; GIT: Gastrointestinal tract. Green dotted lines/arrows represent activation.
adipose tissue; GIT: Gastrointestinal tract. Green dotted lines/arrows represent activation. Red dotted
Red dotted lines/arrows represent inhibition. Please refer to Section 2 for more details on the hypo-
lines/arrows represent inhibition. Please refer to Section 2 for more details on the hypothalamic and
thalamic and brainstem neural circuits.
brainstem neural circuits.
3. Crosstalk between
3. Crosstalk Hypothalamic
between Hypothalamicand
andBrainstem Nucleiwith
Brainstem Nuclei withMetabolic
Metabolic Organs
Organs to to
Regulate Energy and Glucose Homeostasis
Regulate Energy and Glucose Homeostasis
Autonomic dysfunction is associated with an elevated risk of developing metabolic
Autonomic dysfunction is associated with an elevated risk of developing metabolic
syndrome and cardiovascular diseases [128,186]. In the case of metabolic disorders, this is
syndrome and cardiovascular diseases [128,186]. In the case of metabolic disorders, this is
due to an augmentation of sympathetic activity resulting in a breakdown of the glucose
duehomeostatic
to an augmentation
processes of sympathetic
[187]. activity
The end result is aresulting in a breakdown
chronic elevation of the glucose
in blood glucose due
homeostatic processes [187]. The end result is a chronic elevation in blood glucose due to
Cells 2023, 12, 1801 9 of 28
to an imbalance between glucose production and glucose clearance from the blood by
insulin-sensitive organs. The resulting hyperglycemic condition is known to result in
extensive vascular complications due to endothelial damage, and hence serves as an
independent risk factor for cardiovascular diseases [188,189]. Understanding the potential
mechanisms involved in the maintenance of glucose homeostasis is therefore of high
clinical relevance. Hypothalamic and brainstem nuclei are key components of a central
network that help maintain a balance between sympathetic and parasympathetic nerve
activity to the endocrine organs, resulting in exerting significant control over glucose
metabolism. Circulating signals act on these neurons to recalibrate autonomic efferents
to the peripheral metabolic organs. This section focusses on the crosstalk between the
various brain regions discussed in the preceding section, and the important metabolic
organs involved in maintenance of glucose and energy homeostasis.
insulin being able to modulate hypothalamic and brainstem neuronal activity, there is
evidence of insulin being produced locally in the brain as well [210,211]. While insulin
producing hypothalamic neurons were shown to have both anabolic and catabolic roles, in
the case of brainstem a recent study highlighted an anabolic role for them [212–214]. All of
the aforementioned studies highlight the importance and diversity of hypothalamic and
brainstem insulin signaling in metabolic control.
Figure
Figure Contrasting
2. 2. Contrastingroles rolesofofAGRP
AGRPand andPOMC POMCneurons
neuronsininglucose
glucoseandandlipid
lipidhomeostasis.
homeostasis. AGRP AGRP
neurons
neurons are
aredepolarized
depolarizedby by orexigenic hormonessuch
orexigenic hormones suchasasghrelin
ghrelinandand hyperpolarized
hyperpolarized by insulin
by insulin and
andleptin. AGRP
leptin. AGRP neurons havehave
neurons integral rolesroles
integral in increasing hepatic
in increasing glucose
hepatic production,
glucose while its
production, inacti-
while its
vation results
inactivation in ain
results suppression
a suppression of endogenous
of endogenous glucose production
glucose fromfrom
production the liver. Activation
the liver. of IR
Activation
of and LepR
IR and hyperpolarize
LepR hyperpolarize AGRP neurons,
AGRP whilewhile
neurons, GHSRGHSRactivation depolarizes
activation AGRP neurons.
depolarizes AGRP neurons.Insulin
receptor activation in AGRP neurons results in hyperpolarization via K-ATP channels and a de-
Insulin receptor activation in AGRP neurons results in hyperpolarization via K-ATP channels and a
crease in AGRP neuronal activity. This inturn alters hepatic vagal efferents to reduce endogenous
decrease in AGRP neuronal activity. This inturn alters hepatic vagal efferents to reduce endogenous
glucose production. This mechanism involves regulation of IL6 release from the liver. Briefly, a de-
glucose
crease production.
in AGRP neuronal This mechanism
activity results involves regulation
in an increase in IL6of release
IL6 release
fromfrom
Kupffer thecells.
liver.Apart
Briefly,
from a
decrease in AGRP neuronal activity results in an increase in IL6 release
having inflammatory roles, IL6 also mediates hypoglycemic effects. IL6 acts in a paracrine mannerfrom Kupffer cells. Apart
from having inflammatory
on hepatocytes to suppressroles,
hepaticIL6gluconeogenic
also mediates gene hypoglycemic
expression,effects.
resulting IL6inacts in a paracrine
a reduction in en-
dogenous
manner glucose production.
on hepatocytes to suppress Apart from gluconeogenic
hepatic regulating parasympathetic
gene expression, efferent outflow
resulting in atoreduction
the liver,
in AGRP activation
endogenous also results
glucose in reduced
production. Apartsympathetic
from regulatingoutflow to adipose depots.
parasympathetic This outflow
efferent results intomet-
the
abolic impairments characterized by a shift in substrate utilization for energy
liver, AGRP activation also results in reduced sympathetic outflow to adipose depots. This results production. Mainly, in
a lesser reliance on lipid as a predominant energy source, and reduced thermogenesis in BAT.
metabolic impairments characterized by a shift in substrate utilization for energy production. Mainly,
ROCK1 is an important mediator of leptin’s effects in AGRP neurons. Loss of ROCK1 in AGRP has
a lesser reliancetoon
been shown lipid as leptin’s
attenuate a predominant
effect and energy
resultsource, andresistance.
in leptin reduced thermogenesis
In contrast to AGRPin BAT.neurons,
ROCK1
is IR
an and
important
LepR havemediator
beenofpredominantly
leptin’s effectsshown in AGRP neurons. Loss
to depolarize POMC of ROCK1
neurons.inHowever,
AGRP hasdue beento
shown
POMC to attenuate
neuronal leptin’s effect and
heterogeneity, result inofleptin
activation resistance. In
POMC-specific contrast
insulin to AGRP
signaling neurons,
pathway hasIRbeen
and
shown
LepR havetobeen
both predominantly
reduce and increase shown hepatic glucose POMC
to depolarize production. Incretins
neurons. such as
However, dueGLP1
to POMChave been
neu-
shown
ronal to act on ARC
heterogeneity, neurons,
activation ofpredominantly
POMC-specificvia the GLP1R
insulin signalingin POMC
pathway neurons.
has beenGLP1R
shown activation
to both
stimulates
reduce POMC neurons
and increase resultingproduction.
hepatic glucose in an improved metabolic
Incretins such phenotype.
as GLP1 have POMCbeenactivation
shown to results
act on
in augmented sympathetic activity to adipose depots, leading to increased thermogenesis and re-
ARC neurons, predominantly via the GLP1R in POMC neurons. GLP1R activation stimulates POMC
duced adiposity. Thereby POMC neuronal activation can improve metabolic parameters via the
neurons resulting in an improved metabolic phenotype. POMC activation results in augmented
brain–adipose tissue axis. AGRP: Agouti-related protein; POMC: Pro-opiomelanocortin; ARC: Ar-
sympathetic
cuate nucleus;activity
ME:tomedian
adipose depots, leading
eminence; to increased thermogenesis
PVH: Paraventricular and reduced
nucleus; IR: Insulin receptor;adiposity.
LepR:
Thereby POMC neuronal activation can improve metabolic parameters
Leptin receptor; GHSR: Growth Hormone Secretagogue Receptor; PI3K: phosphoinositide 3-kinase;via the brain–adipose tissue
axis.
ROCK:AGRP: Agouti-related
Rho-associated protein;
kinase; AMPK: POMC: Pro-opiomelanocortin;
AMP-activated protein kinase;ARC: GLP1R: Arcuate nucleus; pep-
Glucagon-like ME:
tide-1 receptor; cAMP: Cyclic adenosine monophosphate; HGP: Hepatic
median eminence; PVH: Paraventricular nucleus; IR: Insulin receptor; LepR: Leptin receptor; GHSR: glucose production; IL6:
Interleukin 6; STAT3: Signal transducer and activator of transcription
Growth Hormone Secretagogue Receptor; PI3K: phosphoinositide 3-kinase; ROCK: Rho-associated 3. Green dotted lines/arrows
represent
kinase; AMPK:activation. Red dottedprotein
AMP-activated lines/arrows
kinase;represent
GLP1R: inhibition.
Glucagon-like Blackpeptide-1
dotted lines represent
receptor; par-
cAMP:
asympathetic innervation. Black solid lines represent sympathetic stimulation.
Cyclic adenosine monophosphate; HGP: Hepatic glucose production; IL6: Interleukin 6; STAT3: Sig-
nal transducer and activator of transcription 3. Green dotted lines/arrows represent activation. Red
dotted lines/arrows represent inhibition. Black dotted lines represent parasympathetic innervation.
Black solid lines represent sympathetic stimulation.
Cells 2023, 12, 1801 13 of 28
while glucose lowering ability of central GLP1R has been mostly reported, there have been
reports of hyperglycemic responses by high doses of GLP1R agonist, exendin-4 [287]. In
hyperglycemic
line with this, ICV responses by highof
administration doses
GLP1 ofalso
GLP1R agonist, exendin-4
paradoxically [287]. In line with
reduced glucose-stimulated
this, ICV
insulin administration
secretion and caused of GLP1
mildalso paradoxically
glucose intolerance reduced glucose-stimulated
[288]. However, both theseinsulin
effects
are a consequence of the sympathetic nerve activity activation, and could be due are
secretion and caused mild glucose intolerance [288]. However, both these effects a
to the
consequence of the sympathetic nerve activity activation, and could be due
activation of GLP1R in several distinct neuronal populations present in the various hypo- to the activation
of GLP1R
thalamic in several
nuclei. distinct
This could neuronal
also suggestpopulations present in
a negative feedback the various
mechanism byhypothalamic
which central
nuclei. This could also suggest a negative feedback mechanism by
GLP1R localized on distinct neuronal populations limits insulin release. Further which central GLP1R
investi-
localized on distinct neuronal populations limits insulin release. Further
gation is needed to explore this aspect. Apart from incretins, other postprandial signals investigation is
needed to explore this aspect. Apart from incretins, other postprandial signals have also
have also been involved in regulating glucose and lipid metabolism via the CNS. For in-
been involved in regulating glucose and lipid metabolism via the CNS. For instance, FGF19,
stance, FGF19, a postprandial enterokine that has hypoglycemic effects, elicits its effects
a postprandial enterokine that has hypoglycemic effects, elicits its effects by modulating
by modulating both hypothalamic and brainstem neuronal populations to improve glu-
both hypothalamic and brainstem neuronal populations to improve glucose homeosta-
cose homeostasis [289–292]. Amylin’s effects on food intake and body weight were
sis [289–292]. Amylin’s effects on food intake and body weight were demonstrated to
demonstrated to be dependent on modulation of brainstem neuronal signaling, specifi-
be dependent on modulation of brainstem neuronal signaling, specifically lateral dorsal
cally lateralnucleus,
tegmental dorsal tegmental
resulting innucleus, resulting
increased in increased
SNS activity to BATSNS
[293].activity to BAT [293].
The
TheCNS,
CNS, specifically
specifically the
the hypothalamic
hypothalamic and brainstem neural
and brainstem neural circuits,
circuits, regulates
regulatessev-
sev-
eral different facets of energy balance by altering autonomic outflow to multiple
eral different facets of energy balance by altering autonomic outflow to multiple metabolic metabolic
tissues
tissues and
and endocrine
endocrine glands.
glands. AA schematic
schematic summarizing
summarizing somesome ofof the
the important
important compli-
compli-
mentary
mentary and distinct metabolic roles of the neural pathways discussed in this review, isis
and distinct metabolic roles of the neural pathways discussed in this review,
shown
shownin in Figure
Figure 3.3.
Figure 3. Overview of hypothalamic and brainstem control of energy, glucose, and lipid homeosta-
Figure 3. Overview of hypothalamic and brainstem control of energy, glucose, and lipid homeostasis.
sis. Both hypothalamic and brainstem neuronal populations exert prominent homeostatic control
Bothenergy
over hypothalamic andenergy
intake and brainstem neuronalCirculating
expenditure. populationssignals
exert prominent homeostatic control
can also activate/inhibit distinctover
neu-
ral pathways to recalibrate autonomic outflow to various metabolic organs and endocrine neural
energy intake and energy expenditure. Circulating signals can also activate/inhibit distinct glands.
pathways
This to recalibrate
crosstalk between theautonomic
CNS and outflow to various
the periphery is metabolic organs
essential for and endocrineofglands.
the maintenance glucoseThis
and
crosstalk
lipid between It
homeostasis. theshould
CNS and the periphery
be noted is essential
that the figure for theonly
highlights maintenance
a limited of glucose
number ofand lipid
metaboli-
cally relevant pathways
homeostasis. due
It should be to space
noted that restrictions. Please see
the figure highlights texta for
only details.
limited AGRP:
number of Agouti-related
metabolically
protein; POMC: Pro-opiomelanocortin; NTS: nucleus tractus solitarius; DMH: Dorsomedial
relevant pathways due to space restrictions. Please see text for details. AGRP: Agouti-related protein; hypo-
thalamus; PVH: Paraventricular nucleus; DVC: Dorsal vagal complex; DMV: Dorsal
POMC: Pro-opiomelanocortin; NTS: nucleus tractus solitarius; DMH: Dorsomedial hypothalamus; PVH:motor nucleus
of the vagus; ARC:
Paraventricular Arcuate
nucleus; nucleus;
DVC: DorsalNPY:
vagalNeuropeptide
complex; DMV:Y;Dorsal
SF1: Steroidogenic
motor nucleusfactor
of the1; NMDA:
vagus; ARC:N-
methyl-D-aspartate; GLP1R: Glucagon-like peptide-1 receptor; GIT: Gastrointestinal
Arcuate nucleus; NPY: Neuropeptide Y; SF1: Steroidogenic factor 1; NMDA: N-methyl-D-aspartate; tract. Orange
Cells 2023, 12, 1801 15 of 28
GLP1R: Glucagon-like peptide-1 receptor; GIT: Gastrointestinal tract. Orange dotted lines/arrows
represent modulation of hypothalamic neural circuits. Blue dotted lines/arrows represent modulation
of brainstem neural circuits.
4. Clinical Implications
Multiple clinical studies have underscored the importance of the appetite/satiety
centers in the brain for mediating the effects of gut hormones and circulating peptides
on energy homeostasis [294,295]. Weight-loss drugs act by inducing a negative energy
balance by either central or peripheral mechanisms, or a combination of both. This mainly
includes appetite reduction via the melanocortin system, increased energy expenditure
via both central and peripheral mechanisms, or restriction of calorie absorption from the
intestine by acting on the intestinal enzymes [296]. Several of the anti-obesity drugs in the
past were effective in inducing significant weight loss, however they were discontinued
due to adverse effects. For instance, rimonabant improved several metabolic parameters
along with promoting anorexia in several clinical studies, but it was associated with high
neuropsychiatric adverse effects leading it to be withdrawn from the market [297]. Other
drugs such as aminorex and sibutramine have been discontinued due to severe cardiovas-
cular events [296,298]. The currently approved anti-obesity drugs demonstrate not only
equivalent therapeutic efficacy, but also have favorable cardiovascular and neurological
profile [296]. Centrally acting drug combinations such as naltrexone + bupropion, which
act on the melanocortin system via the opioid receptors, have been shown to be efficacious
in reducing body weight without any CNS adverse effects [299]. Drugs such as orlistat act
exclusively by inhibiting fatty acid absorption from the gut [300], while GLP1 analogs such
as semaglutide act via multiple mechanisms which encompass both central and peripheral
mechanisms to suppress appetite, improve glucose and lipid metabolism, and delay gastric
emptying [301,302]. While these drugs have a much-improved cardiometabolic risk profile
compared with the previous generations of weight loss medications, the long-term risk pro-
file remains an outstanding question [303]. Additionally, gastrointestinal side effects such as
nausea and diarrhea are commonly observed, and may diminish patient compliance which
further limits their long-term efficacy [296]. Future research should be geared towards
evaluating long term risk-benefit profile, using combination therapy with reduced doses to
avoid GIT side effects. Deciphering the neural circuits that suppress appetite without trig-
gering aversive responses could also aid in developing drugs with a favorable risk-benefit
profile. Interestingly, both orexigenic and anorectic neuronal populations exhibit sexual
dimorphism in metabolism and glucoregulation [63,304,305]. A better understanding of
gender differences in energy and glucose homeostasis should aid in developing tailored
therapeutic strategies for the treatment of obesity [306].
5. Conclusions
Obesity has been long considered to be at epidemic proportions globally, and is both
a significant health and economic burden [307,308]. It is now evident that the brain is at
the apex of the whole-body energy homeostatic machinery. Our understanding of the
hypothalamic and brainstem neuronal circuits has already aided in the development of
highly efficacious anti-obesity drugs. While several of these neuronal populations exhibit
overlapping metabolic roles, recent studies have brought to light distinct and contrasting
mechanisms, thereby enabling the CNS to fine tune metabolic functions under physiological
conditions. It is important to note that metabolic disorders are highly heterogenous with
distinct metabolic profiles [309,310]. A deeper understanding of the molecular architecture
of neuronal populations could aid in exploring multiple drug targets, potentially even
tailor-made for the treatment of a specific metabolic profile. Such personalized therapies are
already employed for several other pathological conditions; hence, it is feasible that this goal
can be achieved for the future treatment of obesity and related metabolic disorders [311].
Cells 2023, 12, 1801 16 of 28
Author Contributions: All authors contributed to the conceptualization, literature search, writing
and editing of the review paper. All authors have read and agreed to the published version of
the manuscript.
Funding: The authors’ research is supported by the Intramural Research Program of the NIH, NIDDK,
Bethesda, MD, USA.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: Artwork obtained from Servier Medical Art was used to construct aspects of the
figure (www.servier.com; accessed on 4 April 2023). The authors would like to thank Jurgen Wess
and Oksana Gavrilova for their many helpful discussions.
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Ahima, R.S.; Antwi, D.A. Brain Regulation of Appetite and Satiety. Endocrinol. Metab. Clin. N. Am. 2008, 37, 811–823. [CrossRef]
[PubMed]
2. Hetherington, A.W.; Ranson, S.W. Hypothalamic Lesions and Adiposity in the Rat. Anat. Rec. 1940, 78, 149–172. [CrossRef]
3. Wess, J.; Nakajima, K.; Jain, S. Novel Designer Receptors to Probe GPCR Signaling and Physiology. Trends Pharmacol. Sci. 2013, 34,
385–392. [CrossRef]
4. Locke, A.E.; Kahali, B.; Berndt, S.I.; Justice, A.E.; Pers, T.H.; Day, F.R.; Powell, C.; Vedantam, S.; Buchkovich, M.L.; Yang, J.; et al.
Genetic Studies of Body Mass Index Yield New Insights for Obesity Biology. Nature 2015, 518, 197–206. [CrossRef]
5. Matikainen-Ankney, B.A.; Kravitz, A.V. Persistent Effects of Obesity: A Neuroplasticity Hypothesis. Ann. N. Y. Acad. Sci. 2018,
1428, 221. [CrossRef] [PubMed]
6. Linehan, V.; Fang, L.Z.; Parsons, M.P.; Hirasawa, M. High-Fat Diet Induces Time-Dependent Synaptic Plasticity of the Lateral
Hypothalamus. Mol. Metab. 2020, 36, 100977. [CrossRef]
7. Wang, X.; Li, H. Chronic High-Fat Diet Induces Overeating and Impairs Synaptic Transmission in Feeding-Related Brain Regions.
Front. Mol. Neurosci. 2022, 15, 1019446. [CrossRef]
8. Parton, L.E.; Ye, C.P.; Coppari, R.; Enriori, P.J.; Choi, B.; Zhang, C.Y.; Xu, C.; Vianna, C.R.; Balthasar, N.; Lee, C.E.; et al. Glucose
Sensing by POMC Neurons Regulates Glucose Homeostasis and Is Impaired in Obesity. Nature 2007, 449, 228–232. [CrossRef]
9. Belgardt, B.F.; Okamura, T.; Brüning, J.C. Hormone and Glucose Signalling in POMC and AgRP Neurons. J. Physiol. 2009, 587,
5305–5314. [CrossRef]
10. Roh, E.; Song, D.K.; Kim, M.S. Emerging Role of the Brain in the Homeostatic Regulation of Energy and Glucose Metabolism. Exp.
Mol. Med. 2016, 48, e216. [CrossRef]
11. Yoon, N.A.; Diano, S. Hypothalamic Glucose-Sensing Mechanisms. Diabetologia 2021, 64, 985–993. [CrossRef]
12. Yang, Y.; Atasoy, D.; Su, H.H.; Sternson, S.M. Hunger States Switch a Flip-Flop Memory Circuit via a Synaptic AMPK-Dependent
Positive Feedback Loop. Cell 2011, 146, 992–1003. [CrossRef]
13. Millington, G.W.M. The Role of Proopiomelanocortin (POMC) Neurones in Feeding Behaviour. Nutr. Metab. 2007, 4, 1–16.
[CrossRef]
14. Rau, A.R.; Hentges, S.T. GABAergic Inputs to POMC Neurons Originating from the Dorsomedial Hypothalamus Are Regulated
by Energy State. J. Neurosci. 2019, 39, 6449–6459. [CrossRef] [PubMed]
15. O’Shea, D.; Morgan, D.G.A.; Meeran, K.; Edwards, C.M.B.; Turton, M.D.; Choi, S.J.; Heath, M.M.; Gunn, I.; Taylor, G.M.; Howard,
J.K.; et al. Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor. Endocrinology 1997, 138, 196–202.
[CrossRef]
16. Nijenhuis, W.A.J.; Oosterom, J.; Adan, R.A.H. AgRP(83-132) Acts as an Inverse Agonist on the Human-Melanocortin-4 Receptor.
Mol. Endocrinol. 2001, 15, 164–171. [CrossRef]
17. Luquet, S.; Perez, F.A.; Hnasko, T.S.; Palmiter, R.D. NPY/AgRP Neurons Are Essential for Feeding in Adult Mice but Can Be
Ablated in Neonates. Science 2005, 310, 683–685. [CrossRef] [PubMed]
18. Krashes, M.J.; Koda, S.; Ye, C.P.; Rogan, S.C.; Adams, A.C.; Cusher, D.S.; Maratos-Flier, E.; Roth, B.L.; Lowell, B.B. Rapid,
Reversible Activation of AgRP Neurons Drives Feeding Behavior in Mice. J. Clin. Investig. 2011, 121, 1424–1428. [CrossRef]
19. Joly-Amado, A.; Denis, R.G.P.; Castel, J.; Lacombe, A.; Cansell, C.; Rouch, C.; Kassis, N.; Dairou, J.; Cani, P.D.; Ventura-Clapier,
R.; et al. Hypothalamic AgRP-Neurons Control Peripheral Substrate Utilization and Nutrient Partitioning. EMBO J. 2012, 31,
4276–4288. [CrossRef]
20. Nakajima, K.I.; Cui, Z.; Li, C.; Meister, J.; Cui, Y.; Fu, O.; Smith, A.S.; Jain, S.; Lowell, B.B.; Krashes, M.J.; et al. Gs-Coupled GPCR
Signalling in AgRP Neurons Triggers Sustained Increase in Food Intake. Nat. Commun. 2016, 7, 10268. [CrossRef] [PubMed]
21. Krashes, M.J.; Shah, B.P.; Koda, S.; Lowell, B.B. Rapid versus Delayed Stimulation of Feeding by the Endogenously Released
AgRP Neuron Mediators GABA, NPY, and AgRP. Cell Metab. 2013, 18, 588–595. [CrossRef] [PubMed]
Cells 2023, 12, 1801 17 of 28
22. Qi, Y.; Lee, N.J.; Ip, C.K.; Enriquez, R.; Tasan, R.; Zhang, L.; Herzog, H. NPY Derived from AGRP Neurons Controls Feeding via
Y1 and Energy Expenditure and Food Foraging Behaviour via Y2 Signalling. Mol. Metab. 2022, 59, 101455. [CrossRef] [PubMed]
23. Luo, N.; Marcelin, G.; Liu, S.M.; Schwartz, G.; Chua, S. Neuropeptide Y and Agouti-Related Peptide Mediate Complementary
Functions of Hyperphagia and Reduced Energy Expenditure in Leptin Receptor Deficiency. Endocrinology 2011, 152, 883–889.
[CrossRef] [PubMed]
24. Tong, Q.; Ye, C.P.; Jones, J.E.; Elmquist, J.K.; Lowell, B.B. Synaptic Release of GABA by AgRP Neurons Is Required for Normal
Regulation of Energy Balance. Nat. Neurosci. 2008, 11, 998–1000. [CrossRef]
25. Deem, J.D.; Faber, C.L.; Morton, G.J. AgRP Neurons: Regulators of Feeding, Energy Expenditure, and Behavior. FEBS J 2022, 289,
2362–2381. [CrossRef]
26. D’agostino, G.; Diano, S. Alpha-Melanocyte Stimulating Hormone: Production and Degradation. J. Mol. Med. 2010, 88, 1195–1201.
[CrossRef] [PubMed]
27. Greenman, Y.; Kuperman, Y.; Drori, Y.; Asa, S.L.; Navon, I.; Forkosh, O.; Gil, S.; Stern, N.; Chen, A. Postnatal Ablation of POMC
Neurons Induces an Obese Phenotype Characterized by Decreased Food Intake and Enhanced Anxiety-like Behavior. Mol.
Endocrinol. 2013, 27, 1091–1102. [CrossRef]
28. Zhan, C.; Zhou, J.; Feng, Q.; Zhang, J.-e.; Lin, S.; Bao, J.; Wu, P.; Luo, M. Acute and Long-Term Suppression of Feeding Behavior
by POMC Neurons in the Brainstem and Hypothalamus, Respectively. J. Neurosci. 2013, 33, 3624–3632. [CrossRef]
29. Toda, C.; Santoro, A.; Kim, J.D.; Diano, S. POMC Neurons: From Birth to Death. Annu. Rev. Physiol. 2017, 79, 209–236. [CrossRef]
30. Quarta, C.; Claret, M.; Zeltser, L.M.; Williams, K.W.; Yeo, G.S.H.; Tschöp, M.H.; Diano, S.; Brüning, J.C.; Cota, D. POMC Neuronal
Heterogeneity in Energy Balance and beyond: An Integrated View. Nat. Metab. 2021, 3, 299–308. [CrossRef]
31. Saucisse, N.; Mazier, W.; Simon, V.; Binder, E.; Catania, C.; Bellocchio, L.; Romanov, R.A.; Léon, S.; Matias, I.; Zizzari, P.; et al.
Functional Heterogeneity of POMC Neurons Relies on MTORC1 Signaling. Cell Rep. 2021, 37, 109800. [CrossRef]
32. Wu, Q.; Howell, M.P.; Cowley, M.A.; Palmiter, R.D. Starvation after AgRP Neuron Ablation Is Independent of Melanocortin
Signaling. Proc. Natl. Acad. Sci. USA 2008, 105, 2687–2692. [CrossRef] [PubMed]
33. Chen, S.R.; Chen, H.; Zhou, J.J.; Pradhan, G.; Sun, Y.; Pan, H.L.; Li, D.P. Ghrelin Receptors Mediate Ghrelin-Induced Excitation of
Agouti-Related Protein/Neuropeptide Y but Not pro-Opiomelanocortin Neurons. J. Neurochem. 2017, 142, 512–520. [CrossRef]
34. Rau, A.R.; Hentges, S.T. The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and
Evoked Release. J. Neurosci. 2017, 37, 7362–7372. [CrossRef]
35. Dutia, R.; Meece, K.; Dighe, S.; Kim, A.J.; Wardlaw, S.L. β-Endorphin Antagonizes the Effects of α-MSH on Food Intake and Body
Weight. Endocrinology 2012, 153, 4246–4255. [CrossRef]
36. Kelly, M.J.; Loose, M.D.; Ronnekleiv, O.K. Opioids Hyperpolarize Beta-Endorphin Neurons via Mu-Receptor Activation of a
Potassium Conductance. Neuroendocrinology 1990, 52, 268–275. [CrossRef]
37. Koch, M.; Varela, L.; Kim, J.G.; Kim, J.D.; Hernández-Nuño, F.; Simonds, S.E.; Castorena, C.M.; Vianna, C.R.; Elmquist, J.K.;
Morozov, Y.M.; et al. Hypothalamic POMC Neurons Promote Cannabinoid-Induced Feeding. Nature 2015, 519, 45–50. [CrossRef]
[PubMed]
38. Tolentino, L.; Iqbal, A.; Rahman, S.; Lutfy, K. The Role of Beta-Endorphin in Food Deprivation-Mediated Increases in Food Intake
and Binge-Eating. Brain Sciences 2023, 13, 212. [CrossRef]
39. Panigrahi, S.K.; Meece, K.; Wardlaw, S.L. Effects of Naltrexone on Energy Balance and Hypothalamic Melanocortin Peptides in
Male Mice Fed a High-Fat Diet. J. Endocr. Soc. 2019, 3, 590–601. [CrossRef] [PubMed]
40. Gordon, R.J.; Panigrahi, S.K.; Meece, K.; Atalayer, D.; Smiley, R.; Wardlaw, S.L. Effects of Opioid Antagonism on Cerebrospinal
Fluid Melanocortin Peptides and Cortisol Levels in Humans. J. Endocr. Soc. 2017, 1, 1235–1246. [CrossRef]
41. Elias, C.F.; Kelly, J.F.; Lee, C.E.; Ahima, R.S.; Drucker, D.J.; Saper, C.B.; Elmquist, J.K. Chemical Characterization of Leptin-
Activated Neurons in the Rat Brain. J. Comp. Neurol. 2000, 423, 261–281. [CrossRef]
42. Cowley, M.A.; Smart, J.L.; Rubinstein, M.; Cerdán, M.G.; Diano, S.; Horvath, T.L.; Cone, R.D.; Low, M.J. Leptin Activates
Anorexigenic POMC Neurons through a Neural Network in the Arcuate Nucleus. Nature 2001, 411, 480–484. [CrossRef]
43. Korner, J.; Savontaus, E.; Chua, S.C.; Leibel, R.L.; Wardlaw, S.L. Leptin Regulation of Agrp and Npy MRNA in the Rat
Hypothalamus. J. Neuroendocrinol. 2001, 13, 959–966. [CrossRef]
44. Takahashi, K.A.; Cone, R.D. Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of
Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons. Endocrinology 2005, 146, 1043–1047. [CrossRef]
45. Baver, S.B.; Hope, K.; Guyot, S.; Bjørbaek, C.; Kaczorowski, C.; O’Connell, K.M.S. Leptin Modulates the Intrinsic Excitability of
AgRP/NPY Neurons in the Arcuate Nucleus of the Hypothalamus. J. Neurosci. 2014, 34, 5486–5496. [CrossRef] [PubMed]
46. Huang, H.; Kong, D.; Byun, K.H.; Ye, C.; Koda, S.; Lee, D.H.; Oh, B.C.; Lee, S.W.; Lee, B.; Zabolotny, J.M.; et al. Rho-Kinase
Regulates Energy Balance by Targeting Hypothalamic Leptin Receptor Signaling. Nat. Neurosci. 2012, 15, 1391–1398. [CrossRef]
47. Huang, H.; Lee, S.H.; Ye, C.; Lima, I.S.; Oh, B.C.; Lowell, B.B.; Zabolotny, J.M.; Kim, Y.B. ROCK1 in AgRP Neurons Regulates
Energy Expenditure and Locomotor Activity in Male Mice. Endocrinology 2013, 154, 3660–3670. [CrossRef] [PubMed]
48. Koch, L.; Wunderlich, F.T.; Seibler, J.; Könner, A.C.; Hampel, B.; Irlenbusch, S.; Brabant, G.; Kahn, C.R.; Schwenk, F.; Brüning,
J.C. Central Insulin Action Regulates Peripheral Glucose and Fat Metabolism in Mice. J. Clin. Investig. 2008, 118, 2132–2147.
[CrossRef]
Cells 2023, 12, 1801 18 of 28
49. Dodd, G.T.; Kim, S.J.; Méquinion, M.; Xirouchaki, C.E.; Brüning, J.C.; Andrews, Z.B.; Tiganis, T. Insulin Signaling in AgRP
Neurons Regulates Meal Size to Limit Glucose Excursions and Insulin Resistance. Sci. Adv. 2021, 7, eabf4100. [CrossRef]
[PubMed]
50. Balthasar, N.; Dalgaard, L.T.; Lee, C.E.; Yu, J.; Funahashi, H.; Williams, T.; Ferreira, M.; Tang, V.; McGovern, R.A.; Kenny, C.D.;
et al. Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure. Cell 2005, 123, 493–505.
[CrossRef]
51. Könner, A.C.; Janoschek, R.; Plum, L.; Jordan, S.D.; Rother, E.; Ma, X.; Xu, C.; Enriori, P.; Hampel, B.; Barsh, G.S.; et al. Insulin
Action in AgRP-Expressing Neurons Is Required for Suppression of Hepatic Glucose Production. Cell Metab. 2007, 5, 438–449.
[CrossRef]
52. Andrews, Z.B.; Liu, Z.W.; Walllingford, N.; Erion, D.M.; Borok, E.; Friedman, J.M.; Tschöp, M.H.; Shanabrough, M.; Cline, G.;
Shulman, G.I.; et al. UCP2 Mediates Ghrelin’s Action on NPY/AgRP Neurons by Lowering Free Radicals. Nature 2008, 454,
846–851. [CrossRef]
53. Guan, X.; Shi, X.; Li, X.; Chang, B.; Wang, Y.; Li, D.; Chan, L. GLP-2 Receptor in POMC Neurons Suppresses Feeding Behavior and
Gastric Motility. Am. J. Physiol. Endocrinol. Metab. 2012, 303, E853. [CrossRef] [PubMed]
54. Su, Z.; Alhadeff, A.L.; Betley, J.N. Nutritive, Post-Ingestive Signals Are the Primary Regulators of AgRP Neuron Activity. Cell Rep.
2017, 21, 2724–2736. [CrossRef] [PubMed]
55. Lutz, T.A.; Coester, B.; Whiting, L.; Dunn-Meynell, A.A.; Boyle, C.N.; Bouret, S.G.; Levin, B.E.; Le Foll, C. Amylin Selectively
Signals onto POMC Neurons in the Arcuate Nucleus of the Hypothalamus. Diabetes 2018, 67, 805–817. [CrossRef]
56. Gouveia, A.; de Oliveira Beleza, R.; Steculorum, S.M. AgRP Neuronal Activity across Feeding-Related Behaviours. Eur. J. Neurosci.
2021, 54, 7458–7475. [CrossRef] [PubMed]
57. Üner, A.G.; Keçik, O.; Quaresma, P.G.F.; De Araujo, T.M.; Lee, H.; Li, W.; Kim, H.J.; Chung, M.; Bjørbæk, C.; Kim, Y.B. Role of
POMC and AgRP Neuronal Activities on Glycaemia in Mice. Sci. Rep. 2019, 9, 13068. [CrossRef] [PubMed]
58. Iwen, K.A.; Oelkrug, R.; Brabant, G. Effects of Thyroid Hormones on Thermogenesis and Energy Partitioning. J. Mol. Endocrinol.
2018, 60, R157–R170. [CrossRef]
59. Fekete, C.; Kelly, J.; Mihály, E.; Sarkar, S.; Rand, W.M.; Légrádi, G.; Emerson, C.H.; Lechan, R.M. Neuropeptide Y Has a Central
Inhibitory Action on the Hypothalamic-Pituitary-Thyroid Axis. Endocrinology 2001, 142, 2606–2613. [CrossRef]
60. Kim, M.S.; Small, C.J.; Stanley, S.A.; Morgan, D.G.A.; Seal, L.J.; Kong, W.M.; Edwards, C.M.B.; Abusnana, S.; Sunter, D.; Ghatei,
M.A.; et al. The Central Melanocortin System Affects the Hypothalamo-Pituitary Thyroid Axis and May Mediate the Effect of
Leptin. J. Clin. Investig. 2000, 105, 1005–1011. [CrossRef]
61. Fekete, C.; Sarkar, S.; Rand, W.M.; Harney, J.W.; Emerson, C.H.; Bianco, A.C.; Lechan, R.M. Agouti-Related Protein (AGRP) Has a
Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and
Neuropeptide Y on Energy Homeostasis and the HPT Axis. Endocrinology 2002, 143, 3846–3853. [CrossRef] [PubMed]
62. Martin, N.M.; Smith, K.L.; Bloom, S.R.; Small, C.J. Interactions between the Melanocortin System and the Hypothalamo–Pituitary–
Thyroid Axis. Peptides 2006, 27, 333–339. [CrossRef] [PubMed]
63. Wang, C.; He, Y.; Xu, P.; Yang, Y.; Saito, K.; Xia, Y.; Yan, X.; Hinton, A.; Yan, C.; Ding, H.; et al. TAp63 Contributes to Sexual
Dimorphism in POMC Neuron Functions and Energy Homeostasis. Nat. Commun. 2018, 9, 1544. [CrossRef]
64. Xu, Y.; Nedungadi, T.P.; Zhu, L.; Sobhani, N.; Irani, B.G.; Davis, K.E.; Zhang, X.; Zou, F.; Gent, L.M.; Hahner, L.D.; et al. Distinct
Hypothalamic Neurons Mediate Estrogenic Effects on Energy Homeostasis and Reproduction. Cell Metab. 2011, 14, 453–465.
[CrossRef] [PubMed]
65. Yang, Y.; van der Klaauw, A.A.; Zhu, L.; Cacciottolo, T.M.; He, Y.; Stadler, L.K.J.; Wang, C.; Xu, P.; Saito, K.; Hinton, A.; et al.
Steroid Receptor Coactivator-1 Modulates the Function of Pomc Neurons and Energy Homeostasis. Nat. Commun. 2019, 10, 1718.
[CrossRef]
66. Xu, A.W.; Ste-Marie, L.; Kaelin, C.B.; Barsh, G.S. Inactivation of Signal Transducer and Activator of Transcription 3 in Proop-
iomelanocortin (Pomc) Neurons Causes Decreased Pomc Expression, Mild Obesity, and Defects in Compensatory Refeeding.
Endocrinology 2007, 148, 72–80. [CrossRef] [PubMed]
67. Yu, M.; Bean, J.C.; Liu, H.; He, Y.; Yang, Y.; Cai, X.; Yu, K.; Pei, Z.; Liu, H.; Tu, L.; et al. SK3 in POMC Neurons Plays a Sexually
Dimorphic Role in Energy and Glucose Homeostasis. Cell Biosci. 2022, 12, 170. [CrossRef] [PubMed]
68. Pei, Z.; He, Y.; Bean, J.C.; Yang, Y.; Liu, H.; Yu, M.; Yu, K.; Hyseni, I.; Cai, X.; Liu, H.; et al. Gabra5 Plays a Sexually Dimorphic
Role in POMC Neuron Activity and Glucose Balance. Front. Endocrinol. 2022, 13, 889122. [CrossRef]
69. Li, Y.; Zhu, S.; Du, D.; Li, Q.; Xie, K.; Chen, L.; Feng, X.; Wu, X.; Sun, Z.; Zhou, J.; et al. TLR4 in POMC Neurons Regulates
Thermogenesis in a Sex-Dependent Manner. J. Lipid Res. 2023, 64, 100368. [CrossRef]
70. Nuzzaci, D.; Laderrière, A.; Lemoine, A.; Nédélec, E.; Pénicaud, L.; Rigault, C.; Benani, A. Plasticity of the Melanocortin System:
Determinants and Possible Consequences on Food Intake. Front. Endocrinol. 2015, 6, 143. [CrossRef]
71. Benani, A.; Hryhorczuk, C.; Gouazé, A.; Fioramonti, X.; Brenachot, X.; Guissard, C.; Krezymon, A.; Duparc, T.; Colom, A.;
Nédélec, E.; et al. Food Intake Adaptation to Dietary Fat Involves PSA-Dependent Rewiring of the Arcuate Melanocortin System
in Mice. J. Neurosci. 2012, 32, 11970–11979. [CrossRef]
72. Liu, T.; Kong, D.; Shah, B.P.; Ye, C.; Koda, S.; Saunders, A.; Ding, J.B.; Yang, Z.; Sabatini, B.L.; Lowell, B.B. Fasting Activation of
AgRP Neurons Requires NMDA Receptors and Involves Spinogenesis and Increased Excitatory Tone. Neuron 2012, 73, 511–522.
[CrossRef] [PubMed]
Cells 2023, 12, 1801 19 of 28
73. Nuzzaci, D.; Cansell, C.; Liénard, F.; Nédélec, E.; Ben Fradj, S.; Castel, J.; Foppen, E.; Denis, R.; Grouselle, D.; Laderrière, A.; et al.
Postprandial Hyperglycemia Stimulates Neuroglial Plasticity in Hypothalamic POMC Neurons after a Balanced Meal. Cell Rep.
2020, 30, 3067–3078.e5. [CrossRef] [PubMed]
74. McNay, D.E.G.; Briançon, N.; Kokoeva, M.V.; Maratos-Flier, E.; Flier, J.S. Remodeling of the Arcuate Nucleus Energy-Balance
Circuit Is Inhibited in Obese Mice. J. Clin. Investig. 2012, 122, 142. [CrossRef]
75. Horvath, T.L.; Sarman, B.; García-Cáceres, C.; Enriori, P.J.; Sotonyi, P.; Shanabrough, M.; Borok, E.; Argente, J.; Chowen, J.A.;
Perez-Tilve, D.; et al. Synaptic Input Organization of the Melanocortin System Predicts Diet-Induced Hypothalamic Reactive
Gliosis and Obesity. Proc. Natl. Acad. Sci. USA 2010, 107, 14875–14880. [CrossRef]
76. Lee, D.A.; Bedont, J.L.; Pak, T.; Wang, H.; Song, J.; Miranda-Angulo, A.; Takiar, V.; Charubhumi, V.; Balordi, F.; Takebayashi,
H.; et al. Tanycytes of the Hypothalamic Median Eminence Form a Diet-Responsive Neurogenic Niche. Nat. Neurosci. 2012, 15,
700–702. [CrossRef]
77. Lee, D.A.; Yoo, S.; Pak, T.; Salvatierra, J.; Velarde, E.; Aja, S.; Blackshaw, S. Dietary and Sex-Specific Factors Regulate Hypothalamic
Neurogenesis in Young Adult Mice. Front. Neurosci. 2014, 8, 157. [CrossRef]
78. Jacobowitz, D.M.; O’Donohue, T.L. α-Melanocyte Stimulating Hormone: Immunohistochemical Identification and Mapping in
Neurons of Rat Brain. Proc. Natl. Acad. Sci. USA 1978, 75, 6300–6304. [CrossRef] [PubMed]
79. Mountjoy, K.G.; Mortrud, M.T.; Low, M.J.; Simerly, R.B.; Cone, R.D. Localization of the Melanocortin-4 Receptor (MC4-R) in
Neuroendocrine and Autonomic Control Circuits in the Brain. Mol. Endocrinol. 1994, 8, 1298–1308. [CrossRef]
80. Lu, D.; Willard, D.; Patel, I.R.; Kadwell, S.; Overton, L.; Kost, T.; Luther, M.; Chen, W.; Woychik, R.P.; Wilkison, W.O.; et al. Agouti
Protein Is an Antagonist of the Melanocyte-Stimulating-Hormone Receptor. Nature 1994, 371, 799–802. [CrossRef]
81. Ollmann, M.M.; Wilson, B.D.; Yang, Y.K.; Kerns, J.A.; Chen, Y.; Gantz, I.; Barsh, G.S. Antagonism of Central Melanocortin
Receptors in Vitro and in Vivo by Agouti-Related Protein. Science 1997, 278, 135–138. [CrossRef]
82. Michaud, J.L.; Rosenquist, T.; May, N.R.; Fan, C.M. Development of Neuroendocrine Lineages Requires the BHLH-PAS Transcrip-
tion Factor SIM1. Genes Dev. 1998, 12, 3264–3275. [CrossRef] [PubMed]
83. Michaud, J.L.; Boucher, F.; Melnyk, A.; Gauthier, F.; Goshu, E.; Lévy, E.; Mitchell, G.A.; Himms-Hagen, J.; Fan, C.M. Sim1
Haploinsufficiency Causes Hyperphagia, Obesity and Reduction of the Paraventricular Nucleus of the Hypothalamus. Hum. Mol.
Genet. 2001, 10, 1465–1473. [CrossRef] [PubMed]
84. Tolson, K.P.; Gemelli, T.; Meyer, D.; Yazdani, U.; Kozlitina, J.; Zinn, A.R. Inducible Neuronal Inactivation of Sim1 in Adult Mice
Causes Hyperphagic Obesity. Endocrinology 2014, 155, 2436–2444. [CrossRef]
85. Hinney, A.; Schmidt, A.; Nottebom, K.; Heibült, O.; Becker, I.; Ziegler, A.; Gerber, G.; Sina, M.; Görg, T.; Mayer, H.; et al. Several
Mutations in the Melanocortin-4 Receptor Gene Including a Nonsense and a Frameshift Mutation Associated with Dominantly
Inherited Obesity in Humans. J. Clin. Endocrinol. Metab. 1999, 84, 1483–1486. [CrossRef] [PubMed]
86. Vaisse, C.; Clement, K.; Durand, E.; Hercberg, S.; Guy-Grand, B.; Froguel, P. Melanocortin-4 Receptor Mutations Are a Frequent
and Heterogeneous Cause of Morbid Obesity. J. Clin. Investig. 2000, 106, 253–262. [CrossRef]
87. Farooqi, I.S.; Keogh, J.M.; Yeo, G.S.H.; Lank, E.J.; Cheetham, T.; O’Rahilly, S. Clinical Spectrum of Obesity and Mutations in the
Melanocortin 4 Receptor Gene. N. Engl. J. Med. 2003, 348, 1085–1095. [CrossRef]
88. Loos, R.J.F.; Lindgren, C.M.; Li, S.; Wheeler, E.; Hua Zhao, J.; Prokopenko, I.; Inouye, M.; Freathy, R.M.; Attwood, A.P.; Beckmann,
J.S.; et al. Common Variants near MC4R Are Associated with Fat Mass, Weight and Risk of Obesity. Nat. Genet. 2008, 40, 768–775.
[CrossRef]
89. Li, Y.Q.; Shrestha, Y.; Pandey, M.; Chen, M.; Kablan, A.; Gavrilova, O.; Offermanns, S.; Weinstein, L.S. Gq/11α and Gsα Mediate
Distinct Physiological Responses to Central Melanocortins. J. Clin. Investig. 2016, 126, 40–49. [CrossRef]
90. Garfield, A.S.; Li, C.; Madara, J.C.; Shah, B.P.; Webber, E.; Steger, J.S.; Campbell, J.N.; Gavrilova, O.; Lee, C.E.; Olson, D.P.; et al. A
Neural Basis for Melanocortin-4 Receptor Regulated Appetite. Nat. Neurosci. 2015, 18, 863. [CrossRef]
91. Matsumura, S.; Miyakita, M.; Miyamori, H.; Kyo, S.; Shima, D.; Yokokawa, T.; Ishikawa, F.; Sasaki, T.; Jinno, T.; Tanaka, J.; et al.
Stimulation of GSsignaling in MC4R Cells by DREADD Increases Energy Expenditure, Suppresses Food Intake, and Increases
Locomotor Activity in Mice. Am. J. Physiol. Endocrinol. Metab. 2022, 322, E436–E445. [CrossRef] [PubMed]
92. Chen, K.Y.; Muniyappa, R.; Abel, B.S.; Mullins, K.P.; Staker, P.; Brychta, R.J.; Zhao, X.; Ring, M.; Psota, T.L.; Cone, R.D.; et al. RM-
493, a Melanocortin-4 Receptor (MC4R) Agonist, Increases Resting Energy Expenditure in Obese Individuals. J. Clin. Endocrinol.
Metab. 2015, 100, 1639–1645. [CrossRef]
93. Wang, X.; Cui, X.; Li, Y.; Li, F.; Li, Y.; Dai, J.; Hu, H.; Wang, X.; Sun, J.; Yang, Y.; et al. MC4R Deficiency Causes Dysregulation of
Postsynaptic Excitatory Synaptic Transmission as a Crucial Culprit for Obesity. Diabetes 2022, 71, 2331–2343. [CrossRef]
94. Podyma, B.; Sun, H.; Wilson, E.A.; Carlson, B.; Pritikin, E.; Gavrilova, O.; Weinstein, L.S.; Chen, M. The Stimulatory G Protein Gsα
Is Required in Melanocortin 4 Receptor–Expressing Cells for Normal Energy Balance, Thermogenesis, and Glucose Metabolism.
J. Biol. Chem. 2018, 293, 10993. [CrossRef]
95. Kuo, J.J.; Silva, A.A.; Hall, J.E. Hypothalamic Melanocortin Receptors and Chronic Regulation of Arterial Pressure and Renal
Function. Hypertension 2003, 41, 768–774. [CrossRef]
96. Sohn, J.W.; Harris, L.E.; Berglund, E.D.; Liu, T.; Vong, L.; Lowell, B.B.; Balthasar, N.; Williams, K.W.; Elmquist, J.K. Melanocortin 4
Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons. Cell 2013, 152, 612–619. [CrossRef]
[PubMed]
Cells 2023, 12, 1801 20 of 28
97. Iwasa, M.; Kawabe, K.; Sapru, H.N. Activation of Melanocortin Receptors in the Intermediolateral Cell Column of the Upper
Thoracic Cord Elicits Tachycardia in the Rat. Am. J. Physiol. Heart Circ. Physiol. 2013, 305, H885. [CrossRef] [PubMed]
98. Berglund, E.D.; Liu, T.; Kong, X.; Sohn, J.W.; Vong, L.; Deng, Z.; Lee, C.E.; Lee, S.; Williams, K.W.; Olson, D.P.; et al. Melanocortin 4
Receptors in Autonomic Neurons Regulate Thermogenesis and Glycemia. Nat. Neurosci. 2014, 17, 911–913. [CrossRef] [PubMed]
99. Li, M.M.; Madara, J.C.; Steger, J.S.; Krashes, M.J.; Balthasar, N.; Campbell, J.N.; Resch, J.M.; Conley, N.J.; Garfield, A.S.; Lowell,
B.B. The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits. Neuron
2019, 102, 653–667. [CrossRef]
100. An, J.J.; Liao, G.Y.; Kinney, C.E.; Sahibzada, N.; Xu, B. Discrete BDNF Neurons in the Paraventricular Hypothalamus Control
Feeding and Energy Expenditure. Cell Metab. 2015, 22, 175–188. [CrossRef]
101. Li, C.; Navarrete, J.; Liang-Guallpa, J.; Lu, C.; Funderburk, S.C.; Chang, R.B.; Liberles, S.D.; Olson, D.P.; Krashes, M.J. Defined
Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State. Cell Metab. 2019,
29, 681–694.e5. [CrossRef]
102. Varela, L.; Horvath, T.L. Parallel Paths in PVH Control of Feeding. Neuron 2019, 102, 514–516. [CrossRef] [PubMed]
103. An, J.J.; Kinney, C.E.; Tan, J.W.; Liao, G.Y.; Kremer, E.J.; Xu, B. TrkB-Expressing Paraventricular Hypothalamic Neurons Suppress
Appetite through Multiple Neurocircuits. Nat. Commun. 2020, 11, 1729. [CrossRef]
104. Krashes, M.J.; Lowell, B.B.; Garfield, A.S. Melanocortin-4 Receptor–Regulated Energy Homeostasis. Nat. Neurosci. 2016, 19,
206–219. [CrossRef] [PubMed]
105. Baldini, G.; Phelan, K.D. The Melanocortin Pathway and Control of Appetite-Progress and Therapeutic Implications. J. Endocrinol.
2019, 241, R1–R33. [CrossRef] [PubMed]
106. King, B.M. The Rise, Fall, and Resurrection of the Ventromedial Hypothalamus in the Regulation of Feeding Behavior and Body
Weight. Physiol. Behav. 2006, 87, 221–244. [CrossRef]
107. Becker, E.E.; Kissileff, H.R. Inhibitory Controls of Feeding by the Ventromedial Hypothalamus. Am. J. Physiol. 1974, 226, 383–396.
[CrossRef]
108. Maes, H. Time Course of Feeding Induced by Pentobarbital-Injections into the Rat’s VMH. Physiol. Behav. 1980, 24, 1107–1114.
[CrossRef]
109. Gaur, A.; Pal, G.K.; Ananthanarayanan, P.H.; Pal, P. Role of Ventromedial Hypothalamus in High Fat Diet Induced Obesity in
Male Rats: Association with Lipid Profile, Thyroid Profile and Insulin Resistance. Ann. Neurosci. 2014, 21, 104–107. [CrossRef]
110. Wang, Q.; Zhang, B.; Stutz, B.; Liu, Z.W.; Horvath, T.L.; Yang, X. Ventromedial Hypothalamic OGT Drives Adipose Tissue
Lipolysis and Curbs Obesity. Sci. Adv. 2022, 8, eabn8092. [CrossRef] [PubMed]
111. Viskaitis, P.; Irvine, E.E.; Smith, M.A.; Choudhury, A.I.; Alvarez-Curto, E.; Glegola, J.A.; Hardy, D.G.; Pedroni, S.M.A.; Paiva
Pessoa, M.R.; Fernando, A.B.P.; et al. Modulation of SF1 Neuron Activity Coordinately Regulates Both Feeding Behavior and
Associated Emotional States. Cell Rep. 2017, 21, 3559–3572. [CrossRef] [PubMed]
112. Coutinho, E.A.; Okamoto, S.; Ishikawa, A.W.; Yokota, S.; Wada, N.; Hirabayashi, T.; Saito, K.; Sato, T.; Takagi, K.; Wang, C.C.;
et al. Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in
Peripheral Tissues. Diabetes 2017, 66, 2372–2386. [CrossRef] [PubMed]
113. Sternson, S.M.; Shepherd, G.M.G.; Friedman, J.M. Topographic Mapping of VMH → Arcuate Nucleus Microcircuits and Their
Reorganization by Fasting. Nat. Neurosci. 2005, 8, 1356–1363. [CrossRef]
114. Zhang, J.; Chen, D.; Sweeney, P.; Yang, Y. An Excitatory Ventromedial Hypothalamus to Paraventricular Thalamus Circuit That
Suppresses Food Intake. Nat. Commun. 2020, 11, 6326. [CrossRef] [PubMed]
115. Dhillon, H.; Zigman, J.M.; Ye, C.; Lee, C.E.; McGovern, R.A.; Tang, V.; Kenny, C.D.; Christiansen, L.M.; White, R.D.; Edelstein,
E.A.; et al. Leptin Directly Activates SF1 Neurons in the VMH, and This Action by Leptin Is Required for Normal Body-Weight
Homeostasis. Neuron 2006, 49, 191–203. [CrossRef]
116. Meek, T.H.; Nelson, J.T.; Matsen, M.E.; Dorfman, M.D.; Guyenet, S.J.; Damian, V.; Allison, M.B.; Scarlett, J.M.; Nguyen, H.T.;
Thaler, J.P.; et al. Functional Identification of a Neurocircuit Regulating Blood Glucose. Proc. Natl. Acad. Sci. USA 2016, 113,
E2073–E2082. [CrossRef]
117. Fosch, A.; Zagmutt, S.; Casals, N.; Rodríguez-Rodríguez, R. New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity
and Diabetes. Int. J. Mol. Sci. 2021, 22, 22. [CrossRef]
118. Bellinger, L.L.; Bernardis, L.L. The Dorsomedial Hypothalamic Nucleus and Its Role in Ingestive Behavior and Body Weight
Regulation: Lessons Learned from Lesioning Studies. Physiol. Behav. 2002, 76, 431–442. [CrossRef]
119. Kesterson, R.A.; Huszar, D.; Lynch, C.A.; Simerly, R.B.; Cone, R.D. Induction of Neuropeptide Y Gene Expression in the Dorsal
Medial Hypothalamic Nucleus in Two Models of the Agouti Obesity Syndrome. Mol. Endocrinol. 1997, 11, 630–637. [CrossRef]
120. Guan, X.M.; Yu, H.; Van Der Ploeg, L.H.T. Evidence of Altered Hypothalamic Pro-Opiomelanocortin/Neuropeptide Y MRNA
Expression in Tubby Mice. Mol. Brain Res. 1998, 59, 273–279. [CrossRef]
121. Bi, S.; Ladenheim, E.E.; Schwartz, G.J.; Moran, T.H. A Role for NPY Overexpression in the Dorsomedial Hypothalamus in
Hyperphagia and Obesity of OLETF Rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2001, 281, R254–R260. [CrossRef] [PubMed]
122. Yang, L.; Scott, K.A.; Hyun, J.; Tamashiro, K.L.; Tray, N.; Moran, T.H.; Bi, S. Role of Dorsomedial Hypothalamic Neuropeptide Y
in Modulating Food Intake and Energy Balance. J. Neurosci. 2009, 29, 179–190. [CrossRef] [PubMed]
Cells 2023, 12, 1801 21 of 28
123. Otgon-Uul, Z.; Suyama, S.; Onodera, H.; Yada, T. Optogenetic Activation of Leptin- and Glucose-Regulated GABAergic Neurons
in Dorsomedial Hypothalamus Promotes Food Intake via Inhibitory Synaptic Transmission to Paraventricular Nucleus of
Hypothalamus. Mol. Metab. 2016, 5, 709–715. [CrossRef]
124. Chen, J.; Scott, K.A.; Zhao, Z.; Moran, T.H.; Bi, S. Characterization of the Feeding Inhibition and Neural Activation Produced by
Dorsomedial Hypothalamic Cholecystokinin Administration. Neuroscience 2008, 152, 178–188. [CrossRef]
125. Rust, V.A.; Crosby, K.M. Cholecystokinin Acts in the Dorsomedial Hypothalamus of Young Male Rats to Suppress Appetite in a
Nitric Oxide-Dependent Manner. Neurosci. Lett. 2021, 764, 136295. [CrossRef] [PubMed]
126. Imoto, D.; Yamamoto, I.; Matsunaga, H.; Yonekura, T.; Lee, M.L.; Kato, K.X.; Yamasaki, T.; Xu, S.; Ishimoto, T.; Yamagata, S.;
et al. Refeeding Activates Neurons in the Dorsomedial Hypothalamus to Inhibit Food Intake and Promote Positive Valence. Mol.
Metab. 2021, 54, 101366. [CrossRef]
127. Han, Y.; He, Y.; Harris, L.; Xu, Y.; Wu, Q. Identification of a GABAergic Neural Circuit Governing Leptin Signaling Deficiency-
Induced Obesity. Elife 2023, 12, e82649. [CrossRef]
128. Haspula, D.; Clark, M.A. Neuroinflammation and Sympathetic Overactivity: Mechanisms and Implications in Hypertension.
Auton. Neurosci. 2018, 210, 10–17. [CrossRef]
129. Grill, H.J.; Norgren, R. Chronically Decerebrate Rats Demonstrate Satiation but Not Bait Shyness. Science 1978, 201, 267–269.
[CrossRef]
130. Dirocco, R.J.; Grill, H.J. The Forebrain Is Not Essential for Sympathoadrenal Hyperglycemic Response to Glucoprivation. Science
1979, 204, 1112–1114. [CrossRef]
131. Jeong, J.K.; Dow, S.A.; Young, C.N. Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation.
Metabolites 2021, 11, 494. [CrossRef] [PubMed]
132. Watts, A.G.; Kanoski, S.E.; Sanchez-Watts, G.; Langhans, W. The Physiological Control of Eating: Signals, Neurons, and Networks.
Physiol. Rev. 2022, 102, 689–813. [CrossRef] [PubMed]
133. Grill, H.J.; Hayes, M.R. The Nucleus Tractus Solitarius: A Portal for Visceral Afferent Signal Processing, Energy Status Assessment
and Integration of Their Combined Effects on Food Intake. Int. J. Obes. 2009, 33 (Suppl. 1), S11–S15. [CrossRef] [PubMed]
134. Kandalam, U.; Sarmiento, N.; Haspula, D.; Clark, M.A. Angiotensin III Induces Signal Transducer and Activator of Transcription
3 and Interleukin-6 MRNA Levels in Cultured Rat Astrocytes. J. Renin-Angiotensin-Aldosterone Syst. 2015, 16, 758–767. [CrossRef]
135. Haspula, D.; Clark, M.A. MAPK Activation Patterns of AT1R and CB1R in SHR versus Wistar Astrocytes: Evidence of CB1R
Hypofunction and Crosstalk between AT1R and CB1R. Cell. Signal. 2017, 40, 81–90. [CrossRef]
136. Haspula, D.; Clark, M.A. Molecular Basis of the Brain Renin Angiotensin System in Cardiovascular and Neurologic Disorders:
Uncovering a Key Role for the Astroglial Angiotensin Type 1 Receptor AT1R. J. Pharmacol. Exp. Ther. 2018, 366, 251–264.
[CrossRef]
137. O’Connor, A.T.; Haspula, D.; Alanazi, A.Z.; Clark, M.A. Roles of Angiotensin III in the Brain and Periphery. Peptides 2022, 153,
170802. [CrossRef]
138. Moura-Assis, A.; Friedman, J.M.; Velloso, L.A. Gut-to-Brain Signals in Feeding Control. Am. J. Physiol. Endocrinol. Metab. 2021,
320, E326. [CrossRef]
139. Kaelberer, M.M.; Buchanan, K.L.; Klein, M.E.; Barth, B.B.; Montoya, M.M.; Shen, X.; Bohórquez, D.V. A Gut-Brain Neural Circuit
for Nutrient Sensory Transduction. Science 2018, 361, eaat5236. [CrossRef]
140. Owyang, C.; Heldsinger, A. Vagal Control of Satiety and Hormonal Regulation of Appetite. J. Neurogastroenterol. Motil. 2011, 17,
338–348. [CrossRef]
141. Berthoud, H.R.; Neuhuber, W.L. Vagal Mechanisms as Neuromodulatory Targets for the Treatment of Metabolic Disease. Ann. N.
Y. Acad. Sci. 2019, 1454, 42–55. [CrossRef]
142. Gibbs, J.; Young, R.C.; Smith, G.P. Cholecystokinin Decreases Food Intake in Rats. J. Comp. Physiol. Psychol. 1973, 84, 488–495.
[CrossRef] [PubMed]
143. Widdop, R.E.; Krstew, E.; Mercer, L.D.; Carlsberg, M.; Beart, P.M.; Jarrott, B. Electrophysiological and Autoradiographical
Evidence for Cholecystokinin A Receptors on Rat Isolated Nodose Ganglia. J. Auton. Nerv. Syst. 1994, 46, 65–73. [CrossRef]
[PubMed]
144. Schwartz, G.J.; Moran, T.H. CCK Elicits and Modulates Vagal Afferent Activity Arising from Gastric and Duodenal Sites. Ann. N.
Y. Acad. Sci. 1994, 713, 121–128. [CrossRef] [PubMed]
145. Leon Mercado, L.; Caron, A.; Wang, Y.; Burton, M.; Gautron, L. Identification of Leptin Receptor–Expressing Cells in the Nodose
Ganglion of Male Mice. Endocrinology 2019, 160, 1307–1322. [CrossRef] [PubMed]
146. Barrachina, M.D.; Martínez, V.; Wang, L.; Wei, J.Y.; Taché, Y. Synergistic Interaction between Leptin and Cholecystokinin to
Reduce Short-Term Food Intake in Lean Mice. Proc. Natl. Acad. Sci. USA 1997, 94, 10455. [CrossRef]
147. Brierley, D.I.; de Lartigue, G. Reappraising the Role of the Vagus Nerve in GLP-1-Mediated Regulation of Eating. Br. J. Pharmacol.
2022, 179, 584–599. [CrossRef]
148. Campbell, J.E.; Drucker, D.J. Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action. Cell Metab. 2013, 17,
819–837. [CrossRef]
149. Krieger, J.P.; Arnold, M.; Pettersen, K.G.; Lossel, P.; Langhans, W.; Lee, S.J. Knockdown of GLP-1 Receptors in Vagal Afferents
Affects Normal Food Intake and Glycemia. Diabetes 2016, 65, 34–43. [CrossRef]
Cells 2023, 12, 1801 22 of 28
150. Bai, L.; Mesgarzadeh, S.; Ramesh, K.S.; Huey, E.L.; Liu, Y.; Gray, L.A.; Aitken, T.J.; Chen, Y.; Beutler, L.R.; Ahn, J.S.; et al. Genetic
Identification of Vagal Sensory Neurons That Control Feeding. Cell 2019, 179, 1129–1143.e23. [CrossRef]
151. Egerod, K.L.; Petersen, N.; Timshel, P.N.; Rekling, J.C.; Wang, Y.; Liu, Q.; Schwartz, T.W.; Gautron, L. Profiling of G Protein-
Coupled Receptors in Vagal Afferents Reveals Novel Gut-to-Brain Sensing Mechanisms. Mol. Metab. 2018, 12, 62–75. [CrossRef]
[PubMed]
152. Baumgartner, I.; Pacheco-López, G.; Rüttimann, E.B.; Arnold, M.; Asarian, L.; Langhans, W.; Geary, N.; Hillebrand, J.J.G. Hepatic-
Portal Vein Infusions of Glucagon-like Peptide-1 Reduce Meal Size and Increase c-Fos Expression in the Nucleus Tractus Solitarii,
Area Postrema and Central Nucleus of the Amygdala in Rats. J. Neuroendocrinol. 2010, 22, 557–563. [CrossRef] [PubMed]
153. Campos, C.A.; Wright, J.S.; Czaja, K.; Ritter, R.C. CCK-Induced Reduction of Food Intake and Hindbrain MAPK Signaling Are
Mediated by NMDA Receptor Activation. Endocrinology 2012, 153, 2633–2646. [CrossRef] [PubMed]
154. Punjabi, M.; Arnold, M.; Rüttimann, E.; Graber, M.; Geary, N.; Pacheco-López, G.; Langhans, W. Circulating Glucagon-like
Peptide-1 (GLP-1) Inhibits Eating in Male Rats by Acting in the Hindbrain and Without Inducing Avoidance. Endocrinology 2014,
155, 1690–1699. [CrossRef]
155. Barrera, J.G.; Jones, K.R.; Herman, J.P.; D’Alessio, D.A.; Woods, S.C.; Seeley, R.J. Hyperphagia and Increased Fat Accumulation in
Two Models of Chronic CNS Glucagon-Like Peptide-1 Loss of Function. J. Neurosci. 2011, 31, 3904–3913. [CrossRef]
156. Finan, B.; Ma, T.; Ottaway, N.; Müller, T.D.; Habegger, K.M.; Heppner, K.M.; Kirchner, H.; Holland, J.; Hembree, J.; Raver, C.; et al.
Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans. Sci. Transl. Med. 2013, 5, 209ra151.
[CrossRef]
157. Zhang, C.; Vincelette, L.K.; Reimann, F.; Liberles, S.D. A Brainstem Circuit for Nausea Suppression. Cell Rep. 2022, 39, 110953.
[CrossRef]
158. Samms, R.J.; Cosgrove, R.; Snider, B.M.; Furber, E.C.; Droz, B.A.; Briere, D.A.; Dunbar, J.; Dogra, M.; Alsina-Fernandez, J.; Borner,
T.; et al. GIPR Agonism Inhibits PYY-Induced Nausea-Like Behavior. Diabetes 2022, 71, 1410–1423. [CrossRef]
159. Lutz, T.A.; Mollet, A.; Rushing, P.A.; Riediger, T.; Scharrer, E. The Anorectic Effect of a Chronic Peripheral Infusion of Amylin Is
Abolished in Area Postrema/Nucleus of the Solitary Tract (AP/NTS) Lesioned Rats. Int. J. Obes. Relat. Metab. Disord. 2001, 25,
1005–1011. [CrossRef]
160. Halatchev, I.G.; Cone, R.D. Peripheral Administration of PYY(3-36) Produces Conditioned Taste Aversion in Mice. Cell Metab.
2005, 1, 159–168. [CrossRef]
161. Woods, S.C.; Lutz, T.A.; Geary, N.; Langhans, W. Pancreatic Signals Controlling Food Intake; Insulin, Glucagon and Amylin.
Philos. Trans. R. Soc. B Biol. Sci. 2006, 361, 1219. [CrossRef] [PubMed]
162. Braegger, F.E.; Asarian, L.; Dahl, K.; Lutz, T.A.; Boyle, C.N. The Role of the Area Postrema in the Anorectic Effects of Amylin and
Salmon Calcitonin: Behavioral and Neuronal Phenotyping. Eur. J. Neurosci. 2014, 40, 3055–3066. [CrossRef] [PubMed]
163. Coester, B.; Le Foll, C.; Lutz, T.A. Viral Depletion of Calcitonin Receptors in the Area Postrema: A Proof-of-Concept Study. Physiol.
Behav. 2020, 223, 112992. [CrossRef] [PubMed]
164. Scott, M.M.; Williams, K.W.; Rossi, J.; Lee, C.E.; Elmquist, J.K. Leptin Receptor Expression in Hindbrain Glp-1 Neurons Regulates
Food Intake and Energy Balance in Mice. J. Clin. Investig. 2011, 121, 2413–2421. [CrossRef]
165. Kanoski, S.E.; Zhao, S.; Guarnieri, D.J.; DiLeone, R.J.; Yan, J.; De Jonghe, B.C.; Bence, K.K.; Hayes, M.R.; Grill, H.J. Endogenous
Leptin Receptor Signaling in the Medial Nucleus Tractus Solitarius Affects Meal Size and Potentiates Intestinal Satiation Signals.
Am. J. Physiol. Endocrinol. Metab. 2012, 303, E496–E503. [CrossRef]
166. Cheng, W.; Ndoka, E.; Hutch, C.; Roelofs, K.; MacKinnon, A.; Khoury, B.; Magrisso, J.; Kim, K.S.; Rhodes, C.J.; Olson, D.P.; et al.
Leptin Receptor-Expressing Nucleus Tractus Solitarius Neurons Suppress Food Intake Independently of GLP1 in Mice. JCI Insight.
2020, 5, e134359. [CrossRef]
167. Venkatraman, A.; Edlow, B.L.; Immordino-Yang, M.H. The Brainstem in Emotion: A Review. Front. Neuroanat. 2017, 11, 15.
[CrossRef]
168. Vander Weele, C.M.; Siciliano, C.A.; Matthews, G.A.; Namburi, P.; Izadmehr, E.M.; Espinel, I.C.; Nieh, E.H.; Schut, E.H.S.;
Padilla-Coreano, N.; Burgos-Robles, A.; et al. Dopamine Enhances Signal-to-Noise Ratio in Cortical-Brainstem Encoding of
Aversive Stimuli. Nature 2018, 563, 397–401. [CrossRef]
169. Wu, Q.; Clark, M.S.; Palmiter, R.D. Deciphering a Neuronal Circuit That Mediates Appetite. Nature 2012, 483, 594–597. [CrossRef]
170. Roman, C.W.; Derkach, V.A.; Palmiter, R.D. Genetically and Functionally Defined NTS to PBN Brain Circuits Mediating Anorexia.
Nat. Commun. 2016, 7, 11905. [CrossRef]
171. D’Agostino, G.; Lyons, D.J.; Cristiano, C.; Burke, L.K.; Madara, J.C.; Campbell, J.N.; Garcia, A.P.; Land, B.B.; Lowell, B.B.; Dileone,
R.J.; et al. Appetite Controlled by a Cholecystokinin Nucleus of the Solitary Tract to Hypothalamus Neurocircuit. eLife 2016,
5, e12225. [CrossRef]
172. Roman, C.W.; Sloat, S.R.; Palmiter, R.D. A Tale of Two Circuits: CCKNTS Neuron Stimulation Controls Appetite and Induces
Opposing Motivational States by Projections to Distinct Brain Regions. Neuroscience 2017, 358, 316–324. [CrossRef]
173. Cheng, W.; Gonzalez, I.; Pan, W.; Tsang, A.H.; Adams, J.; Ndoka, E.; Gordian, D.; Khoury, B.; Roelofs, K.; Evers, S.S.; et al.
Calcitonin Receptor Neurons in the Mouse Nucleus Tractus Solitarius Control Energy Balance via the Non-Aversive Suppression
of Feeding. Cell Metab. 2020, 31, 301–312.e5. [CrossRef]
174. Larsen, P.J.; Tang-Christensen, M.; Holst, J.J.; Ørskov, C. Distribution of Glucagon-like Peptide-1 and Other Preproglucagon-
Derived Peptides in the Rat Hypothalamus and Brainstem. Neuroscience 1997, 77, 257–270. [CrossRef] [PubMed]
Cells 2023, 12, 1801 23 of 28
175. Alhadeff, A.L.; Rupprecht, L.E.; Hayes, M.R. GLP-1 Neurons in the Nucleus of the Solitary Tract Project Directly to the Ventral
Tegmental Area and Nucleus Accumbens to Control for Food Intake. Endocrinology 2012, 153, 647–658. [CrossRef] [PubMed]
176. Palkovits, M.; Eskay, R.L. Distribution and Possible Origin of β-Endorphin and ACTH in Discrete Brainstem Nuclei of Rats.
Neuropeptides 1987, 9, 123–137. [CrossRef] [PubMed]
177. Bronstein, D.M.; Schafer, M.K.H.; Watson, S.J.; Akil, H. Evidence That Beta-Endorphin Is Synthesized in Cells in the Nucleus
Tractus Solitarius: Detection of POMC MRNA. Brain Res 1992, 587, 269–275. [CrossRef]
178. Appleyard, S.M.; Bailey, T.W.; Doyle, M.W.; Jin, Y.H.; Smart, J.L.; Low, M.J.; Andresen, M.C. Proopiomelanocortin Neurons in
Nucleus Tractus Solitarius Are Activated by Visceral Afferents: Regulation by Cholecystokinin and Opioids. J. Neurosci. 2005, 25,
3578–3585. [CrossRef]
179. Georgescu, T.; Lyons, D.; Doslikova, B.; Garcia, A.P.; Marston, O.; Burke, L.K.; Chianese, R.; Lam, B.Y.H.; Yeo, G.S.H.; Rochford,
J.J.; et al. Neurochemical Characterization of Brainstem Pro-Opiomelanocortin Cells. Endocrinology 2020, 161, bqaa032. [CrossRef]
180. D’Agostino, G.; Lyons, D.; Cristiano, C.; Lettieri, M.; Olarte-Sanchez, C.; Burke, L.K.; Greenwald-Yarnell, M.; Cansell, C.;
Doslikova, B.; Georgescu, T.; et al. Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake. Cell Metab.
2018, 28, 619–630.e5. [CrossRef]
181. Wagner, S.; Brierley, D.I.; Leeson-Payne, A.; Jiang, W.; Chianese, R.; Lam, B.Y.H.; Dowsett, G.K.C.; Cristiano, C.; Lyons, D.;
Reimann, F.; et al. Obesity Medication Lorcaserin Activates Brainstem GLP-1 Neurons to Reduce Food Intake and Augments
GLP-1 Receptor Agonist Induced Appetite Suppression. Mol. Metab. 2023, 68, 101665. [CrossRef]
182. Ritter, S.; Dinh, T.T.; Zhang, Y. Localization of Hindbrain Glucoreceptive Sites Controlling Food Intake and Blood Glucose. Brain
Res. 2000, 856, 37–47. [CrossRef]
183. Boychuk, C.R.; Smith, K.C.; Peterson, L.E.; Boychuk, J.A.; Butler, C.R.; Derera, I.D.; McCarthy, J.J.; Smith, B.N. A Hindbrain
Inhibitory Microcircuit Mediates Vagally-Coordinated Glucose Regulation. Sci. Rep. 2019, 9, 2722. [CrossRef] [PubMed]
184. Zhang, L.; Koller, J.; Ip, C.K.; Gopalasingam, G.; Bajaj, N.; Lee, N.J.; Enriquez, R.F.; Herzog, H. Lack of Neuropeptide FF Signalling
in Mice Leads to Reduced Repetitive Behavior, Altered Drinking Behavior, and Fuel Type Selection. FASEB J. 2021, 35, e21980.
[CrossRef] [PubMed]
185. Zhang, L.; Koller, J.; Gopalasingam, G.; Qi, Y.; Herzog, H. Central NPFF Signalling Is Critical in the Regulation of Glucose
Homeostasis. Mol. Metab. 2022, 62, 101525. [CrossRef]
186. Wulsin, L.R.; Horn, P.S.; Perry, J.L.; Massaro, J.M.; D’Agostino, R.B. Autonomic Imbalance as a Predictor of Metabolic Risks,
Cardiovascular Disease, Diabetes, and Mortality. J. Clin. Endocrinol. Metab. 2015, 100, 2443–2448. [CrossRef]
187. Licht, C.M.M.; Vreeburg, S.A.; Van Reedt Dortland, A.K.B.; Giltay, E.J.; Hoogendijk, W.J.G.; DeRijk, R.H.; Vogelzangs, N.; Zitman,
F.G.; De Geus, E.J.C.; Penninx, B.W.J.H. Increased Sympathetic and Decreased Parasympathetic Activity Rather than Changes in
Hypothalamic-Pituitary-Adrenal Axis Activity Is Associated with Metabolic Abnormalities. J. Clin. Endocrinol. Metab. 2010, 95,
2458–2466. [CrossRef]
188. Aronson, D.; Rayfield, E.J. How Hyperglycemia Promotes Atherosclerosis: Molecular Mechanisms. Cardiovasc. Diabetol. 2002, 1, 1.
[CrossRef] [PubMed]
189. Haspula, D.; Vallejos, A.K.; Moore, T.M.; Tomar, N.; Dash, R.K.; Hoffmann, B.R. Influence of a Hyperglycemic Microenvironment
on a Diabetic versus Healthy Rat Vascular Endothelium Reveals Distinguishable Mechanistic and Phenotypic Responses. Front.
Physiol. 2019, 10, 558. [CrossRef]
190. Jansen, A.S.P.; Hoffman, J.L.; Loewy, A.D. CNS Sites Involved in Sympathetic and Parasympathetic Control of the Pancreas: A
Viral Tracing Study. Brain Res. 1997, 766, 29–38. [CrossRef]
191. Buijs, R.M.; La Fleur, S.E.; Wortel, J.; Van Heyningen, C.; Zuiddam, L.; Mettenleiter, T.C.; Kalsbeek, A.; Nagai, K.; Niijima,
A. The Suprachiasmatic Nucleus Balances Sympathetic and Parasympathetic Output to Peripheral Organs through Separate
Preautonomic Neurons. J. Comp. Neurol. 2003, 464, 36–48. [CrossRef] [PubMed]
192. Rosario, W.; Singh, I.; Wautlet, A.; Patterson, C.; Flak, J.; Becker, T.C.; Ali, A.; Tamarina, N.; Philipson, L.H.; Enquist, L.W.;
et al. The Brain-to-Pancreatic Islet Neuronal Map Reveals Differential Glucose Regulation from Distinct Hypothalamic Regions.
Diabetes 2016, 65, 2711–2723. [CrossRef] [PubMed]
193. Ma, Y.; Ratnasabapathy, R.; Izzi-Engbeaya, C.; Nguyen-Tu, M.S.; Richardson, E.; Hussain, S.; De Backer, I.; Holton, C.; Norton, M.;
Carrat, G.; et al. Hypothalamic Arcuate Nucleus Glucokinase Regulates Insulin Secretion and Glucose Homeostasis. Diabetes
Obes. Metab. 2018, 20, 2246–2254. [CrossRef] [PubMed]
194. Papazoglou, I.; Lee, J.-H.; Cui, Z.; Enquist, L.W.; Krashes, M.J.; Rane, S.G. A Distinct Hypothalamus-to-β Cell Circuit
Modulates Insulin Secretion. Cell Metab. 2022, 34, 285–298.e7. [CrossRef]
195. Wan, S.; Coleman, F.H.; Travagli, R.A. Glucagon-like Peptide-1 Excites Pancreas-Projecting Preganglionic Vagal Motoneurons.
Am. J. Physiol. Gastrointest Liver Physiol. 2007, 292, G1474–G1482. [CrossRef]
196. Wan, S.; Browning, K.N.; Travagli, R.A. Glucagon-like Peptide-1 Modulates Synaptic Transmission to Identified Pancreas-
Projecting Vagal Motoneurons. Peptides 2007, 28, 2184–2191. [CrossRef]
197. Bruning, J.C.; Gautam, D.; Burks, D.J.; Gillette, J.; Schubert, M.; Orban, P.C.; Klein, R.; Krone, W.; Muller-Wieland, D.; Kahn, C.R.
Role of Brain Insulin Receptor in Control of Body Weight and Reproduction. Science 2000, 289, 2122–2125. [CrossRef]
198. Dampney, R.A.L. Arcuate Nucleus—A Gateway for Insulin’s Action on Sympathetic Activity. J. Physiol. 2011, 589, 2109–2110.
[CrossRef]
Cells 2023, 12, 1801 24 of 28
199. Gelling, R.W.; Morton, G.J.; Morrison, C.D.; Niswender, K.D.; Myers, M.G.; Rhodes, C.J.; Schwartz, M.W. Insulin Action in the
Brain Contributes to Glucose Lowering during Insulin Treatment of Diabetes. Cell Metab. 2006, 3, 67–73. [CrossRef]
200. Kishore, P.; Boucai, L.; Zhang, K.; Li, W.; Koppaka, S.; Kehlenbrink, S.; Schiwek, A.; Esterson, Y.B.; Mehta, D.; Bursheh, S.; et al.
Activation of K(ATP) Channels Suppresses Glucose Production in Humans. J. Clin. Investig. 2011, 121, 4916–4920. [CrossRef]
201. Obici, S.; Zhang, B.B.; Karkanias, G.; Rossetti, L. Hypothalamic Insulin Signaling Is Required for Inhibition of Glucose Production.
Nat. Med. 2002, 8, 1376–1382. [CrossRef]
202. Shin, A.C.; Filatova, N.; Lindtner, C.; Chi, T.; Degann, S.; Oberlin, D.; Buettner, C. Insulin Receptor Signaling in POMC, but Not
AgRP, Neurons Controls Adipose Tissue Insulin Action. Diabetes 2017, 66, 1560–1571. [CrossRef]
203. Dodd, G.T.; Michael, N.J.; Lee-Young, R.S.; Mangiafico, S.P.; Pryor, J.T.; Munder, A.C.; Simonds, S.E.; Brüning, J.C.; Zhang, Z.Y.;
Cowley, M.A.; et al. Insulin Regulates POMC Neuronal Plasticity to Control Glucose Metabolism. Elife 2018, 7, e38704. [CrossRef]
[PubMed]
204. El Mehdi, M.; Takhlidjt, S.; Devère, M.; Arabo, A.; Le Solliec, M.A.; Maucotel, J.; Bénani, A.; Nedelec, E.; Duparc, C.; Lefranc, B.;
et al. The 26RFa (QRFP)/GPR103 Neuropeptidergic System in Mice Relays Insulin Signalling into the Brain to Regulate Glucose
Homeostasis. Diabetologia 2022, 65, 1198–1211. [CrossRef] [PubMed]
205. Niu, S.N.; Huang, Z.B.; Wang, H.; Rao, X.R.; Kong, H.; Xu, J.; Li, X.J.; Yang, C.; Sheng, G.Q. Brainstem Hap1-Ahi1 Is Involved in
Insulin-Mediated Feeding Control. FEBS Lett. 2011, 585, 85–91. [CrossRef]
206. Filippi, B.M.; Yang, C.S.; Tang, C.; Lam, T.K.T. Insulin Activates Erk1/2 Signaling in the Dorsal Vagal Complex to Inhibit Glucose
Production. Cell Metab. 2012, 16, 500–510. [CrossRef]
207. Krowicki, Z.K.; Nathan, N.A.; Hornby, P.J. Gastric Motor and Cardiovascular Effects of Insulin in Dorsal Vagal Complex of the
Rat. Am. J. Physiol. 1998, 275, G964–G972. [CrossRef] [PubMed]
208. Blake, C.B.; Smith, B.N. Insulin Reduces Excitation in Gastric-Related Neurons of the Dorsal Motor Nucleus of the Vagus. Am. J.
Physiol. Regul. Integr. Comp. Physiol. 2012, 303, R807–R814. [CrossRef]
209. Blake, C.B.; Smith, B.N. CAMP-Dependent Insulin Modulation of Synaptic Inhibition in Neurons of the Dorsal Motor Nucleus of
the Vagus Is Altered in Diabetic Mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 307, R711–R720. [CrossRef]
210. Schechter, R.; Holtzclaw, L.; Sadiq, F.; Kahn, A.; Devaskar, S. Insulin Synthesis by Isolated Rabbit Neurons. Endocrinology 1988,
123, 505–513. [CrossRef]
211. Devaskar, S.U.; Singh, B.S.; Carnaghi, L.R.; Rajakumar, P.A.; Giddings, S.J. Insulin II Gene Expression in Rat Central Nervous
System. Regul. Pept. 1993, 48, 55–63. [CrossRef] [PubMed]
212. Kong, D.; Tong, Q.; Ye, C.; Koda, S.; Fuller, P.M.; Krashes, M.J.; Vong, L.; Ray, R.S.; Olson, D.P.; Lowell, B.B. GABAergic RIP-Cre
Neurons in the Arcuate Nucleus Selectively Regulate Energy Expenditure. Cell 2012, 151, 645–657. [CrossRef] [PubMed]
213. Rother, E.; Belgardt, B.F.; Tsaousidou, E.; Hampel, B.; Waisman, A.; Myers, M.G.; Brüning, J.C. Acute Selective Ablation of
Rat Insulin Promoter-Expressing (RIP HER) Neurons Defines Their Orexigenic Nature. Proc. Natl. Acad. Sci. USA 2012, 109,
18132–18137. [CrossRef]
214. Eerola, K.; Longo, F.; Reinbothe, T.M.; Richard, J.E.; Shevchouk, O.T.; López-Ferreras, L.; Mishra, D.; Asker, M.; Tolö, J.; Miranda,
C.; et al. Hindbrain Insulin Controls Feeding Behavior. Mol. Metab. 2022, 66, 101614. [CrossRef]
215. Püschel, G.P.; Püschel, P.; Pü, G.P. Control of Hepatocyte Metabolism by Sympathetic and Parasympathetic Hepatic Nerves. Anat.
Rec. Part A Discov. Mol. Cell. Evol. Biol. 2004, 280A, 854–867. [CrossRef]
216. Yi, C.X.; la Fleur, S.E.; Fliers, E.; Kalsbeek, A. The Role of the Autonomic Nervous Liver Innervation in the Control of Energy
Metabolism. Biochim. Biophys Acta. 2010, 1802, 416–431. [CrossRef] [PubMed]
217. Pocal, A.; Lam, T.K.T.; Gutierrez-Juarez, R.; Obici, S.; Schwartz, G.J.; Bryan, J.; Aguilar-Bryan, L.; Rossetti, L. Hypothalamic
K(ATP) Channels Control Hepatic Glucose Production. Nature 2005, 434, 1026–1031. [CrossRef]
218. Liss, B.; Roeper, J. Molecular Physiology of Neuronal K-ATP Channels. Mol. Membr. Biol. 2001, 18, 117–127. [CrossRef]
219. Van Den Hoek, A.M.; Van Heijningen, C.; Schröder-van Der Elst, J.P.; Ouwens, D.M.; Havekes, L.M.; Romijn, J.A.; Kalsbeek,
A.; Pijl, H. Intracerebroventricular Administration of Neuropeptide Y Induces Hepatic Insulin Resistance via Sympathetic
Innervation. Diabetes 2008, 57, 2304–2310. [CrossRef]
220. Kimura, K.; Tanida, M.; Nagata, N.; Inaba, Y.; Watanabe, H.; Nagashimada, M.; Ota, T.; Asahara, S.I.; Kido, Y.; Matsumoto,
M.; et al. Central Insulin Action Activates Kupffer Cells by Suppressing Hepatic Vagal Activation via the Nicotinic Alpha 7
Acetylcholine Receptor. Cell Rep. 2016, 14, 2362–2374. [CrossRef]
221. Williams, K.W.; Margatho, L.O.; Lee, C.E.; Choi, M.; Lee, S.; Scott, M.M.; Elias, C.F.; Elmquist, J.K. Segregation of Acute Leptin
and Insulin Effects in Distinct Populations of Arcuate Proopiomelanocortin Neurons. J. Neurosci. 2010, 30, 2472–2479. [CrossRef]
[PubMed]
222. Qiu, J.; Zhang, C.; Borgquist, A.; Nestor, C.C.; Smith, A.W.; Bosch, M.A.; Ku, S.; Wagner, E.J.; Rønnekleiv, O.K.; Kelly, M.J. Insulin
Excites Anorexigenic Proopiomelanocortin Neurons via Activation of Canonical Transient Receptor Potential Channels. Cell
Metab. 2014, 19, 682–693. [CrossRef] [PubMed]
223. Qiu, J.; Wagner, E.J.; Rønnekleiv, O.K.; Kelly, M.J. Insulin and Leptin Excite Anorexigenic Pro-Opiomelanocortin Neurones via
Activation of TRPC5 Channels. J. Neuroendocrinol. 2018, 30, e12501. [CrossRef] [PubMed]
224. Huo, L.; Gamber, K.; Greeley, S.; Silva, J.; Huntoon, N.; Leng, X.H.; Bjørbæk, C. Leptin-Dependent Control of Glucose Balance and
Locomotor Activity by POMC Neurons. Cell Metab. 2009, 9, 537–547. [CrossRef] [PubMed]
Cells 2023, 12, 1801 25 of 28
225. Berglund, E.D.; Vianna, C.R.; Donato, J.; Kim, M.H.; Chuang, J.C.; Lee, C.E.; Lauzon, D.A.; Lin, P.; Brule, L.J.; Scott, M.M.; et al.
Direct Leptin Action on POMC Neurons Regulates Glucose Homeostasis and Hepatic Insulin Sensitivity in Mice. J. Clin. Investig.
2012, 122, 1000–1009. [CrossRef]
226. Liu, L.; Karkanias, G.B.; Morales, J.C.; Hawkins, M.; Barzilai, N.; Wang, J.; Rossetti, L. Intracerebroventricular Leptin Regulates
Hepatic but Not Peripheral Glucose Fluxes. J. Biol. Chem. 1998, 273, 31160–31167. [CrossRef]
227. Gutiérrez-Juárez, R.; Obici, S.; Rossetti, L. Melanocortin-Independent Effects of Leptin on Hepatic Glucose Fluxes. J. Biol. Chem.
2004, 279, 49704–49715. [CrossRef]
228. Tong, Q.; Ye, C.P.; McCrimmon, R.J.; Dhillon, H.; Choi, B.; Kramer, M.D.; Yu, J.; Yang, Z.; Christiansen, L.M.; Lee, C.E.; et al.
Synaptic Glutamate Release by Ventromedial Hypothalamic Neurons Is Part of the Neurocircuitry That Prevents Hypoglycemia.
Cell Metab. 2007, 5, 383–393. [CrossRef]
229. Shimazu, T.; Ogasawara, S. Effects of Hypothalamic Stimulation on Gluconeogenesis and Glycolysis in Rat Liver. Am. J. Physiol.
1975, 228, 1787–1793. [CrossRef]
230. Tu, L.; Fukuda, M.; Tong, Q.; Xu, Y. The Ventromedial Hypothalamic Nucleus: Watchdog of Whole-Body Glucose Homeostasis.
Cell Biosci. 2022, 12, 71. [CrossRef]
231. Gao, H.; Molinas, A.J.R.; Miyata, K.; Qiao, X.; Zsombok, A. Overactivity of Liver-Related Neurons in the Paraventricular Nucleus
of the Hypothalamus: Electrophysiological Findings in Db/Db Mice. J. Neurosci. 2017, 37, 11140. [CrossRef]
232. Pocai, A.; Obici, S.; Schwartz, G.J.; Rossetti, L. A Brain-Liver Circuit Regulates Glucose Homeostasis. Cell Metab. 2005, 1, 53–61.
[CrossRef] [PubMed]
233. Kwon, E.; Joung, H.Y.; Liu, S.M.; Chua, S.C.; Schwartz, G.J.; Jo, Y.H. Optogenetic Stimulation of the Liver-Projecting Melanocortin-
ergic Pathway Promotes Hepatic Glucose Production. Nat. Commun. 2020, 11, 6295. [CrossRef] [PubMed]
234. Lam, C.K.L.; Chari, M.; Su, B.B.; Cheung, G.W.C.; Kokorovic, A.; Yang, C.S.; Wang, P.Y.T.; Lai, T.Y.Y.; Lam, T.K.T. Activation
of N-Methyl-d-Aspartate (NMDA) Receptors in the Dorsal Vagal Complex Lowers Glucose Production. J. Biol. Chem. 2010,
285, 21913. [CrossRef] [PubMed]
235. Wang, P.Y.T.; Caspi, L.; Lam, C.K.L.; Chari, M.; Li, X.; Light, P.E.; Gutierrez-Juarez, R.; Ang, M.; Schwartz, G.J.; Lam, T.K.T. Upper
Intestinal Lipids Trigger a Gut-Brain-Liver Axis to Regulate Glucose Production. Nature 2008, 452, 1012–1016. [CrossRef]
236. Wang, L.; Pydi, S.P.; Zhu, L.; Barella, L.F.; Cui, Y.; Gavrilova, O.; Bence, K.K.; Vernochet, C.; Wess, J. Adipocyte Gi Signaling Is
Essential for Maintaining Whole-Body Glucose Homeostasis and Insulin Sensitivity. Nat. Commun. 2020, 11, 2995. [CrossRef]
237. Tajima, K.; Ikeda, K.; Tanabe, Y.; Thomson, E.A.; Yoneshiro, T.; Oguri, Y.; Ferro, M.D.; Poon, A.S.Y.; Kajimura, S. Wireless
Optogenetics Protects against Obesity via Stimulation of Non-Canonical Fat Thermogenesis. Nat. Commun. 2020, 11, 1730.
[CrossRef]
238. Lyons, C.E.; Razzoli, M.; Larson, E.; Svedberg, D.; Frontini, A.; Cinti, S.; Vulchanova, L.; Sanders, M.; Thomas, M.; Bartolomucci,
A. Optogenetic-Induced Sympathetic Neuromodulation of Brown Adipose Tissue Thermogenesis. FASEB J. 2020, 34, 2765–2773.
[CrossRef]
239. Kimura, T.; Pydi, S.P.; Wang, L.; Haspula, D.; Cui, Y.; Lu, H.; König, G.M.; Kostenis, E.; Steinberg, G.R.; Gavrilova, O.; et al.
Adipocyte Gq Signaling Is a Regulator of Glucose and Lipid Homeostasis in Mice. Nat. Commun. 2022, 13, 1652. [CrossRef]
240. Bamshad, M.; Aoki, V.T.; Adkison, M.G.; Warren, W.S.; Bartness, T.J. Central Nervous System Origins of the Sympathetic Nervous
System Outflow to White Adipose Tissue. Am. J. Physiol. 1998, 275, R291–R299. [CrossRef]
241. Bartness, T.J.; Song, C.K. Brain-Adipose Tissue Neural Crosstalk. Physiol. Behav. 2007, 91, 343–351. [CrossRef]
242. Stanley, S.; Pinto, S.; Segal, J.; Pérez, C.A.; Viale, A.; DeFalco, J.; Cai, X.; Heisler, L.K.; Friedman, J.M. Identification of Neuronal
Subpopulations That Project from Hypothalamus to Both Liver and Adipose Tissue Polysynaptically. Proc. Natl. Acad. Sci. USA
2010, 107, 7024–7029. [CrossRef] [PubMed]
243. Ryu, V.; Bartness, T.J. Short and Long Sympathetic-Sensory Feedback Loops in White Fat. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 2014, 306, R886–R900. [CrossRef] [PubMed]
244. Steculorum, S.M.; Ruud, J.; Karakasilioti, I.; Backes, H.; Engström Ruud, L.; Timper, K.; Hess, M.E.; Tsaousidou, E.; Mauer, J.;
Vogt, M.C.; et al. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue. Cell
2016, 165, 125–138. [CrossRef] [PubMed]
245. Cavalcanti-de-Albuquerque, J.P.; Bober, J.; Zimmer, M.R.; Dietrich, M.O. Regulation of Substrate Utilization and Adiposity by
Agrp Neurons. Nat. Commun. 2019, 10, 311. [CrossRef]
246. Chao, P.T.; Yang, L.; Aja, S.; Moran, T.H.; Bi, S. Knockdown of NPY Expression in the Dorsomedial Hypothalamus Promotes
Development of Brown Adipocytes and Prevents Diet-Induced Obesity. Cell Metab. 2011, 13, 573–583. [CrossRef]
247. Gómez-Valadés, A.G.; Pozo, M.; Varela, L.; Boudjadja, M.B.; Ramírez, S.; Chivite, I.; Eyre, E.; Haddad-Tóvolli, R.; Obri, A.;
Milà-Guasch, M.; et al. Mitochondrial Cristae-Remodeling Protein OPA1 in POMC Neurons Couples Ca2+ Homeostasis with
Adipose Tissue Lipolysis. Cell Metab. 2021, 33, 1820–1835.e9. [CrossRef]
248. López, M. Hypothalamic AMPK and Energy Balance. Eur J. Clin. Investig. 2018, 48, e12996. [CrossRef]
249. Martínez De Morentin, P.B.; González-García, I.; Martins, L.; Lage, R.; Fernández-Mallo, D.; Martínez-Sánchez, N.; Ruíz-Pino, F.;
Liu, J.; Morgan, D.A.; Pinilla, L.; et al. Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK. Cell
Metab. 2014, 20, 41–53. [CrossRef]
Cells 2023, 12, 1801 26 of 28
250. Seoane-Collazo, P.; Roa, J.; Rial-Pensado, E.; Liñares-Pose, L.; Beiroa, D.; Ruíz-Pino, F.; López-González, T.; Morgan, D.A.;
Pardavila, J.Á.; Sánchez-Tapia, M.J.; et al. SF1-Specific AMPKa1 Deletion Protects against Diet-Induced Obesity. Diabetes 2018, 67,
2213–2226. [CrossRef] [PubMed]
251. Buettner, C.; Muse, E.D.; Cheng, A.; Chen, L.; Scherer, T.; Pocai, A.; Su, K.; Cheng, B.; Li, X.; Harvey-White, J.; et al. Leptin
Controls Adipose Tissue Lipogenesis via Central, STAT3-Independent Mechanisms. Nat. Med. 2008, 14, 667–675. [CrossRef]
[PubMed]
252. Zeng, W.; Pirzgalska, R.M.; Pereira, M.M.A.; Kubasova, N.; Barateiro, A.; Seixas, E.; Lu, Y.H.; Kozlova, A.; Voss, H.; Martins, G.G.;
et al. Sympathetic Neuro-Adipose Connections Mediate Leptin-Driven Lipolysis. Cell 2015, 163, 84–94. [CrossRef]
253. Dodd, G.T.; Decherf, S.; Loh, K.; Simonds, S.E.; Wiede, F.; Balland, E.; Merry, T.L.; Münzberg, H.; Zhang, Z.Y.; Kahn, B.B.; et al.
Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat. Cell 2015, 160, 88–104. [CrossRef] [PubMed]
254. Mark, A.L.; Agassandian, K.; Morgan, D.A.; Liu, X.; Cassell, M.D.; Rahmouni, K. Leptin Signaling in the Nucleus Tractus Solitarii
Increases Sympathetic Nerve Activity to the Kidney. Hypertension 2009, 53, 375–380. [CrossRef]
255. Barnes, M.J.; McDougal, D.H. Leptin into the Rostral Ventral Lateral Medulla (RVLM) Augments Renal Sympathetic Nerve
Activity and Blood Pressure. Front. Neurosci. 2014, 8, 232. [CrossRef] [PubMed]
256. Shi, Z.; Pelletier, N.E.; Wong, J.; Li, B.; Sdrulla, A.D.; Madden, C.J.; Marks, D.L.; Brooks, V.L. Leptin Increases Sympathetic Nerve
Activity via Induction of Its Own Receptor in the Paraventricular Nucleus. Elife 2020, 9, e55357. [CrossRef] [PubMed]
257. Coester, B.; Koester-Hegmann, C.; Lutz, T.A.; Foll, C. Le Amylin/Calcitonin Receptor–Mediated Signaling in POMC Neurons
Influences Energy Balance and Locomotor Activity in Chow-Fed Male Mice. Diabetes 2020, 69, 1110–1125. [CrossRef]
258. Psichas, A.; Reimann, F.; Gribble, F.M. Gut Chemosensing Mechanisms. J. Clin. Investig. 2015, 125, 908–917. [CrossRef]
259. Kim, W.; Egan, J.M. The Role of Incretins in Glucose Homeostasis and Diabetes Treatment. Pharmacol. Rev. 2008, 60, 470–512.
[CrossRef]
260. Ørskov, C.; Poulsen, S.S.; Møller, M.; Holst, J.J. Glucagon-like Peptide I Receptors in the Subfornical Organ and the Area Postrema
Are Accessible to Circulating Glucagon-like Peptide I. Diabetes 1996, 45, 832–835. [CrossRef]
261. Gu, G.; Roland, B.; Tomaselli, K.; Dolman, C.S.; Lowe, C.; Heilig, J.S. Glucagon-like Peptide-1 in the Rat Brain: Distribution of
Expression and Functional Implication. J. Comp. Neurol. 2013, 521, 2235–2261. [CrossRef] [PubMed]
262. Secher, A.; Jelsing, J.; Baquero, A.F.; Hecksher-Sørensen, J.; Cowley, M.A.; Dalbøge, L.S.; Hansen, G.; Grove, K.L.; Pyke, C.;
Raun, K.; et al. The Arcuate Nucleus Mediates GLP-1 Receptor Agonist Liraglutide-Dependent Loss. J. Clin. Investig. 2014, 124,
4473–4488. [CrossRef]
263. Adriaenssens, A.E.; Biggs, E.K.; Darwish, T.; Tadross, J.; Sukthankar, T.; Girish, M.; Polex-Wolf, J.; Lam, B.Y.; Zvetkova, I.; Pan, W.;
et al. Glucose-Dependent Insulinotropic Polypeptide Receptor-Expressing Cells in the Hypothalamus Regulate Food Intake. Cell
Metab. 2019, 30, 987–996.e6. [CrossRef]
264. Zhang, Q.; Delessa, C.T.; Augustin, R.; Bakhti, M.; Colldén, G.; Drucker, D.J.; Feuchtinger, A.; Caceres, C.G.; Grandl, G.; Harger,
A.; et al. The Glucose-Dependent Insulinotropic Polypeptide (GIP) Regulates Body Weight and Food Intake via CNS-GIPR
Signaling. Cell Metab. 2021, 33, 833–844.e5. [CrossRef] [PubMed]
265. Fukuda, M. The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity. Diabetes 2021, 70, 1929–1937. [CrossRef]
[PubMed]
266. Turton, M.D.; O’Shea, D.; Gunn, I.; Beak, S.A.; Edwards, C.M.B.; Meeran, K.; Choi, S.J.; Taylor, G.M.; Heath, M.M.; Lambert, P.D.;
et al. A Role for Glucagon-like Peptide-1 in the Central Regulation of Feeding. Nature 1996, 379, 69–72. [CrossRef]
267. Meeran, K.; O’Shea, D.; Edwards, C.M.B.; Turton, M.D.; Heath, M.M.; Gunn, I.; Abusnana, S.; Rossi, M.; Small, C.J.; Goldstone,
A.P.; et al. Repeated Intracerebroventricular Administration of Glucagon-Like Peptide-1-(7–36) Amide or Exendin-(9–39) Alters
Body Weight in the Rat*This Work Was Supported by the United Kingdom Medical Research Council. Endocrinology 1999, 140,
244–250. [CrossRef]
268. Heppner, K.M.; Kirigiti, M.; Secher, A.; Paulsen, S.J.; Buckingham, R.; Pyke, C.; Knudsen, L.B.; Vrang, N.; Grove, K.L. Expression
and Distribution of Glucagon-like Peptide-1 Receptor MRNA, Protein and Binding in the Male Nonhuman Primate (Macaca
Mulatta) Brain. Endocrinology 2015, 156, 255–267. [CrossRef]
269. NamKoong, C.; Kim, M.S.; Jang, B.T.; Lee, Y.H.; Cho, Y.M.; Choi, H.J. Central Administration of GLP-1 and GIP Decreases Feeding
in Mice. Biochem. Biophys. Res. Commun. 2017, 490, 247–252. [CrossRef]
270. Costa, A.; Ai, M.; Nunn, N.; Culotta, I.; Hunter, J.; Boudjadja, M.B.; Valencia-Torres, L.; Aviello, G.; Hodson, D.J.; Snider, B.M.;
et al. Anorectic and Aversive Effects of GLP-1 Receptor Agonism Are Mediated by Brainstem Cholecystokinin Neurons, and
Modulated by GIP Receptor Activation. Mol. Metab. 2022, 55, 101407. [CrossRef]
271. Samms, R.J.; Sloop, K.W.; Gribble, F.M.; Reimann, F.; Adriaenssens, A.E. GIPR Function in the Central Nervous System:
Implications and Novel Perspectives for GIP-Basedz Therapies in Treating Metabolic Disorders. Diabetes 2021, 70, 1938–1944.
[CrossRef] [PubMed]
272. Kim, S.J.; Nian, C.; Karunakaran, S.; Clee, S.M.; Isales, C.M.; McIntosh, C.H.S. GIP-Overexpressing Mice Demonstrate Reduced
Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis. PLoS ONE 2012, 7, e40156. [CrossRef] [PubMed]
273. Mroz, P.A.; Finan, B.; Gelfanov, V.; Yang, B.; Tschöp, M.H.; DiMarchi, R.D.; Perez-Tilve, D. Optimized GIP Analogs Promote Body
Weight Lowering in Mice through GIPR Agonism Not Antagonism. Mol. Metab. 2019, 20, 51–62. [CrossRef] [PubMed]
Cells 2023, 12, 1801 27 of 28
274. Han, W.; Wang, L.; Ohbayashi, K.; Takeuchi, M.; O’Farrell, L.; Coskun, T.; Rakhat, Y.; Yabe, D.; Iwasaki, Y.; Seino, Y.; et al.
Glucose-Dependent Insulinotropic Polypeptide Counteracts Diet-Induced Obesity along with Reduced Feeding, Elevated Plasma
Leptin and Activation of Leptin-Responsive and Proopiomelanocortin Neurons in the Arcuate Nucleus. Diabetes Obes. Metab.
2023, 25, 1534–1546.e6. [CrossRef]
275. Falko, J.M.; Crockett, S.E.; Cataland, S.; Mazzaferri, E.L. Gastric Inhibitory Polypeptide (GIP) Stimulated by Fat Ingestion in Man.
J. Clin. Endocrinol. Metab. 1975, 41, 260–265.e5. [CrossRef]
276. Brøns, C.; Jensen, C.B.; Storgaard, H.; Hiscock, N.J.; White, A.; Appel, J.S.; Jacobsen, S.; Nilsson, E.; Larsen, C.M.; Astrup, A.;
et al. Impact of Short-Term High-Fat Feeding on Glucose and Insulin Metabolism in Young Healthy Men. J. Physiol. 2009, 587,
2387–2397. [CrossRef]
277. Miyawaki, K.; Yamada, Y.; Ban, N.; Ihara, Y.; Tsukiyama, K.; Zhou, H.; Fujimoto, S.; Oku, A.; Tsuda, K.; Toyokuni, S.; et al.
Inhibition of Gastric Inhibitory Polypeptide Signaling Prevents Obesity. Nat. Med. 2002, 8, 738–742. [CrossRef]
278. Szecowka, J.; Grill, V.; Sandberg, E.; Efendic, S. Effect of GIP on the Secretion of Insulin and Somatostatin and the Accumulation
of Cyclic AMP in Vitro in the Rat. Acta. Endocrinol. 1982, 99, 416–421. [CrossRef]
279. Drucker, D.J.; Philippe, J.; Mojsov, S.; Chick, W.L.; Habener, J.F. Glucagon-like Peptide I Stimulates Insulin Gene Expression and
Increases Cyclic AMP Levels in a Rat Islet Cell Line. Proc. Natl. Acad. Sci. USA 1987, 84, 3434–3438. [CrossRef]
280. Ahrén, B. Sensory Nerves Contribute to Insulin Secretion by Glucagon-like Peptide-1 in Mice. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 2004, 286, R269–R272. [CrossRef]
281. Baggio, L.L.; Drucker, D.J. Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131–2157. [CrossRef] [PubMed]
282. Cheung, G.W.C.; Kokorovic, A.; Lam, C.K.L.; Chari, M.; Lam, T.K.T. Intestinal Cholecystokinin Controls Glucose Production
through a Neuronal Network. Cell Metab. 2009, 10, 99–109. [CrossRef] [PubMed]
283. Blouet, C.; Schwartz, G.J. Duodenal Lipid Sensing Activates Vagal Afferents to Regulate Non-Shivering Brown Fat Thermogenesis
in Rats. PLoS ONE 2012, 7, e51898. [CrossRef] [PubMed]
284. Sandoval, D.A.; Bagnol, D.; Woods, S.C.; D’Alessio, D.A.; Seeley, R.J. Arcuate Glucagon-like Peptide 1 Receptors Regulate Glucose
Homeostasis but Not Food Intake. Diabetes 2008, 57, 2046–2054. [CrossRef]
285. Burmeister, M.A.; Ferre, T.; Ayala, J.E.; King, E.M.; Holt, R.M.; Ayala, J.E. Acute Activation of Central GLP-1 Receptors Enhances
Hepatic Insulin Action and Insulin Secretion in High-Fat-Fed, Insulin Resistant Mice. Am. J. Physiol. Endocrinol. Metab. 2012, 302,
334–343. [CrossRef]
286. Huang, Z.; Liu, L.; Zhang, J.; Conde, K.; Phansalkar, J.; Li, Z.; Yao, L.; Xu, Z.; Wang, W.; Zhou, J.; et al. Glucose-Sensing
Glucagon-like Peptide-1 Receptor Neurons in the Dorsomedial Hypothalamus Regulate Glucose Metabolism. Sci. Adv. 2022,
8, eabn5345. [CrossRef]
287. Pérez-Tilve, D.; González-Matías, L.; Aulinger, B.A.; Alvarez-Crespo, M.; Gil-Lozano, M.; Alvarez, E.; Andrade-Olivie, A.M.;
Tschöp, M.H.; D’Alessio, D.A.; Mallo, F. Exendin-4 Increases Blood Glucose Levels Acutely in Rats by Activation of the
Sympathetic Nervous System. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E1088–E1096. [CrossRef] [PubMed]
288. Jessen, L.; Smith, E.P.; Ulrich-Lai, Y.; Herman, J.P.; Seeley, R.J.; Sandoval, D.; D’Alessio, D. Central Nervous System GLP-
1 Receptors Regulate Islet Hormone Secretion and Glucose Homeostasis in Male Rats. Endocrinology 2017, 158, 2124–2133.
[CrossRef]
289. Marcelin, G.; Jo, Y.H.; Li, X.; Schwartz, G.J.; Zhang, Y.; Dun, N.J.; Lyu, R.M.; Blouet, C.; Chang, J.K.; Chua, S. Central Action of
FGF19 Reduces Hypothalamic AGRP/NPY Neuron Activity and Improves Glucose Metabolism. Mol. Metab. 2013, 3, 19–28.
[CrossRef]
290. Liu, S.; Marcelin, G.; Blouet, C.; Jeong, J.H.; Jo, Y.H.; Schwartz, G.J.; Chua, S. A Gut-Brain Axis Regulating Glucose Metabolism
Mediated by Bile Acids and Competitive Fibroblast Growth Factor Actions at the Hypothalamus. Mol. Metab. 2018, 8, 37–50.
[CrossRef]
291. Liu, S.-M.; Ifebi, B.; Johnson, F.; Xu, A.; Ho, J.; Yang, Y.; Schwartz, G.J.; Jo, Y.-H.; Chua, S. The Gut Signals to AGRP-Expressing
Cells of the Pituitary to Control Glucose Homeostasis. J. Clin. Investig. 2023, 133, e164185. [CrossRef]
292. Wean, J.B.; Smith, B.N. FGF19 in the Hindbrain Lowers Blood Glucose and Alters Excitability of Vagal Motor Neurons in
Hyperglycemic Mice. Endocrinology 2021, 162, bqab021. [CrossRef]
293. Fan, K.; Li, Q.; Pan, D.; Liu, H.; Li, P.; Hai, R.; Du, C. Effects of Amylin on Food Intake and Body Weight via Sympathetic
Innervation of the Interscapular Brown Adipose Tissue. Nutr. Neurosci. 2020, 25, 343–355. [CrossRef]
294. Batterham, R.L.; Ffytche, D.H.; Rosenthal, J.M.; Zelaya, F.O.; Barker, G.J.; Withers, D.J.; Williams, S.C.R. PYY Modulation of
Cortical and Hypothalamic Brain Areas Predicts Feeding Behaviour in Humans. Nature 2007, 450, 106–109. [CrossRef] [PubMed]
295. De Silva, A.; Salem, V.; Long, C.J.; Makwana, A.; Newbould, R.D.; Rabiner, E.A.; Ghatei, M.A.; Bloom, S.R.; Matthews, P.M.;
Beaver, J.D.; et al. The Gut Hormones PYY 3-36 and GLP-1 7-36 Amide Reduce Food Intake and Modulate Brain Activity in
Appetite Centers in Humans. Cell Metab. 2011, 14, 700–706. [CrossRef]
296. Tak, Y.J.; Lee, S.Y. Long-Term Efficacy and Safety of Anti-Obesity Treatment: Where Do We Stand? Curr. Obes. Rep. 2021, 10, 14–30.
[CrossRef] [PubMed]
297. Haspula, D.; Clark, M.A. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic
Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases. Int. J. Mol. Sci. 2020, 21, 7693. [CrossRef] [PubMed]
298. Coulter, A.A.; Rebello, C.J.; Greenway, F.L. Centrally Acting Agents for Obesity: Past, Present, and Future. Drugs 2018, 78,
1113–1132. [CrossRef]
Cells 2023, 12, 1801 28 of 28
299. Greenway, F.L.; Fujioka, K.; Plodkowski, R.A.; Mudaliar, S.; Guttadauria, M.; Erickson, J.; Kim, D.D.; Dunayevich, E. Effect of
Naltrexone plus Bupropion on Weight Loss in Overweight and Obese Adults (COR-I): A Multicentre, Randomised, Double-Blind,
Placebo-Controlled, Phase 3 Trial. Lancet 2010, 376, 595–605. [CrossRef]
300. Padwal, R.S.; Majumdar, S.R. Drug Treatments for Obesity: Orlistat, Sibutramine, and Rimonabant. Lancet 2007, 369, 71–77.
[CrossRef]
301. Blundell, J.; Finlayson, G.; Axelsen, M.; Flint, A.; Gibbons, C.; Kvist, T.; Hjerpsted, J.B. Effects of Once-Weekly Semaglutide on
Appetite, Energy Intake, Control of Eating, Food Preference and Body Weight in Subjects with Obesity. Diabetes Obes. Metab. 2017,
19, 1242–1251. [CrossRef]
302. Hjerpsted, J.B.; Flint, A.; Brooks, A.; Axelsen, M.B.; Kvist, T.; Blundell, J. Semaglutide Improves Postprandial Glucose and Lipid
Metabolism, and Delays First-Hour Gastric Emptying in Subjects with Obesity. Diabetes Obes. Metab. 2018, 20, 610–619. [CrossRef]
303. Chao, A.M.; Wadden, T.A.; Berkowitz, R.I.; Quigley, K.; Silvestry, F. The Risk of Cardiovascular Complications with Current
Obesity Drugs. Expert Opin. Drug. Saf. 2020, 19, 1095–1104. [CrossRef] [PubMed]
304. Josipovic, M.; Staricoff, E.O.; Riches, C.H.; Sheppard, L.; Evans, M. 1311-P: Glucokinase in AGRP Neurons Is Required for Normal
Insulin Secretion and Action in Female Mice. Diabetes 2022, 71, 1311. [CrossRef]
305. Caughey, S.D.; Wilson, P.W.; Mukhtar, N.; Brocklehurst, S.; Reid, A.; D’Eath, R.B.; Boswell, T.; Dunn, I.C. Sex Differences in Basal
Hypothalamic Anorectic and Orexigenic Gene Expression and the Effect of Quantitative and Qualitative Food Restriction. Biol
Sex Differ 2018, 9, 20. [CrossRef]
306. Kroll, D.S.; Feldman, D.E.; Biesecker, C.L.; McPherson, K.L.; Manza, P.; Joseph, P.V.; Volkow, N.D.; Wang, G.J. Neuroimaging of
Sex/Gender Differences in Obesity: A Review of Structure, Function, and Neurotransmission. Nutrients 2020, 12, 1942. [CrossRef]
307. Pi-Sunyer, X. The Medical Risks of Obesity. Postgrad. Med. 2009, 121, 21–33. [CrossRef] [PubMed]
308. Haththotuwa, R.N.; Wijeyaratne, C.N.; Senarath, U. Worldwide Epidemic of Obesity. Obes. Obstet. 2020, 3–8. [CrossRef]
309. Karalliedde, J.; Gnudi, L. Diabetes Mellitus, a Complex and Heterogeneous Disease, and the Role of Insulin Resistance as a
Determinant of Diabetic Kidney Disease. Nephrol. Dial. Transplant. 2016, 31, 206–213. [CrossRef] [PubMed]
310. Neeland, I.J.; Poirier, P.; Després, J.P. The Cardiovascular and Metabolic Heterogeneity of Obesity: Clinical Challenges and
Implications for Management. Circulation 2018, 137, 1391–1406. [CrossRef] [PubMed]
311. Rodgers, R.J.; Tschöp, M.H.; Wilding, J.P.H. Anti-Obesity Drugs: Past, Present and Future. Dis. Model Mech. 2012, 5, 621–626.
[CrossRef] [PubMed]
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