Elsevier

Vitamins & Hormones

Volume 65, 2002, Pages 281-311
Vitamins & Hormones

Leptin and melanocortin signaling in the hypothalamus

https://doi.org/10.1016/S0083-6729(02)65068-XGet rights and content

Abstract

The regulation of body weight in humans is coordinated by the interplay between food intake and energy expenditure. The identification of the adipocytesecreted hormone leptin as a key regulator on both of these processes has shed new light on the pathways involved in their regulation. Indeed, mutations in the gene's encoding leptin and its cognate receptor cause severe obesity in humans. Leptin's actions are mediated principally by target neurons in the hypothalamus where it acts to alter food intake, energy expenditure, and neuroendocrine-function. Recently, it has become clear that a number of critical neuropeptides are regulated by leptin in the hypothalamus. Among these is the proopiomelanocortin (POMC)-derived peptide, α-melanocyte-stimulating hormone (α-MSH), which is produced in the arcuate nucleus and is a potent negative regulator of food intake. Like leptin, mutations in POMC or in central melanocortin receptors lead to obesity in humans. Thus, an understanding of the mechanisms by which the leptin and melanocortin pathways signal in the hypothalamus is critical in order to begin to clarify the pathways involved in regulating body weight in humans.

References (188)

  • H Chen et al.

    Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice

    Cell

    (1996)
  • W Chen et al.

    Exocrine gland dysfunction in MC5-R-deficient mice: Evidence for coordinated regulation of exocrine gland function by melanocortin peptides

    Cell

    (1997)
  • A Cheng et al.

    Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B

    Dev. Cell

    (2002)
  • V Chhajlani et al.

    Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA

    FEBS Lett.

    (1992)
  • S.P Commins et al.

    Central leptin regulates the UCPI and ob genes in brown and white adipose tissue via different beta-adrenoceptor subtypes

    J. Biol. Chem.

    (2000)
  • R.V Considine et al.

    Mutation screening and identification of a sequence variation in the human ob gene coding region

    Biochem. Biophys. Res. Commun.

    (1996)
  • M.A Cowley et al.

    Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: Evidence of a cellular basis for the adipostat

    Neuron

    (1999)
  • R Devos et al.

    Ligand-independent dimerization of the extracellular domain of the leptin receptor and determination of the stoichiometry of leptin binding

    J. Biol. Chem.

    (1997)
  • D.M Dinulescu et al.

    Agouti and agouti-related protein: Analogies and contrasts

    J. Biol. Chem.

    (2000)
  • C.F Elias et al.

    Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area

    Neuron

    (1999)
  • C.F Elias et al.

    Leptin activates hypothalamic CART neurons projecting to the spinal cord

    Neuron

    (1998)
  • J.K Elmquist et al.

    From lesions to leptin: Hypothalamic control of food intake and body weight

    Neuron

    (1999)
  • S Eyckerman et al.

    Identification of the Y985 and y]1077 motifs as SOCS3 recruitment sites in the murine leptin receptor

    FEBS Lett

    (2000)
  • T.M Fong et al.

    ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors

    Biochem. Biophys. Res. Commun.

    (1997)
  • I Gantz et al.

    Molecular cloning of a novel melanocortin receptor

    J. Biota Chem.

    (1993)
  • I Gantz et al.

    Molecular cloning, expression, and gene localization of a fourth melanocortin receptor

    J. Biol. Chem.

    (1993)
  • O Gavrilova et al.

    Hyperleptinemia of pregnancy associated with the appearance of a circulating form of the leptin receptor

    J. Biol. Chem.

    (1997)
  • X.M Guan et al.

    Differential expression of mRNA for leptin receptor isoforms in the rat brain

    Mol. Cell. Endocrinol.

    (1997)
  • D Huszar et al.

    Targeted disruption of the melanocortin-4 receptor results in obesity in mice

    Cell

    (1997)
  • M Jang et al.

    Leptin rapidly inhibits hypothalamic neuropeptide Y secretion and stimulates corticotropin-releasing hormone secretion in adrenalectomized mice

    J. Nutr

    (2000)
  • A.J Kastin et al.

    Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor

    Peptides

    (1999)
  • P.J King et al.

    Regulation of neuropeptide Y release from hypothalamic slices by melanocortin-4 agonists and leptin

    Peptides

    (2000)
  • Y Konda et al.

    Interaction of dual intracellular signaling pathways activated by the melanocortin-3 receptor

    J. Biol. Chem.

    (1994)
  • R.S Ahima et al.

    Role of leptin in the neuroendocrine response to fasting

    Nature

    (1996)
  • F Al-Obeidi et al.

    Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics

    J. Med. Chem.

    (1989)
  • C.J Auernhammer et al.

    Pituitary corticotroph SOCS-3: Novel intracellular regulation of leukemia-inhibitory factor-mediated proopiomelanocortin gene expression and adrenocorticotropin secretion

    Mol. Endocrinol.

    (1998)
  • D Bagnol et al.

    Anatomy of an endogenous antagonist: Relationship between Agouti-related protein and proopiomelanocortin in brain

    J. Neurosci.

    (1999)
  • S.H Bates et al.

    Leptin receptor-STAT3 signaling integrates energy balance and metabolic homeostasis

    (2001)
  • H Baumann et al.

    The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors

  • S Benjannet et al.

    PC1 and PC2 are proprotein convertases capable of cleaving proopiomelanocortin at distinct pairs of basic residues

  • L Berti et al.

    Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: Evidence for a P13-kinase mediated effect

    Diabetologia

    (1997)
  • C Bjorbaek et al.

    Expression of leptin receptor isoforms in rat brain microvessels

    Endocrinology

    (1998)
  • C Bjorbaek et al.

    Regulation of POMC expression by leptin: Roles of STAT3 and cAMP

    (20016)
  • N.G Blake et al.

    Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation

    Endocrinology

    (1991)
  • B.A Boston et al.

    Independent and additive effects of central POMC and leptin pathways on murine obesity

    Science

    (1997)
  • C Bousquet et al.

    Direct regulation of pituitary proopiomelanocortin by STAT3 provides a novel mechanism for immuno-neuroendocrine interfacing

    J. Clin. Invest.

    (2000)
  • C Broberger et al.

    The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice

  • A.A Butler et al.

    A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse

    Endocrinology

    (2000)
  • A.A Butler et al.

    Melanocortin4 receptor is required for acute homeostatic responses to increased dietary fat

    Nat. Neurosci.

    (2001)
  • L.A Campfield et al.

    Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks

    Science

    (1995)
  • Cited by (26)

    • Direct and indirect effects of liraglutide on hypothalamic POMC and NPY/AgRP neurons – Implications for energy balance and glucose control

      2019, Molecular Metabolism
      Citation Excerpt :

      There is increasing evidence that highlights a potential melanocortin-dependent compensatory/additive role for GLP-1Rs in the absence/presence of leptin. In particular, the acute effects of GLP-1 receptor activation in melanocortin neurons mirrors that of the description of leptin [33–37]. GLP-1 may also be beneficial in the absence of leptin [38,39].

    • NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways

      2011, Cell Metabolism
      Citation Excerpt :

      Two possible mechanisms have been proposed to explain leptin's actions on the HPT axis. These two mechanisms both involve hypothalamic neurocircuitry that regulates TRH production in the PVN: (1) Leptin acts directly through its receptors on hypophysiotropic TRH neurons that project to the median eminence to regulate TSH production in the pituitary (Harris et al., 2001; Nillni et al., 2000; Perello et al., 2006); or (2) leptin regulates TRH neurons indirectly via its actions on pro-opiomelanocortin (POMC) and agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons in the arcuate nucleus (Bjørbaek and Hollenberg, 2002; Fekete et al., 2001; Fekete et al., 2000a; Fekete et al., 2002b; Legradi et al., 1998). Although these pathways are not mutually exclusive, genetic data suggest that leptin signaling is absolutely required for normal function of the HPT axis as mice with leptin receptor mutations have central hypothyroidism whereas mice that lack the MC4R or NPY have normal T4 levels at baseline (Bates et al., 2004; Erickson et al., 1997; Fekete et al., 2004).

    • Identification of the Downstream Targets of SIM1 and ARNT2, a Pair of Transcription Factors Essential for Neuroendocrine Cell Differentiation

      2003, Journal of Biological Chemistry
      Citation Excerpt :

      Jak2 is thought to be a positive participant in leptin receptor signaling (34, 35). Both melanocortin-stimulating hormone and leptin are well known negative regulators of food intake (36). Although their actions have been investigated in the arcuate nucleus, their actions in the PVN are less well studied.

    View all citing articles on Scopus
    View full text