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Neuropeptides in Obesity and Metabolic Disease.

Obesity and its associated complications, such as diabetes mellitus, dyslipidemia, and osteoarthritis, form an important threat to global health. Weight gain follows when energy intake exceeds energy expenditure. Energy intake is a complex behavior with strong biological underpinnings. This was first illustrated by lesion studies in rodents that indicated that the hypothalamus is crucial in the control of appetite: lesions in the lateral hypothalamus (LH) [2] resulted in anorexia, and lesions in the ventromedial hypothalamus (VMH) led to obesity (1). Subsequently, studies in knockout rodents have identified many neuropeptides that are involved in the regulation of food intake and body weight, i.e., neuropeptides that are regulated by nutritional state and can influence food intake and/or energy expenditure. Understanding the role of these neuropeptides is of vital importance to design treatments for obesity.

Neurons communicate with each other by virtue of chemical signals that are released by one cell and received by another. Neurons often synthesize a conventional neurotransmitter (such as glutamate, GABA), neuromodulators (such as serotonin, dopamine, acetylcholine), as well as one or more neuropeptides. Classically, neurotransmitters affect the excitability of their target neuron by depolarization or hyperpolarization. In contrast, neuropeptides have more diverse effects (2). They modulate neurotransmission by altering gene expression, local blood flow, and synaptogenesis, and they act as autocrine/paracrine regulators and as hormones. Their storage is tightly regulated and release follows demand. Almost all neuropeptides signal through G-protein coupled receptors and thus tend to have prolonged actions compared to rapid-acting neurotransmitters.

Much of the current knowledge of the role of these neuropeptides comes from the study of knockout animals and more recently neural pathway mapping through optogenetics and designer receptors exclusively activated by designer drugs (DREADD) techniques. Analytical biochemistry methods, qualitative and quantitative genetic methods, and more recently single-cell transcriptomics have helped to refine the neuropeptide signatures of specific neural populations involved in the control of food intake. In humans, research has been hampered by a lack of easily accessible analytical techniques to quantify neuropeptides in vivo. Although some neuropeptides such as brain-derived neurotrophic factor (BDNF) and oxytocin can be measured in the serum by direct enzyme-linked immunoassays (3, 4), this might not reflect central bioavailability.

This review provides an overview of some selected neuropeptides involved in the regulation of appetite and metabolism. The review begins by first describing peripheral hormones that regulate food intake, followed by a discussion of the role of the neuropeptides in arcuate nucleus (ARC). It then discusses downstream neuronal targets of the ARC such as the paraventricular nucleus (PVN), the LH, and the parabrachial nucleus (PBN) in the brainstem. Finally, neuropeptides involved in satiety and energy expenditure are highlighted.


The discovery of adipocyte-derived leptin illustrates the power of analytical chemistry combined with genetics. Seminal parabiosis experiments in inbred strains of mice with severe obesity (ob/ob and db/db rodents) led to the notion that a circulating factor, leptin, regulated body weight (5-7). Following this, a new leptin immunoassay played a role in the discovery of leptin's importance in human body-weight regulation. In 1997, 2 severely obese cousins from a highly consanguineous family of Pakistani origin were found to have undetectable serum leptin, and genetic studies revealed they were homozygous for a frameshift mutation in the LEP gene ([DELTA]G133), which resulted in a truncated protein that was not secreted (8).

Leptin finds itself among many other hormones, such as insulin and gut peptides, as well as nutrients (glucose, fatty acids, and peptides) that signal peripheral energy state to the central nervous system. Gut peptides such as ghrelin, peptide YY, and glucagon-like peptide 1 (GLP1) are secreted from entero-endocrine cells in response to meal ingestion and the presence of nutrients in the intestinal lumen (9, 10). Pioneering human infusion studies have demonstrated that a number of gut peptides modulate food intake when administered acutely in humans (11). The synthetic GLP1 receptor agonist liraglutide has recently been approved for the treatment of obesity alone by the FDA and several other gut peptide analogs, as well as gut hormone receptor agonists, are currently being studied in clinical trials.

Receptors for nutritional hormones are predominantly found in the brainstem and the hypothalamus. In addition, the nucleus of the solitary tract (NTS) in the brainstem also receives afferent nervous signals from mechanoreceptors, i.e., for gastric distension, and chemoreceptors indicating changes in nutrient composition via the vagus nerve. The ARC is an aggregation of neurons in the mediobasal hypothalamus adjacent to the third ventricle. It is known for its complex and unique anatomical relationship with the blood-brain barrier, ensuring privileged access to peripheral hormones and nutrients, and forms the first point-of-call for peripheral leptin.


Two populations of neurons in the ARC have distinct biochemical signatures: neurons that produce the neuropeptides agouti-related peptide (AgRP)/neuropeptide Y (NPY) and neurons that produce proopiomelanocortin (POM)/cocaine- and amphetamine-regulated transcript (CART), which both produce the leptin receptor (LepR). These 2 neuronal populations are traditionally regarded as the key sensors of energy state. They relay information to second-order neurons, located in the paraventricular nucleus (PVN), the dorsomedial hypothalamus (DMN), LH, the brainstem, as well as wider brain areas such as the limbic system, nucleus accumbens, and prefrontal cortex. Collectively, they integrate and respond to peripheral signals from hormones and nutrients by altering food intake and energy expenditure (Fig. 1).

Leptin binds to the LepR on POMC-producing neurons in the ARC and stimulates POMC transcription. POMC is a 241-amino acid precursor polypeptide and is cleaved to produce multiple peptide hormones including [alpha]-melanocyte-stimulating hormone ([alpha]-MSH), the predominant anorexigenic neuropeptide of the ARC-PVN neurocircuitry. Alpha-MSH binds to the melanocortin-4-receptor (MC4R). Rodents that lack POMC or MC4R become severely obese (12). Disruption of this circuit in humans results in severe early-onset obesity, as in individuals with genetic variants in POMC, [3] prohormone convertase 1 (PC1), an enzyme involved in POMC processing, and MC4R (13, 14) (Table 1 and Table 2). In addition, genome-wide association studies have revealed more than 100 different candidate genes for body mass index. Pathway analyses on those genes support roles in the central nervous system, including many components of the melanocortin pathway (15). Therefore, disappointment followed the observation that early synthetic MC4R agonists increased blood pressure in humans, which revealed a key circuit linking body weight to blood pressure (16). However, renewed efforts from the pharmaceutical industry with the selective MC4R agonist (RM-493) do suggest that there might be a future for MC4R agonists in the treatment of obesity (17, 18).

In addition to [alpha]-MSH, [beta]-endorphin is produced from POMC. Beta-endorphin autoinhibits hypothalamic POMC neurons through their [mu]-opioid receptors (19, 20). The [mu]-opioid receptor antagonist naloxone and the newer one GSK1521498 reduce both the consumption of palatable (high fat/high sugar) foods (21) and the hedonic responses and motivation for these foods (22). Several classical neurotransmitters and neuropeptides have been found to modulate the activity of the melanocortin system. POMC neurons produce the serotonin (5HT) 2C receptor (5HT2CR) and selective reinstatement of the 5HT2CR on POMC neurons rescues the obesity phenotype in 5HT2CR-null mice (23). This modulation of POMC neuronal activation seems to be the core mediator of the weight-reducing effects of lorcaserin, a selective 5HT2CR agonist approved by the FDA for the treatment of obesity (24).

Several neuropeptides have been found to modulate PC1 activity. proSAAS, a protein encoded by the mouse gene Pcsk1 and precursor to 5 different neuropeptides (big SAAS, little SAAS, PEN, big LEN, and little LEN), seems to act as an inhibitor of PC1 (25), and genetic overproduction of proSAAS leads to late-onset obesity in mice (26). The effects on PC1 might be specific to embryonic development (27, 28) and the mechanisms underlying the obesity need further exploration.

CART shows almost 100% colocalization with POMC in the ARC and complete segregation from the AgrP/NPY-producing neurons (29). However, differences with humans might exist here (30). In rodents, CART mRNA concentrations are regulated by circulating leptin (31) and injections of CART in nucleus accumbens inhibit feeding in rodents (32).

AgRP/NPY-producing neurons form the orexigenic arm of the ARC-PVN hypothalamic neurocircuitry; i.e., they send signals of energy deficit onwards through AgRP, NPY, and GABA release to increase food seeking and eating (33). AgRP is a 132-amino acid peptide and acts as an inverse agonist for the MC4R by suppressing its constitutive activity as well as promoting MC4R endocytosis (34). AgRP-producing neurons directly inhibit POMC neurons in energy deficit (35). AgRP-producing neurons send extensive axon projections to other brain areas including core forebrain nodes, which are part of an extended circuit that mediates feeding behavior (36). NPY colocalizes in the majority of AgRP-producing neurons. Intracerebroventricular injection of NPY potently stimulates food intake and continuous infusion of NPY readily leads to obesity in rodents (37). Leptin inhibits arcuate NPY production, and genetic knockout of NPY reduces hyperphagia and obesity in ob/ob mice (38). NPY Y1 and Y2 receptors are produced by POMC neurons, and their activation leads to inhibition of firing activity (39). The Y5 receptor has also been implicated in the regulation of spontaneous release of a-MSH from POMC neurons, further supporting the NPY-mediated inhibition of the melanocortin system (40). In addition to NPY and AgRP, these neurons also release GABA, and elegant studies using DREADD technology found that GABA and NPY are needed for the rapid stimulation of food intake, whereas AgRP through the MC4R receptors induces feeding over a delayed yet prolonged period (41). This elegantly illustrates that neurons can differentially employ classical neurotransmitters as well as neuropeptides to regulate food intake in a temporal manner.

Finally, AgRP neurons project to the PBN directly, a brainstem area important for feeding behavior, and activation of the PBN neurons by AgRP neurons inhibits food intake, an effect mediated by their release of GABA (42, 43).


Production of MC4R is abundant in the hypothalamus, including PVN, LH, VMH, and DMN as well as in anterior hypothalamic regions; the NTS; and the spinal cord (44). Several neuropeptides and neurons have been implicated in mediating the effects of the MC4R-positive, second-order neurons on food intake and bodyweight regulation. Single-minded homolog 1 (SIM1) is a transcription factor involved in the development of the PVN and supraoptic nucleus. SIM1 haplo-insufficiency in mice and loss-of-function mutations in humans cause severe obesity (45, 46). Reproduction of the MC4R receptor on SIM1-positive neurons only is sufficient to abolish the hyperphagia seen in MC4R-null mice (47). These neurons are glutamatergic but do not seem to produce oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin, so their neuropeptide signature remains to be elucidated (47). They are synaptically connected to the PBN, and the loss of this inhibitory hypothalamic input to the PBN leads to starvation (47).

Alpha-MSH induces dendritic release of oxytocin in the PVN through the MC4R (48). Central administration of oxytocin in rodents is anorexigenic, and rodents that lack oxytocin or the oxytocin receptor become obese (49, 50). Magnocellular neurons of the PVN and supraoptic nucleus of the hypothalamus also produce a number of anorexigenic neuropeptides, including CART, pituitary adenylate cyclase-activating polypeptide, cholecystokinin (CCK), and nesfatin-1 (51), and are activated during feeding and by satiety peptides such as CCK and GLP1. In addition, these neurons produce LepR and are activated by leptin (52). Furthermore, AgRP neuron suppression of oxytocin neurons is critical for evoked feeding in rodents (33). The exact sites of locally released oxytocin that mediate the effects of oxytocin are the subjects ofintense study and most likely involve the VMH (53). Oxytocin release is negatively regulated by synaptotagmin-4 and genetic ablation of synaptotagmin-4 prevents against diet-induced obesity in mice (54). Oxytocin has attracted the attention of clinical researchers and several studies have explored the effects of oxytocin on food intake and some variably show minor effects on food intake (55). Therefore, it is conceivable that treatment with oxytocin, an oxytocin analog, or inhibitor of synaptotagmin-4 could form potential targets in the treatment of obesity.

Additionally, both POMC- and AgRP-producing neurons project to the VMH, where BDNF is abundantly produced. MC4R-null mice have decreased hypothalamic BDNF production, and administering an anti-BDNF antibody in the third ventricle blocks the anorexic effects of MC4R activation (56). Haplo-insufficient mice and mice in which BDNF has been deleted postnatally are obese (57), as are humans with genetic disruption of BDNF and its neurotrophic tyrosine kinase receptor type 2 (NTRK2) (58, 59).

Finally, MC4R neurons are involved in the regulation of sympathetic nervous system outflow. In this way, MC4R signaling mediates high-fat diet and cold-induced thermogenesis (60) and thus energy expenditure.


Lesions of the LH cause severe anorexia and adipsia (1). The LH has 3 distinct populations of neurons: neurons that produce orexin, neurons that produce melanin-concentrating hormone (MCH), and neurons containing isoform 65 of glutamic acid decarboxylase (GAD65), named "GAD65 neurons."

Orexin-producing neurons receive direct projections from AgRP- and POMC-producing neurons (61) at the same time as sending direct projections to the ARC neurons (62), which suggests they are involved in coupling the drive for energy intake with energy demands. mRNA for the precursor of orexin, preproorexin, is abundantly and specifically produced in the LH and adjacent areas. Many AgRP/NPY- and POMC-producing neurons in the ARC coproduce the LepR and orexin 1 receptor (OX1R) (63), and orexin neurons can depolarize AgRP neurons (64) and POMC neurons (65). Genetic ablation of orexin neurons in mice leads to a phenotype very similar to human narcolepsy, including behavioral arrests, premature rapid eye movement sleep, and poorly consolidated sleep patterns as well as late-onset obesity despite hypophagia compared to littermates (66, 67).

MCH is a 19-amino acid neuropeptide encoded by the Pmch gene and can bind to 2 G-protein-coupled receptors, the MCH receptor 1 (MCHR1) and MCH receptor 2 (MCHR2). MCH is synthesized in the magnocellular neurons in the lateral hypothalamus. In contrast to orexin neurons, MCH neurons show increased activity when extracellular glucose concentrations increase (68). MCH mRNA is up-regulated in ob/ob mice and by fasting in wild-type mice (69). Mice genetically lacking MCH are hypophagic and lean (70), and central administration of MCH stimulates food intake (71). MCH neurons send dense projections to reward centers in the striatum and midbrain. In addition, there is some evidence to suggest MCH neurons might regulate a taste-independent preference for caloric feeding as mice lacking the sweet taste receptor by deletion of the long transient receptor potential channel 5 normally prefer sucrose over sucralose (72), but do not show this preference when they simultaneously lack MCH neurons (73).


While research has predominantly focused on the satiating properties of CCK and bombesin-like peptides released from the GI tract, these peptides are also produced in the central nervous system. The distribution and cell specificity of bioactive CCK species formed from processed preproCCK have been investigated with the use of sequence-specific immunoassays (74). Enteroendocrine cells contain a mixture of the medium-sized CCK-58, CCK-33, CCK-22, and CCK-8, whereas neurons mainly release CCK-8 and to some extent CCK-5. Intestinal CCK regulates satiety through its actions initiated in NTS in the brainstem as well as locally by slowing gastric emptying through its CCK-A receptors. The role of neural CCK in satiety has been less extensively investigated. CCK immunoreactivity is widespread across the central nervous system, with cortical, hypothalamic, and brainstem production. A high-fat diet downregulates central CCK in rodents (75), and fasting reduces cortical CCK but increases hypothalamic CCK (76). In addition, neural CCK has been implicated in a multitude of roles, regulating thermoregulation, sympathetic nervous system activation, anxiety, and sexual behavior in rodents (74).

As mentioned before, GLP1 is produced in enteroendocrine cells as well as preproglucagon neurons, located in the NTS in the brainstem, that project to hypothalamic targets in the ARC, PVN, and DMN. GLP1 is anorexigenic, and intracerebroventricular injection of a GLP1 receptor antagonist strongly increases food intake in satiated but not in fasted animals, which suggests that endogenous GLP1 tone alters with nutritional state (10).

The mammalian bombesin family consists of neuromedin B (NMB) and gastrin-releasing peptide (GRP). In situ hybridization studies have shown high NMB production in the human hypothalamus (77) and intracerebroventricular infusion of NMB decrease in food intake in rats (78). RIAs and immunohistochemical analyses have confirmed GRP immunoreactivity in a variety of tissues, including gastrointestinal tissues and central nervous system (especially the pituitary gland, spinal cord, and adrenal gland) tissues. GRP mRNA in the PVN decreases with food deprivation in rodents and increases after melanotan II, a nonselective agonist of the melanocortin 3 and 4 receptors, infusion, which suggests that GRP-producing neurons in the PVN are part of hypothalamic circuitry involved in energy homeostasis (79). Bombesin-like peptide receptors include the 7-transmembrane GRP receptor, the NMB receptor, and the bombesin-like receptor-3 (BRS3). BRS3 only interacts with low affinity with the naturally occurring bombesin-related peptides and has no known natural high-affinity ligand. Animals lacking BRS3, however, become obese (80), suggesting that this pathway may also be important in the regulation of body weight.

RNA sequencing experiments have revealed another neuropeptide involved in energy expenditure. Prodynorphin is abundantly produced in the hypothalamus, and approximately 40% of LepR-positive, prodynorphin-producing cells also produce POMC (81). Selective knockdown of prodynorphin in LepR-positive neurons leads to obesity on a high-fat diet due to decrease in energy expenditure (81).

A comprehensive review on the RFamide class of neuropeptides in energy homeostasis is available (82). Prolactin-releasing peptide (PrRP) is a member of this neuropeptide family and is predominantly centrally produced in the brainstem and the DMN. Mice lacking its receptor, the G-protein-coupled 10 receptor (GPR10), become obese (83). Intracerebroventricular injection of PrRP inhibits food intake and increases energy expenditure as it increases body temperature, O2 consumption, and UCP-1 production of brown adipose tissue in rodents (84). Likewise, GPR10 knockout animals have a lower basal metabolic rate than wild-type animals (83). Moreover, the DMN PrRP-producing neurons are activated by leptin, and genetic deletion of PrRP neurons blocks leptin's induction of thermogenesis (85). Therefore, modulation of PrRP and its receptor GPR10 would provide potential targets in the treatment of obesity.


Targets for pharmacotherapy in obesity include the central and peripheral regulation of food intake, but also energy expenditure and physical activity. Neuropeptides regulate this, and drugs that mimic neuropeptides (MC4R agonists) or act as neuromodulators, such as lorcaserin or naltrexone/bupropion, induce weight loss in humans (24). Future drugs will need to be directed at highly specific targets and may consist of combinations of compounds that target different mechanisms, as illustrated by recent studies demonstrating the efficacy of dual MC4R and GLP1 receptor agonism (86) However, for more successful therapeutic strategies, we need more in-depth knowledge of the neuronal circuits in which they are working, the downstream targets, and potential compensatory mechanisms not only in rodents but, critically, also in humans.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: A. van der Klaauw, the Wellcome Trust Early Postdoctoral Fellowship for Clinician Scientists (099038/Z/12/Z).

Expert Testimony: None declared.

Patents: None declared.

Acknowledgments: The author would like to thank Professor I Sadaf Farooqi, Ms. Naomi Clark, Dr. Adrian Park and Dr. Fleur Talbot for their guidance and support in writing this manuscript.


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Agatha A. van der Klaauw [1] *

[1] Department of Clinical Biochemistry, Metabolic Research Laboratories--Institute of Metabolic Science, University of Cambridge, Cambridge, England.

* Address correspondence to the author at: University of Cambridge, Department of Clinical Biochemistry--Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge, CB2 0QQ. Fax 1223-762-657; e-mail

Received September 8, 2017; accepted October 18, 2017.

Previously published online at DOI: 10.1373/clinchem.2017.281568 [c]2017 American Association for Clinical Chemistry

[2] Nonstandard abbreviations: DREADD, designer receptors exclusively activated by designer drugs; ARC, arcuate nucleus; PVN, paraventricular nucleus; VMH, ventromedial hypothalamus; LH, lateral hypothalamus; POMC, proopiomelanocortin; CART, cocaine- and amphetamine-related transcript; NPY, neuropeptide Y; AgRP, agouti-related peptide; SIM 1, single-minded homolog 1; [alpha]-MSH, alpha-melanocyte-stimulating hormone; MCH, melanin-concentrating hormone; BDNF, brain-derived neurotrophic factor; NTS, nucleus of the solitary tract; PBN, parabrachial nucleus.

[3] Genes: POMC, proopiomelanocortin; PC1, prohormone convertase 1; MC4R, melanocortin 4 receptor; Pcskl, proprotein convertase subtilisin/kexintype 1; SIM1, single-minded family bHLH transcription factor 1; BDNF, brain-derived neurotrophic factor; Pmch, promelanin concentrating hormone; NTRK2, neurotrophic receptor tyrosine kinase 2; SNRPN, small nuclear ribonucleoprotein polypeptide N; SNURF, SNRPN upstream reading frame.

Caption: Fig. 1. Hypothalamic control of energy homeostasis.
Table 1. Human genetic obesity syndromes due to perturbation of
neuropeptide synthesis, secretion, orsignaling.

Gene name                Function          Genetics and phenotype

Proopiomelanocortin   Precursor of     Homozygous or compound
(POMC)                neuropeptides    heterozygous complete loss-of-
                                       function variants severe
                                       phenotype of early-onset
                                       obesity, adrenal insufficiency,
                                       and red hair

                                       Heterozygous loss-of-function
                                       mutations in [alpha]-and
                                       hormone ([alpha]-and [beta]-
                                       MSH) significantly increase
                                       obesity risk

Proconvertase         Impaired POMC    Compound heterozygote loss-of-
1 (PCSK1)             processing       function mutations

                                       Phenotype: early-onset obesity,
                                       adrenal insufficiency, elevated
                                       proinsulin, reactive

Melanocortin-4        Receptor for     Homozygous and heterozygous
receptor (MC4R)       POMC-derived     loss of function, severity of
                      neuropeptides    obesity dependent on degree of
                                       preserved signaling (87)

Brain-derived         BDNF             Haploinsufficiency (de novo
neurotrophic                           chromosomal inversion) (58)
factor (BDNF)                          Severe obesity with hyperphagia

Neurotrophic          Receptor         Heterozygous missense mutations
tyrosine kinase       for BDNF         (88) Early-onset obesity
receptor type 2

Single-minded         Likely           Haploinsufficiency and rare
homolog 1 (SIM1)      oxytocin         heterozygous variants (46, 89)

                                       Early-onset obesity,
                                       developmental delay

Prader-Willi          Reduced number   Deficiency for one or more
syndrome              of oxytocin      paternally expressed imprinted
                      neurons in PVN   transcripts within chromosome
                      in postmortem    15q11-q13, including the
                      studies          bicistronic SNURF-SnRpN gene
                                       and multiple small nucleolar
                                       RNAs (90)

                                       Neonatal hypotonia and poor
                                       feeding, obesity, hyperphagia,
                                       behavioral problems

MSH, melanocyte-stimulating hormone; POMC, proopiomelanocortin; PVN,
paraventricular nucleus; SNURF, SNRPN upstream readingframe; SNRPN,
small nuclear ribonucleopro-tein polypeptide N.

Table 2. Overview of neuropeptides discussed.

Neuropeptide               Action              Neuronal circuit

Agouti-related          Orexigenic      AgRP is released by ARC
peptide (AgRP)                          neurons; AgRP is a natural
                                        inverse agonist of the MC4R
                                        receptor and acts in the PVN,
                                        LH, and VMH

                                        AgRP neurons also send
                                        GABAergic projection to the

Neuropeptide            Orexigenic      NPY colocalizes in the
Y (NPY)                                 majority of AgRP-producing
                                        neurons and binds to its
                                        NPYY1-5 receptors. NPY
                                        regulates a-MSH release from
                                        POMC neurons through the Y5

Proopiomelanocortin     Anorexigenic    POMC is cleaved to multiple
(POMC)                                  peptide hormones in ARC
                                        neurons. a-MSH is a core
                                        anorexigenic peptide, which
                                        binds to the MC4R that is
                                        abundantly produced throughout
                                        the hypothalamus. The MC4R,
                                        SIM1-positive, glutamatergic
                                        neurons in the PVN are
                                        critically involved in
                                        regulating food intake

Cocaine- and            Anorexigenic    Sites of action include
amphetamine-related                     hypothalamus, but injections
transcript (CART)                       of CART in the nucleus
                                        accumbens also inhibits food
                                        intake in rodents

Oxytocin                Anorexigenic    Oxytocin is released from
                                        magnocellular neurons in the
                                        PVN and most likely acts as an
                                        anorexigenic neuropeptide
                                        through its receptors in the

Brain-derived           Anorexigenic    BDNF is produced in large
neurotrophic                            quantities in the VMH and acts
factor (BDNF)                           downstream of the MC4R

Orexin                  Orexigenic      Orexin/producing neurons are
                                        located in the LH and regulate
                                        wakefulness/arousal. Orexin
                                        neurons are synaptically
                                        connected to ARC POMC and AgRP

                                        Mice lacking orexin develop a
                                        phenotype similar to
                                        narcolepsy and late-onset
                                        obesity despite hypophagia

Melanin-concentrating   Orexigenic      MCH neurons are located in the
hormone (MCH)                           LH and project within the
                                        hypothalamus and to reward
                                        centers in the brain such as
                                        striatum/midbrain. Mice
                                        lacking MCH are hypophagic

Cholecystokinin (CCK)   Anorexigenic    Bioactive CCK species are
                                        processed in a tissue-
                                        specific manner. CCK receptors
                                        are found in cortical areas
                                        and in the hypothalamus

Glucagon-like           Anorexigenic    Produced by enteroendocrine
peptide 1 (GLP1)                        cells as well as neurons in
                                        the NTS. Receptors are
                                        produced in the hypothalamus
                                        and amygdala

Neuromedin B (NMB)      Anorexigenic    NMB is abundantly produced in
                                        the human hypothalamus and
                                        signals through the NMB-
                                        receptor. ICV NMB inhibits
                                        food intake in rodents

Gastrin-releasing       Anorexigenic    GRP is produced in the PVN and
peptide (GRP)                           increases after infusion of
                                        the MC4R agonist MTII,
                                        suggesting its role is
                                        downstream of the MC4R

Prolactin-releasing     Anorexigenic,   PrRP acts through the GPR10.
peptide (PrRP)          increase in     ICV PrRP decreases food intake
                        energy          and increases energy
                        expenditure     expenditure. PrRP-producing
                                        neurons in the DMN are
                                        critically involved in
                                        leptin's effects on

Neuropeptide            References

Agouti-related             (91)
peptide (AgRP)

Neuropeptide               (91)

Proopiomelanocortin       (91)

Cocaine- and               (32)
transcript (CART)

Oxytocin                 (48-52)

Brain-derived            (56-59)
factor (BDNF)

Orexin                   (61-64)

Melanin-concentrating    (69-71)
hormone (MCH)

Cholecystokinin (CCK)    (74-76)

Glucagon-like              (92)
peptide 1 (GLP1)

Neuromedin B (NMB)       (77-78)

Gastrin-releasing          (79)
peptide (GRP)

Prolactin-releasing      (83-85)
peptide (PrRP)

MC4R, melanocortin-4-receptor; PVN, paraventricular nucleus; LH,
lateral hypothalamus; VMH, ventromedial hypothalamus; PBN, parabrachial
nucleus; ARC-arcuate nucleus; SIM1, single-minded homolog 1; ICV,
intracerebroventricular; MTII, melanotan II; GPR10, G-protein coupled
10 receptor; DMN, dorsomedial hypothalamus.
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Publication:Clinical Chemistry
Article Type:Report
Date:Jan 1, 2018
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