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Melanocortin control of energy balance: evidence from rodent models

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Abstract

Regulation of energy balance is extremely complex, and involves multiple systems of hormones, neurotransmitters, receptors, and intracellular signals. As data have accumulated over the last two decades, the CNS melanocortin system is now identified as a prominent integrative network of energy balance controls in the mammalian brain. Here, we will review findings from rat and mouse models, which have provided an important framework in which to study melanocortin function. Perhaps most importantly, this review attempts for the first time to summarize recent advances in our understanding of the intracellular signaling pathways thought to mediate the action of melanocortin neurons and peptides in control of longterm energy balance. Special attention will be paid to the roles of MC4R/MC3R, as well as downstream neurotransmitters within forebrain and hindbrain structures that illustrate the distributed control of melanocortin signaling in energy balance. In addition, distinctions and controversy between rodent species will be discussed.

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Abbreviations

AY :

Agouti yellow

AAV:

Adeno-associated virus

ACTH:

Adrenocorticotropic hormone

AgRP:

Agouti-related protein

AMPK:

Adenosine monophosphate protein kinase

BAT:

Brown adipose tissue

BDNF:

Brain-derived neurotrophic factor

CART:

Cocaine- and amphetamine-regulated transcript

CCK:

Cholecystokinin

CNS:

Central nervous system

CRH:

Corticotropin-releasing hormone

DIO:

Diet-induced obesity

DVC:

Dorsal vagal complex

FI:

Food intake

Fos-Li:

Fos-like immunoreactivity

GABA:

γ-Aminobutyric acid

GK:

Glucokinase

GLP-1:

Glucagon-like peptide 1

HFD:

High-fat diet

IBAT:

Intrascapular brown adipose tissue

ICV:

Intracerebroventricular

IR:

Insulin receptor

LHA:

Lateral hypothalamic area

LPS:

Lipopolysaccharide

MAPK/ERK:

Mitogen-activated protein kinase (a.k.a. = extracellular signal-regulated kinase)

MCR:

Melanocortin receptor

MC3R:

Melanocortin 3 receptor

MC4R:

Melanocortin 4 receptor

MSH:

Melanocyte-stimulating hormone

MTII:

Melanotan 2

NPY:

Neuropeptide Y

NR:

Not reported

NT-4:

Neurotrophin-4

NTS:

Nucleus tractus solitarius

NUCB2:

NEFA/nucleobindin2

PI3 K:

Phosphatidyl inositol 3-kinase

PBN:

Parabrachial nucleus

PC:

Subtilisin-related prohormone convertase

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

POMC:

Proopiomelanocortin

PTP1B:

Protein tyrosine phosphatase 1B

PVH:

Paraventricular nucleus of the hypothalamus

RER:

Respiratory exchange ratio

RMR:

Resting metabolic rate

RQ:

Respiratory quotient

SHP2:

SH2 domain-containing protein tyrosine phosphatase-2

SIM1:

Single-minded gene 1

SNS:

Sympathetic nervous system

SOCS3:

Suppressor of cytokine signaling 3

SON:

Supraoptic nucleus

STAT3:

Signal transducer and activator of transcription 3

trkB:

Tropomysosin-receptor kinase-B

WAT:

White adipose tissue

Tg:

Transgenic

References

  1. Pi-Sunyer X (2009) The medical risks of obesity. Postgrad Med 121(6):21–33

    Article  PubMed  Google Scholar 

  2. Cattaneo A et al (2010) Overweight and obesity in infants and pre-school children in the European Union: a review of existing data. Obes Rev 11(5):389–398

    Article  PubMed  CAS  Google Scholar 

  3. Flegal KM et al (2010) Prevalence and trends in obesity among US adults, 1999–2008. Jama 303(3):235–241

    Article  PubMed  CAS  Google Scholar 

  4. Ng SW, et al. (2010) The prevalence and trends of overweight, obesity and nutrition-related non-communicable diseases in the Arabian Gulf States. Obes Rev (in press)

  5. Belgardt BF, Bruning JC (2010) CNS leptin and insulin action in the control of energy homeostasis. Ann NY Acad Sci 1212:97–113

    Article  PubMed  CAS  Google Scholar 

  6. Mountjoy KG (2010) Functions for pro-opiomelanocortin-derived peptides in obesity and diabetes. Biochem J 428(3):305–324

    Article  PubMed  CAS  Google Scholar 

  7. Farooqi IS, O’Rahilly S (2005) Monogenic obesity in humans. Annu Rev Med 56:443–458

    Article  PubMed  CAS  Google Scholar 

  8. Mountjoy KG (2010) Distribution and function of melanocortin receptors within the brain. Adv Exp Med Biol 681:29–48

    Article  PubMed  CAS  Google Scholar 

  9. Bicknell AB (2008) The tissue-specific processing of pro-opiomelanocortin. J Neuroendocrinol 20(6):692–699

    Article  PubMed  CAS  Google Scholar 

  10. DeBold CR, Nicholson WE, Orth DN (1988) Immunoreactive proopiomelanocortin (POMC) peptides and POMC-like messenger ribonucleic acid are present in many rat nonpituitary tissues. Endocrinology 122(6):2648–2657

    Article  PubMed  CAS  Google Scholar 

  11. Gao Q, Horvath TL (2008) Neuronal control of energy homeostasis. FEBS Lett 582(1):132–141

    Article  PubMed  CAS  Google Scholar 

  12. Shizume K (1985) Thirty-five years of progress in the study of MSH. Yale J Biol Med 58(6):561–570

    PubMed  CAS  Google Scholar 

  13. Grill HJ (2010) Leptin and the systems neuroscience of meal size control. Front Neuroendocrinol 31(1):61–78

    Article  PubMed  CAS  Google Scholar 

  14. Grill HJ (2006) Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring) 14 Suppl 5:216S–221S

    Article  Google Scholar 

  15. Garfield AS et al (2009) Role of central melanocortin pathways in energy homeostasis. Trends Endocrinol Metab 20(5):203–215

    Article  PubMed  CAS  Google Scholar 

  16. Challis BG et al (2004) Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3–36). Proc Natl Acad Sci USA 101(13):4695–4700

    Article  PubMed  CAS  Google Scholar 

  17. Gropp E et al (2005) Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci 8(10):1289–1291

    Article  PubMed  CAS  Google Scholar 

  18. Graham M et al (1997) Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 17(3):273–274

    Article  PubMed  CAS  Google Scholar 

  19. Luquet S et al (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310(5748):683–685

    Article  PubMed  CAS  Google Scholar 

  20. Krude H et al (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19(2):155–157

    Article  PubMed  CAS  Google Scholar 

  21. Friedman JM (2009) Leptin at 14 years of age: an ongoing story. Am J Clin Nutr 89(3):973S–979S

    Article  PubMed  CAS  Google Scholar 

  22. Zhang Y et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432

    Article  PubMed  CAS  Google Scholar 

  23. Aleixandre de Artinano A, Miguel Castro M (2009) Experimental rat models to study the metabolic syndrome. Br J Nutr 102(9):1246–1253

    Article  PubMed  CAS  Google Scholar 

  24. Hamann A, Matthaei S (1996) Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes 104(4):293–300

    Article  PubMed  CAS  Google Scholar 

  25. Balthasar N (2006) Genetic dissection of neuronal pathways controlling energy homeostasis. Obesity (Silver Spring) 14 Suppl 5:222S–227S

    Article  Google Scholar 

  26. Butler AA (2006) The melanocortin system and energy balance. Peptides 27(2):281–290

    Article  PubMed  CAS  Google Scholar 

  27. Chen AS et al (2000) Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26(1):97–102

    Article  PubMed  CAS  Google Scholar 

  28. Huszar D et al (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88(1):131–141

    Article  PubMed  CAS  Google Scholar 

  29. Santini F et al (2009) Melanocortin-4 receptor mutations in obesity. Adv Clin Chem 48:95–109

    Article  PubMed  CAS  Google Scholar 

  30. Kaelin CB et al (2008) New ligands for melanocortin receptors. Int J Obes (Lond) 32 Suppl 7:S19–S27

    Article  CAS  Google Scholar 

  31. Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nat Neurosci 8(5):571–578

    Article  PubMed  CAS  Google Scholar 

  32. Pritchard LE, White A (2007) Neuropeptide processing and its impact on melanocortin pathways. Endocrinology 148(9):4201–4207

    Article  PubMed  CAS  Google Scholar 

  33. Seidah NG, Chretien M (1992) Proprotein and prohormone convertases of the subtilisin family. Recent developments and future perspectives. Trends Endocrinol Metab 3(4):133–140

    Article  PubMed  CAS  Google Scholar 

  34. Seidah NG et al (1991) Cloning and primary sequence of a mouse candidate prohormone convertase PC1 homologous to PC2, Furin, and Kex2: distinct chromosomal localization and messenger RNA distribution in brain and pituitary compared to PC2. Mol Endocrinol 5(1):111–122

    Article  PubMed  CAS  Google Scholar 

  35. Pan H et al (2006) The role of prohormone convertase-2 in hypothalamic neuropeptide processing: a quantitative neuropeptidomic study. J Neurochem 98(6):1763–1777

    Article  PubMed  CAS  Google Scholar 

  36. Ollmann MM et al (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278(5335):135–138

    Article  PubMed  CAS  Google Scholar 

  37. Quillan JM et al (1998) A synthetic human Agouti-related protein-(83–132)-NH2 fragment is a potent inhibitor of melanocortin receptor function. FEBS Lett 428(1–2):59–62

    Article  PubMed  CAS  Google Scholar 

  38. Li JY et al (2000) Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum. Endocrinology 141(6):1942–1950

    Article  PubMed  CAS  Google Scholar 

  39. Creemers JW et al (2006) Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83–132: interaction between AGRP83–132 and melanocortin receptors cannot be influenced by syndecan-3. Endocrinology 147(4):1621–1631

    Article  PubMed  CAS  Google Scholar 

  40. Reizes O et al (2001) Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Cell 106(1):105–116

    Article  PubMed  CAS  Google Scholar 

  41. Reizes O et al (2003) Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway. Ann NY Acad Sci 994:66–73

    Article  PubMed  CAS  Google Scholar 

  42. Zheng Q et al (2010) Enhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice. Neuroscience 171(4):1032–1040

    Article  PubMed  CAS  Google Scholar 

  43. Takahashi KA, Cone RD (2005) Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. Endocrinology 146(3):1043–1047

    Article  PubMed  CAS  Google Scholar 

  44. Palkovits M, Eskay RL (1987) Distribution and possible origin of beta-endorphin and ACTH in discrete brainstem nuclei of rats. Neuropeptides 9(2):123–137

    Article  PubMed  CAS  Google Scholar 

  45. Grill HJ, Hayes MR (2009) 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 (Lond) 33 Suppl 1:S11–S15

    Article  CAS  Google Scholar 

  46. Ritter RC (2004) Gastrointestinal mechanisms of satiation for food. Physiol Behav 81(2):249–273

    Article  PubMed  CAS  Google Scholar 

  47. Smith GP (1996) The direct and indirect controls of meal size. Neurosci Biobehav Rev 20(1):41–46

    Article  PubMed  CAS  Google Scholar 

  48. Rinaman L et al (1989) Ultrastructural demonstration of a gastric monosynaptic vagal circuit in the nucleus of the solitary tract in rat. J Neurosci 9(6):1985–1996

    PubMed  CAS  Google Scholar 

  49. Hayes MR et al (2010) Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab 11(1):77–83

    Article  PubMed  CAS  Google Scholar 

  50. Skibicka KP, Grill HJ (2009) Hindbrain leptin stimulation induces anorexia and hyperthermia mediated by hindbrain melanocortin receptors. Endocrinology 150(4):1705–1711

    Article  PubMed  CAS  Google Scholar 

  51. Skibicka KP, Grill HJ (2009) Hypothalamic and hindbrain melanocortin receptors contribute to the feeding, thermogenic, and cardiovascular action of melanocortins. Endocrinology 150(12):5351–5361

    Article  PubMed  CAS  Google Scholar 

  52. Huo L, Grill HJ, Bjorbaek C (2006) Divergent regulation of proopiomelanocortin neurons by leptin in the nucleus of the solitary tract and in the arcuate hypothalamic nucleus. Diabetes 55(3):567–573

    Article  PubMed  CAS  Google Scholar 

  53. Ellacott KL, Halatchev IG, Cone RD (2006) Characterization of leptin-responsive neurons in the caudal brainstem. Endocrinology 147(7):3190–3195

    Article  PubMed  CAS  Google Scholar 

  54. Zhang Y et al (2010) Pro-opiomelanocortin gene transfer to the nucleus of the solitary track but not arcuate nucleus ameliorates chronic diet-induced obesity. Neuroscience 169(4):1662–1671

    Article  PubMed  CAS  Google Scholar 

  55. Li G et al (2007) Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss. Am J Physiol Endocrinol Metab 293(1):E252–E258

    Article  PubMed  CAS  Google Scholar 

  56. Blevins JE, Baskin DG (2010) Hypothalamic-brainstem circuits controlling eating. Forum Nutr 63:133–140

    Article  PubMed  CAS  Google Scholar 

  57. Kaelin CB et al (2004) Transcriptional regulation of agouti-related protein (Agrp) in transgenic mice. Endocrinology 145(12):5798–5806

    Article  PubMed  CAS  Google Scholar 

  58. Balthasar N et al (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42(6):983–991

    Article  PubMed  CAS  Google Scholar 

  59. van de Wall E et al (2008) Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion. Endocrinology 149(4):1773–1785

    Article  PubMed  CAS  Google Scholar 

  60. Shi H et al (2010) The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis. Physiol Behav 100(2):165–172

    Article  PubMed  CAS  Google Scholar 

  61. Shi H et al (2008) Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis. Am J Physiol Endocrinol Metab 294(3):E630–E639

    Article  PubMed  CAS  Google Scholar 

  62. Huo L et al (2009) Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab 9(6):537–547

    Article  PubMed  CAS  Google Scholar 

  63. Hill JW et al (2010) Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11(4):286–297

    Article  PubMed  CAS  Google Scholar 

  64. Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556

    Article  PubMed  CAS  Google Scholar 

  65. Kievit P et al (2006) Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab 4(2):123–132

    Article  PubMed  CAS  Google Scholar 

  66. Banno R et al (2010) PTP1B and SHP2 in POMC neurons reciprocally regulate energy balance in mice. J Clin Invest 120(3):720–734

    Article  PubMed  CAS  Google Scholar 

  67. Bates SH et al (2003) STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421(6925):856–859

    Article  PubMed  CAS  Google Scholar 

  68. Bates SH et al (2004) LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53(12):3067–3073

    Article  PubMed  CAS  Google Scholar 

  69. Buettner C et al (2006) Critical role of STAT3 in leptin’s metabolic actions. Cell Metab 4(1):49–60

    Article  PubMed  CAS  Google Scholar 

  70. Xu AW et al (2007) Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding. Endocrinology 148(1):72–80

    Article  PubMed  CAS  Google Scholar 

  71. Ernst MB et al (2009) Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J Neurosci 29(37):11582–11593

    Article  PubMed  CAS  Google Scholar 

  72. Baskin DG et al (1999) Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res 848(1–2):114–123

    Article  PubMed  CAS  Google Scholar 

  73. Woods SC et al (1979) Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282(5738):503–505

    Article  PubMed  CAS  Google Scholar 

  74. Havrankova J, Roth J, Brownstein M (1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272(5656):827–829

    Article  PubMed  CAS  Google Scholar 

  75. Marks JL et al (1990) Localization of insulin receptor mRNA in rat brain by in situ hybridization. Endocrinology 127(6):3234–3236

    Article  PubMed  CAS  Google Scholar 

  76. Werther GA et al (1987) Localization and characterization of insulin receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry. Endocrinology 121(4):1562–1570

    Article  PubMed  CAS  Google Scholar 

  77. Bruning JC et al (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289(5487):2122–2125

    Article  PubMed  CAS  Google Scholar 

  78. Konner AC et al (2007) Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5(6):438–449

    Article  PubMed  CAS  Google Scholar 

  79. Lin HV et al (2010) Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59(2):337–346

    Article  PubMed  CAS  Google Scholar 

  80. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657

    Article  PubMed  CAS  Google Scholar 

  81. Hill JW et al (2009) Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology 150(11):4874–4882

    Article  PubMed  CAS  Google Scholar 

  82. Al-Qassab H et al (2009) Dominant role of the p110beta isoform of PI3 K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab 10(5):343–354

    Article  PubMed  CAS  Google Scholar 

  83. Hill JW et al (2008) Acute effects of leptin require PI3 K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest 118(5):1796–1805

    Article  PubMed  CAS  Google Scholar 

  84. Morton GJ et al (2005) Leptin regulates insulin sensitivity via phosphatidylinositol-3-OH kinase signaling in mediobasal hypothalamic neurons. Cell Metab 2(6):411–420

    Article  PubMed  CAS  Google Scholar 

  85. Plum L et al (2006) Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J Clin Invest 116(7):1886–1901

    Article  PubMed  CAS  Google Scholar 

  86. Padilla SL, Carmody JS, Zeltser LM (2010) Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat Med 16(4):403–405

    Article  PubMed  CAS  Google Scholar 

  87. Robbins LS et al (1993) Pigmentation phenotypes of variant extension locus alleles result from point mutations that alter MSH receptor function. Cell 72(6):827–834

    Article  PubMed  CAS  Google Scholar 

  88. Chen W et al (1997) Exocrine gland dysfunction in MC5-R-deficient mice: evidence for coordinated regulation of exocrine gland function by melanocortin peptides. Cell 91(6):789–798

    Article  PubMed  CAS  Google Scholar 

  89. Chida D et al (2007) Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. Proc Natl Acad Sci USA 104(46):18205–18210

    Article  PubMed  CAS  Google Scholar 

  90. Chida D et al (2009) Characterization of mice deficient in melanocortin 2 receptor on a B6/Balbc mix background. Mol Cell Endocrinol 300(1–2):32–36

    Article  PubMed  CAS  Google Scholar 

  91. Gantz I et al (1993) Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem 268(20):15174–15179

    PubMed  CAS  Google Scholar 

  92. Balthasar N et al (2005) Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123(3):493–505

    Article  PubMed  CAS  Google Scholar 

  93. Garza JC et al (2008) Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity. J Endocrinol 197(3):471–482

    Article  PubMed  CAS  Google Scholar 

  94. Rowland NE et al (2010) Effect of MTII on food intake and brain c-Fos in melanocortin-3, melanocortin-4, and double MC3 and MC4 receptor knockout mice. Peptides 31(12):2314–2317

    Article  PubMed  CAS  Google Scholar 

  95. Fan W et al (2007) Thermogenesis activated by central melanocortin signaling is dependent on neurons in the rostral raphe pallidus (rRPa) area. Brain Res 1179:61–69

    Article  PubMed  CAS  Google Scholar 

  96. Sutton GM et al (2005) Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus. Endocrinology 146(9):3739–3747

    Article  PubMed  CAS  Google Scholar 

  97. Williams DL et al (2002) Behavioral processes underlying the intake suppressive effects of melanocortin 3/4 receptor activation in the rat. Psychopharmacology (Berl) 161(1):47–53

    Article  CAS  Google Scholar 

  98. Skuladottir GV et al (1999) Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist. Br J Pharmacol 126(1):27–34

    Article  PubMed  CAS  Google Scholar 

  99. Vergoni AV et al (1998) Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats. Eur J Pharmacol 362(2–3):95–101

    Article  PubMed  CAS  Google Scholar 

  100. Kask A et al (1998) Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats. Biochem Biophys Res Commun 245(1):90–93

    Article  PubMed  CAS  Google Scholar 

  101. Benoit SC et al (2000) A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. J Neurosci 20(9):3442–3448

    PubMed  CAS  Google Scholar 

  102. Hansen MJ, Schioth HB, Morris MJ (2005) Feeding responses to a melanocortin agonist and antagonist in obesity induced by a palatable high-fat diet. Brain Res 1039(1–2):137–145

    Article  PubMed  CAS  Google Scholar 

  103. Marsh DJ et al (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet 21(1):119–122

    Article  PubMed  CAS  Google Scholar 

  104. Aponte Y, Atasoy D, Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci 14(3):351–355

    Article  PubMed  CAS  Google Scholar 

  105. Wu Q, Boyle MP, Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137(7):1225–1234

    Article  PubMed  Google Scholar 

  106. Wu Q, Palmiter RD (2011) GABAergic signaling by AgRP neurons prevents anorexia via a melanocortin-independent mechanism. Eur J Pharmacol (in press)

  107. Murphy B et al (2000) Centrally administered MTII affects feeding, drinking, temperature, and activity in the Sprague-Dawley rat. J Appl Physiol 89(1):273–282

    PubMed  CAS  Google Scholar 

  108. Fan W et al (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385(6612):165–168

    Article  PubMed  CAS  Google Scholar 

  109. Butler AA et al (2001) Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 4(6):605–611

    Article  PubMed  CAS  Google Scholar 

  110. Rossi J et al (2011) Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab 13(2):195–204

    Article  PubMed  CAS  Google Scholar 

  111. Cai G et al (2006) A quantitative trait locus on chromosome 18q for physical activity and dietary intake in Hispanic children. Obesity (Silver Spring) 14(9):1596–1604

    Article  CAS  Google Scholar 

  112. Bray GA, Inoue S, Nishizawa Y (1981) Hypothalamic obesity. The autonomic hypothesis and the lateral hypothalamus. Diabetologia 20 Suppl:366–377

    Article  PubMed  CAS  Google Scholar 

  113. Minokoshi Y, Haque MS, Shimazu T (1999) Microinjection of leptin into the ventromedial hypothalamus increases glucose uptake in peripheral tissues in rats. Diabetes 48(2):287–291

    Article  PubMed  CAS  Google Scholar 

  114. Toda C et al (2009) Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues. Diabetes 58(12):2757–2765

    Article  PubMed  CAS  Google Scholar 

  115. Haque MS et al (1999) Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats. Diabetes 48(9):1706–1712

    Article  PubMed  CAS  Google Scholar 

  116. Brito MN et al (2007) Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation. Endocrinology 148(11):5339–5347

    Article  PubMed  CAS  Google Scholar 

  117. Song CK et al (2008) Melanocortin-4 receptor mRNA expressed in sympathetic outflow neurons to brown adipose tissue: neuroanatomical and functional evidence. Am J Physiol Regul Integr Comp Physiol 295(2):R417–R428

    Article  PubMed  CAS  Google Scholar 

  118. Vergoni AV, Poggioli R, Bertolini A (1986) Corticotropin inhibits food intake in rats. Neuropeptides 7(2):153–158

    Article  PubMed  CAS  Google Scholar 

  119. Lu XY et al (2003) Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses. J Neurosci 23(21):7863–7872

    PubMed  CAS  Google Scholar 

  120. Xu B et al (2003) Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6(7):736–742

    Article  PubMed  CAS  Google Scholar 

  121. Kernie SG, Liebl DJ, Parada LF (2000) BDNF regulates eating behavior and locomotor activity in mice. EMBO J 19(6):1290–1300

    Article  PubMed  CAS  Google Scholar 

  122. Ono M et al (1997) Brain-derived neurotrophic factor reduces blood glucose level in obese diabetic mice but not in normal mice. Biochem Biophys Res Commun 238(2):633–637

    Article  PubMed  CAS  Google Scholar 

  123. Wang C et al (2010) Brain-derived neurotrophic factor (BDNF) in the hypothalamic ventromedial nucleus increases energy expenditure. Brain Res 1336:66–77

    Article  PubMed  CAS  Google Scholar 

  124. Sauer H et al (1993) Brain-derived neurotrophic factor enhances function rather than survival of intrastriatal dopamine cell-rich grafts. Brain Res 626(1–2):37–44

    Article  PubMed  CAS  Google Scholar 

  125. Pelleymounter MA, Cullen MJ, Wellman CL (1995) Characteristics of BDNF-induced weight loss. Exp Neurol 131(2):229–238

    Article  PubMed  CAS  Google Scholar 

  126. Snider WD (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77(5):627–638

    Article  PubMed  Google Scholar 

  127. Unger TJ et al (2007) Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J Neurosci 27(52):14265–14274

    Article  PubMed  CAS  Google Scholar 

  128. Bariohay B et al (2009) Brain-derived neurotrophic factor/tropomyosin-related kinase receptor type B signaling is a downstream effector of the brainstem melanocortin system in food intake control. Endocrinology 150(6):2646–2653

    Article  PubMed  CAS  Google Scholar 

  129. Xu L et al (2010) TrkB agonist antibody dose-dependently raises blood pressure in mice with diet-induced obesity. Am J Hypertens 23(7):732–736

    Article  PubMed  CAS  Google Scholar 

  130. Tsao D et al (2008) TrkB agonists ameliorate obesity and associated metabolic conditions in mice. Endocrinology 149(3):1038–1048

    Article  PubMed  CAS  Google Scholar 

  131. Bariohay B et al (2005) Brain-derived neurotrophic factor plays a role as an anorexigenic factor in the dorsal vagal complex. Endocrinology 146(12):5612–5620

    Article  PubMed  CAS  Google Scholar 

  132. Yu Y, Wang Q, Huang XF (2009) Energy-restricted pair-feeding normalizes low levels of brain-derived neurotrophic factor/tyrosine kinase B mRNA expression in the hippocampus, but not ventromedial hypothalamic nucleus, in diet-induced obese mice. Neuroscience 160(2):295–306

    Article  PubMed  CAS  Google Scholar 

  133. Kanoski SE et al (2007) The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav Brain Res 182(1):57–66

    Article  PubMed  CAS  Google Scholar 

  134. Michaud JL et al (1998) Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev 12(20):3264–3275

    Article  PubMed  CAS  Google Scholar 

  135. Holder JL Jr et al (2004) Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab 287(1):E105–E113

    Article  PubMed  CAS  Google Scholar 

  136. Kublaoui BM et al (2006) SIM1 overexpression partially rescues agouti yellow and diet-induced obesity by normalizing food intake. Endocrinology 147(10):4542–4549

    Article  PubMed  CAS  Google Scholar 

  137. Lu D et al (1994) Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371(6500):799–802

    Article  PubMed  CAS  Google Scholar 

  138. Michaud JL et al (2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 10(14):1465–1473

    Article  PubMed  CAS  Google Scholar 

  139. Kublaoui BM et al (2006) Sim1 haploinsufficiency impairs melanocortin-mediated anorexia and activation of paraventricular nucleus neurons. Mol Endocrinol 20(10):2483–2492

    Article  PubMed  CAS  Google Scholar 

  140. Tolson KP et al (2010) Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. J Neurosci 30(10):3803–3812

    Article  PubMed  CAS  Google Scholar 

  141. Fazzini E et al (1991) Stereotaxic implantation of autologous adrenal medulla into caudate nucleus in four patients with parkinsonism. One-year follow-up. Arch Neurol 48(8):813–820

    PubMed  CAS  Google Scholar 

  142. Olson BR et al (1991) Brain oxytocin receptor antagonism blunts the effects of anorexigenic treatments in rats: evidence for central oxytocin inhibition of food intake. Endocrinology 129(2):785–791

    Article  PubMed  CAS  Google Scholar 

  143. Kublaoui BM et al (2008) Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol 22(7):1723–1734

    Article  PubMed  CAS  Google Scholar 

  144. Oh IS et al (2006) Identification of nesfatin-1 as a satiety molecule in the hypothalamus. Nature 443(7112):709–712

    Article  CAS  Google Scholar 

  145. Garcia-Galiano D et al (2010) Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation. J Mol Endocrinol 45(5):281–290

    Article  PubMed  CAS  Google Scholar 

  146. Stengel A et al (2009) Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor. Endocrinology 150(11):4911–4919

    Article  PubMed  CAS  Google Scholar 

  147. Shimizu H et al (2009) Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism. Endocrinology 150(2):662–671

    Article  PubMed  CAS  Google Scholar 

  148. Kohno D et al (2008) Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding. Endocrinology 149(3):1295–1301

    Article  PubMed  CAS  Google Scholar 

  149. Maejima Y et al (2009) Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway. Cell Metab 10(5):355–365

    Article  PubMed  CAS  Google Scholar 

  150. Yosten GL, Samson WK (2010) The anorexigenic and hypertensive effects of nesfatin-1 are reversed by pretreatment with an oxytocin receptor antagonist. Am J Physiol Regul Integr Comp Physiol 298(6):R1642–R1647

    Article  PubMed  CAS  Google Scholar 

  151. Price CJ, Samson WK, Ferguson AV (2008) Nesfatin-1 inhibits NPY neurons in the arcuate nucleus. Brain Res 1230:99–106

    Article  PubMed  CAS  Google Scholar 

  152. Qu D et al (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380(6571):243–247

    Article  PubMed  CAS  Google Scholar 

  153. Rossi M et al (1999) Investigation of the feeding effects of melanin concentrating hormone on food intake–action independent of galanin and the melanocortin receptors. Brain Res 846(2):164–170

    Article  PubMed  CAS  Google Scholar 

  154. McBriar MD et al (2006) Discovery of orally efficacious melanin-concentrating hormone receptor-1 antagonists as antiobesity agents. Synthesis, SAR, and biological evaluation of bicyclo[3.1.0]hexyl ureas. J Med Chem 49(7):2294–2310

    Article  PubMed  CAS  Google Scholar 

  155. Ludwig DS et al (1998) Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. Am J Physiol 274(4 Pt 1):E627–E633

    PubMed  CAS  Google Scholar 

  156. Kim RY et al (2005) Dynamic regulation of hypothalamic neuropeptide gene expression and food intake by melanocortin analogues and reversal with melanocortin-4 receptor antagonist. Biochem Biophys Res Commun 329(4):1178–1185

    Article  PubMed  CAS  Google Scholar 

  157. Shimada M et al (1998) Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 396(6712):670–674

    Article  PubMed  CAS  Google Scholar 

  158. Morton GJ et al (2004) Increased hypothalamic melanin concentrating hormone gene expression during energy restriction involves a melanocortin-independent, estrogen-sensitive mechanism. Peptides 25(4):667–674

    Article  PubMed  CAS  Google Scholar 

  159. Hanada R et al (2000) Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system. Biochem Biophys Res Commun 268(1):88–91

    Article  PubMed  CAS  Google Scholar 

  160. Lopez M et al (2007) Orexin expression is regulated by alpha-melanocyte-stimulating hormone. J Neuroendocrinol 19(9):703–707

    Article  PubMed  CAS  Google Scholar 

  161. Hara J et al (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345–354

    Article  PubMed  CAS  Google Scholar 

  162. Chemelli RM et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4):437–451

    Article  PubMed  CAS  Google Scholar 

  163. Li AJ, Dinh TT, Ritter S (2008) Hyperphagia and obesity produced by arcuate injection of NPY-saporin do not require upregulation of lateral hypothalamic orexigenic peptide genes. Peptides 29(10):1732–1739

    Article  PubMed  CAS  Google Scholar 

  164. Zheng H et al (2002) Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. Am J Physiol Regul Integr Comp Physiol 282(6):R1773–R1781

    PubMed  CAS  Google Scholar 

  165. Blevins JE et al (2009) Forebrain melanocortin signaling enhances the hindbrain satiety response to CCK-8. Am J Physiol Regul Integr Comp Physiol 296(3):R476–R484

    Article  PubMed  CAS  Google Scholar 

  166. Fan W et al (2004) Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat Neurosci 7(4):335–336

    Article  PubMed  CAS  Google Scholar 

  167. Vaughan CH et al (2006) Effects of oral preload, CCK or bombesin administration on short term food intake of melanocortin 4-receptor knockout (MC4RKO) mice. Peptides 27(12):3226–3233

    Article  PubMed  CAS  Google Scholar 

  168. Atalayer D et al (2010) Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. Am J Physiol Regul Integr Comp Physiol 298(6):R1667–R1674

    Article  PubMed  CAS  Google Scholar 

  169. Skibicka KP, Grill HJ (2008) Energetic responses are triggered by caudal brainstem melanocortin receptor stimulation and mediated by local sympathetic effector circuits. Endocrinology 149(7):3605–3616

    Article  PubMed  CAS  Google Scholar 

  170. Ruiter M et al (2010) Increased hypothalamic signal transducer and activator of transcription 3 phosphorylation after hindbrain leptin injection. Endocrinology 151(4):1509–1519

    Article  PubMed  CAS  Google Scholar 

  171. Voss-Andreae A et al (2007) Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology 148(4):1550–1560

    Article  PubMed  CAS  Google Scholar 

  172. Williams DL et al (2003) Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Endocrinology 144(11):4692–4697

    Article  PubMed  CAS  Google Scholar 

  173. Zheng H et al (2005) Brain stem melanocortinergic modulation of meal size and identification of hypothalamic POMC projections. Am J Physiol Regul Integr Comp Physiol 289(1):R247–R258

    Article  PubMed  CAS  Google Scholar 

  174. Benoit SC et al (2000) Comparison of central administration of corticotropin-releasing hormone and urocortin on food intake, conditioned taste aversion, and c-Fos expression. Peptides 21(3):345–351

    Article  PubMed  CAS  Google Scholar 

  175. Olson BR et al (1993) c-Fos expression in rat brain and brainstem nuclei in response to treatments that alter food intake and gastric motility. Mol Cell Neurosci 4(1):93–106

    Article  PubMed  CAS  Google Scholar 

  176. Blevins JE, Schwartz MW, Baskin DG (2004) Evidence that paraventricular nucleus oxytocin neurons link hypothalamic leptin action to caudal brain stem nuclei controlling meal size. Am J Physiol Regul Integr Comp Physiol 287(1):R87–R96

    Article  PubMed  CAS  Google Scholar 

  177. Sawchenko PE, Swanson LW (1982) Immunohistochemical identification of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in the rat. J Comp Neurol 205(3):260–272

    Article  PubMed  CAS  Google Scholar 

  178. Zheng H et al (2005) Melanin concentrating hormone innervation of caudal brainstem areas involved in gastrointestinal functions and energy balance. Neuroscience 135(2):611–625

    Article  PubMed  CAS  Google Scholar 

  179. Peyron C et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015

    PubMed  CAS  Google Scholar 

  180. Roselli-Rehfuss L et al (1993) Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc Natl Acad Sci USA 90(19):8856–8860

    Article  PubMed  CAS  Google Scholar 

  181. Fong TM et al (1997) ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem Biophys Res Commun 237(3):629–631

    Article  PubMed  CAS  Google Scholar 

  182. Marks DL et al (2006) The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R). Peptides 27(2):259–264

    Article  PubMed  CAS  Google Scholar 

  183. Butler AA et al (2000) A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141(9):3518–3521

    Article  PubMed  CAS  Google Scholar 

  184. Jegou S, Boutelet I, Vaudry H (2000) Melanocortin-3 receptor mRNA expression in pro-opiomelanocortin neurones of the rat arcuate nucleus. J Neuroendocrinol 12(6):501–505

    Article  PubMed  CAS  Google Scholar 

  185. Bagnol D et al (1999) Anatomy of an endogenous antagonist: relationship between Agouti-related protein and proopiomelanocortin in brain. J Neurosci 19(18):RC26

    PubMed  CAS  Google Scholar 

  186. Cowley MA et al (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411(6836):480–484

    Article  PubMed  CAS  Google Scholar 

  187. Sutton GM et al (2010) Central nervous system melanocortin-3 receptors are required for synchronizing metabolism during entrainment to restricted feeding during the light cycle. FASEB J 24(3):862–872

    Article  PubMed  CAS  Google Scholar 

  188. Sutton GM et al (2008) The melanocortin-3 receptor is required for entrainment to meal intake. J Neurosci 28(48):12946–12955

    Article  PubMed  CAS  Google Scholar 

  189. Begriche K et al (2009) The role of melanocortin neuronal pathways in circadian biology: a new homeostatic output involving melanocortin-3 receptors? Obes Rev 10 Suppl 2:14–24

    Article  PubMed  CAS  Google Scholar 

  190. Berthoud HR et al (2006) Brainstem mechanisms integrating gut-derived satiety signals and descending forebrain information in the control of meal size. Physiol Behav 89(4):517–524

    Article  PubMed  CAS  Google Scholar 

  191. Peters JH, Simasko SM, Ritter RC (2006) Modulation of vagal afferent excitation and reduction of food intake by leptin and cholecystokinin. Physiol Behav 89(4):477–485

    Article  PubMed  CAS  Google Scholar 

  192. Appleyard SM et al (2005) Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. J Neurosci 25(14):3578–3585

    Article  PubMed  CAS  Google Scholar 

  193. Babic T et al (2009) Phenotype of neurons in the nucleus of the solitary tract that express CCK-induced activation of the ERK signaling pathway. Am J Physiol Regul Integr Comp Physiol 296(4):R845–R854

    Article  PubMed  CAS  Google Scholar 

  194. Noetzel S et al (2009) CCK-8S activates c-Fos in a dose-dependent manner in nesfatin-1 immunoreactive neurons in the paraventricular nucleus of the hypothalamus and in the nucleus of the solitary tract of the brainstem. Regul Pept 157(1–3):84–91

    Article  PubMed  CAS  Google Scholar 

  195. Blevins JE et al (2003) Oxytocin innervation of caudal brainstem nuclei activated by cholecystokinin. Brain Res 993(1–2):30–41

    Article  PubMed  CAS  Google Scholar 

  196. Grill HJ, Smith GP (1988) Cholecystokinin decreases sucrose intake in chronic decerebrate rats. Am J Physiol 254(6 Pt 2):R853–R856

    PubMed  CAS  Google Scholar 

  197. Hayes MR, De Jonghe BC, Kanoski SE (2010) Role of the glucagon-like-peptide-1 receptor in the control of energy balance. Physiol Behav 100(5):503–510

    Google Scholar 

  198. Seo S et al (2008) Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr J 55(5):867–874

    Article  PubMed  CAS  Google Scholar 

  199. Huo L et al (2008) Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Endocrinology 149(2):492–497

    Article  PubMed  CAS  Google Scholar 

  200. Levin BE, Dunn-Meynell AA, Routh VH (2002) CNS sensing and regulation of peripheral glucose levels. Int Rev Neurobiol 51:219–258

    Article  PubMed  CAS  Google Scholar 

  201. Levin BE et al (2004) Neuronal glucosensing: what do we know after 50 years? Diabetes 53(10):2521–2528

    Article  PubMed  CAS  Google Scholar 

  202. Routh VH (2002) Glucose-sensing neurons: are they physiologically relevant? Physiol Behav 76(3):403–413

    Article  PubMed  CAS  Google Scholar 

  203. Dunn-Meynell AA et al (2002) Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. Diabetes 51(7):2056–2065

    Article  PubMed  CAS  Google Scholar 

  204. Kang L et al (2004) Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53(3):549–559

    Article  PubMed  CAS  Google Scholar 

  205. Parton LE et al (2007) Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449(7159):228–232

    Article  PubMed  CAS  Google Scholar 

  206. Wang R et al (2004) The regulation of glucose-excited neurons in the hypothalamic arcuate nucleus by glucose and feeding-relevant peptides. Diabetes 53(8):1959–1965

    Article  PubMed  CAS  Google Scholar 

  207. Mounien L et al (2010) Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons. Faseb J 24(6):1747–1758

    Article  PubMed  CAS  Google Scholar 

  208. Skibicka KP, Grill HJ (2009) Hypothalamic and hindbrain nuclei contribute to the anorexic, thermogenic and cardiovascular action of melanocortins. Endocrinology 150:5351–5361

    Google Scholar 

  209. Williams DL, Kaplan JM, Grill HJ (2000) The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology 141(4):1332–1337

    Article  PubMed  CAS  Google Scholar 

  210. Williams DL, Grill HJ, Kaplan JM (2004) Food deprivation after treatment blocks the multiple-day hyperphagic response to SHU9119 administration. Brain Res 996(2):180–186

    Article  PubMed  CAS  Google Scholar 

  211. Wan S et al (2008) Presynaptic melanocortin-4 receptors on vagal afferent fibers modulate the excitability of rat nucleus tractus solitarius neurons. J Neurosci 28(19):4957–4966

    Article  PubMed  CAS  Google Scholar 

  212. Cheung WW et al (2008) Modulation of melanocortin signaling ameliorates uremic cachexia. Kidney Int 74(2):180–186

    Article  PubMed  CAS  Google Scholar 

  213. Cheung W et al (2005) Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 115(6):1659–1665

    Article  PubMed  CAS  Google Scholar 

  214. Wisse BE, Schwartz MW, Cummings DE (2003) Melanocortin signaling and anorexia in chronic disease states. Ann NY Acad Sci 994:275–281

    Article  PubMed  CAS  Google Scholar 

  215. Scarlett JM et al (2010) Genetic and pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in rodent models of heart failure. J Endocrinol 206(1):121–130

    Article  PubMed  CAS  Google Scholar 

  216. Krasnow SM, Marks DL (2010) Neuropeptides in the pathophysiology and treatment of cachexia. Curr Opin Support Palliat Care 4(4):266–271

    Article  PubMed  Google Scholar 

  217. Laviano A et al (2008) Neural control of the anorexia-cachexia syndrome. Am J Physiol Endocrinol Metab 295(5):E1000–E1008

    Article  PubMed  CAS  Google Scholar 

  218. Wisse BE et al (2001) Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142(8):3292–3301

    Article  PubMed  CAS  Google Scholar 

  219. Choudhury AI et al (2005) The role of insulin receptor substrate 2 in hypothalamic and beta cell function. J Clin Invest 115(4):940–950

    PubMed  CAS  Google Scholar 

  220. Mesaros A et al (2008) Activation of Stat3 signaling in AgRP neurons promotes locomotor activity. Cell Metab 7(3):236–248

    Article  PubMed  CAS  Google Scholar 

  221. Plum L et al (2009) The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake. Nat Med 15(10):1195–1201

    Article  PubMed  CAS  Google Scholar 

  222. Janoschek R et al (2006) gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor. Proc Natl Acad Sci USA 103(28):10707–10712

    Article  PubMed  CAS  Google Scholar 

  223. Belgardt BF et al (2008) PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab 7(4):291–301

    Article  PubMed  CAS  Google Scholar 

  224. Mori H et al (2009) Critical role for hypothalamic mTOR activity in energy balance. Cell Metab 9(4):362–374

    Article  PubMed  CAS  Google Scholar 

  225. Claret M et al (2007) AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest 117(8):2325–2336

    Article  PubMed  CAS  Google Scholar 

  226. Ramadori G et al (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab 12(1):78–87

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Bart C. De Jonghe & Kendra K. Bence

  2. Department of Psychiatry, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Matthew R. Hayes

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De Jonghe, B.C., Hayes, M.R. & Bence, K.K. Melanocortin control of energy balance: evidence from rodent models. Cell. Mol. Life Sci. 68, 2569–2588 (2011). https://doi.org/10.1007/s00018-011-0707-5

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