1932

Abstract

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022516-034110
2017-02-10
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/physiol/79/1/annurev-physiol-022516-034110.html?itemId=/content/journals/10.1146/annurev-physiol-022516-034110&mimeType=html&fmt=ahah

Literature Cited

  1. Horvath TL, Naftolin F, Kalra SP, Leranth C. 1.  1992. Neuropeptide-Y innervation of beta-endorphin-containing cells in the rat mediobasal hypothalamus: a light and electron microscopic double immunostaining analysis. Endocrinology 131:2461–67 [Google Scholar]
  2. Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F. 2.  et al. 2015. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45–50 [Google Scholar]
  3. Sternson SM, Atasoy D, Betley JN, Henry FE, Xu S. 3.  2016. An emerging technology framework for the neurobiology of appetite. Cell Metab 23:234–53 [Google Scholar]
  4. Diano S. 4.  2011. New aspects of melanocortin signaling: a role for PRCP in α-MSH degradation. Front. Neuroendocrinol. 32:70–83 [Google Scholar]
  5. McClellan KM, Calver AR, Tobet SA. 5.  2008. GABAB receptors role in cell migration and positioning within the ventromedial nucleus of the hypothalamus. Neuroscience 151:1119–31 [Google Scholar]
  6. Shimada M, Nakamura T. 6.  1973. Time of neuron origin in mouse hypothalamic nuclei. Exp. Neurol. 41:163–73 [Google Scholar]
  7. McNay DEG, Pelling M, Claxton S, Guillemot F, Ang S-L. 7.  2006. Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells. Mol. Endocrinol. 20:1623–32 [Google Scholar]
  8. Marin O, Baker J, Puelles L, Rubenstein JL. 8.  2002. Patterning of the basal telencephalon and hypothalamus is essential for guidance of cortical projections. Development 129:761–73 [Google Scholar]
  9. Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH. 9.  et al. 1996. The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 10:60–69 [Google Scholar]
  10. Blaess S, Szabó N, Haddad-Tóvolli R, Zhou X, Álvarez-Bolado G. 10.  2014. Sonic hedgehog signaling in the development of the mouse hypothalamus. Front. Neuroanat. 8:156 [Google Scholar]
  11. Manning L, Ohyama K, Saeger B, Hatano O, Wilson SA. 11.  et al. 2006. Regional morphogenesis in the hypothalamus: a BMP-Tbx2 pathway coordinates fate and proliferation through Shh downregulation. Dev. Cell 11:873–85 [Google Scholar]
  12. Shimogori T, Lee DA, Miranda-Angulo A, Yang Y, Wang H. 12.  et al. 2010. A genomic atlas of mouse hypothalamic development. Nat. Neurosci. 13:767–75 [Google Scholar]
  13. Lagutin OV, Zhu CC, Kobayashi D, Topczewski J, Shimamura K. 13.  et al. 2003. Six3 repression of Wnt signaling in the anterior neuroectoderm is essential for vertebrate forebrain development. Genes Dev 17:368–79 [Google Scholar]
  14. Geng X, Speirs C, Lagutin O, Inbal A, Liu W. 14.  et al. 2008. Haploinsufficiency of Six3 fails to activate Sonic hedgehog expression in the ventral forebrain and causes holoprosencephaly. Dev. Cell 15:236–47 [Google Scholar]
  15. Zhang L, Mathers PH, Jamrich M. 15.  2000. Function of Rx, but not Pax6, is essential for the formation of retinal progenitor cells in mice. Genesis 28:135–42 [Google Scholar]
  16. Lu F, Kar D, Gruenig N, Zhang ZW, Cousins N. 16.  et al. 2013. Rax is a selector gene for mediobasal hypothalamic cell types. J. Neurosci. 33:259–72 [Google Scholar]
  17. Tamura K, Taniguchi Y, Minoguchi S, Sakai T, Tun T. 17.  et al. 1995. Physical interaction between a novel domain of the receptor Notch and the transcription factor RBP-Jκ/Su(H). Curr. Biol. 5:1416–23 [Google Scholar]
  18. Fortini ME. 18.  2009. Notch signaling: the core pathway and its posttranslational regulation. Dev. Cell 16:633–47 [Google Scholar]
  19. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. 19.  1995. Signalling downstream of activated mammalian Notch. Nature 377:355–58 [Google Scholar]
  20. Maier MM, Gessler M. 20.  2000. Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes. Biochem. Biophys. Res. Commun. 275:652–60 [Google Scholar]
  21. Aujla PK, Naratadam GT, Xu L, Raetzman LT. 21.  2013. Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons. Development 140:3511–21 [Google Scholar]
  22. Bray SJ. 22.  2006. Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell. Biol. 7:678–89 [Google Scholar]
  23. Pelling M, Anthwal N, McNay D, Gradwohl G, Leiter AB. 23.  et al. 2011. Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus. Dev. Biol. 349:406–16 [Google Scholar]
  24. Anthwal N, Pelling M, Claxton S, Mellitzer G, Collin C. 24.  et al. 2013. Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity. Dis. Model. Mech. 6:1133–45 [Google Scholar]
  25. Yee CL, Wang Y, Anderson S, Ekker M, Rubenstein JLR. 25.  2009. Arcuate nucleus expression of NKX2.1 and DLX and lineages expressing these transcription factors in neuropeptide Y+, proopiomelanocortin+, and tyrosine hydroxylase+ neurons in neonatal and adult mice. J. Comp. Neurol. 517:37–50 [Google Scholar]
  26. Padilla SL, Carmody JS, Zeltser LM. 26.  2010. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat. Med. 16:403–5 [Google Scholar]
  27. Padilla SL, Reef D, Zeltser LM. 27.  2012. Defining POMC neurons using transgenic reagents: impact of transient Pomc expression in diverse immature neuronal populations. Endocrinology 153:1219–31 [Google Scholar]
  28. Biehl MJ, Raetzman LT. 28.  2015. Rbpj-κ mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons. Dev. Biol. 406:235–46 [Google Scholar]
  29. Sanz E, Quintana A, Deem JD, Steiner RA, Palmiter RD, McKnight GS. 29.  2015. Fertility-regulating Kiss1 neurons arise from hypothalamic Pomc-expressing progenitors. J. Neurosci. 35:5549–56 [Google Scholar]
  30. Bouret SG, Draper SJ, Simerly RB. 30.  2004. Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J. Neurosci. 24:2797–805 [Google Scholar]
  31. Ahima RS, Prabakaran D, Flier JS. 31.  1998. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J. Clin. Investig. 101:1020–27 [Google Scholar]
  32. Bouret SG, Draper SJ, Simerly RB. 32.  2004. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304:108–10 [Google Scholar]
  33. Bouret SG, Bates SH, Chen S, Myers MG, Simerly RB. 33.  2012. Distinct roles for specific leptin receptor signals in the development of hypothalamic feeding circuits. J. Neurosci. 32:1244–52 [Google Scholar]
  34. Coupé B, Ishii Y, Dietrich MO, Komatsu M, Horvath TL, Bouret SG. 34.  2012. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab 15:247–55 [Google Scholar]
  35. Malik SA, Marino G, BenYounes A, Shen S, Harper F. 35.  et al. 2011. Neuroendocrine regulation of autophagy by leptin. Cell Cycle 10:2917–23 [Google Scholar]
  36. Xu B, Goulding EH, Zang K, Cepoi D, Cone RD. 36.  et al. 2003. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6:736–42 [Google Scholar]
  37. Liao G-Y, Bouyer K, Kamitakahara A, Sahibzada N, Wang C-H. 37.  et al. 2015. Brain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleus. Mol. Metab. 4:471–82 [Google Scholar]
  38. Liao GY, An JJ, Gharami K, Waterhouse EG, Vanevski F. 38.  et al. 2012. Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin. Nat. Med. 18:564–71 [Google Scholar]
  39. Li J, Tang Y, Cai D. 39.  2012. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat. Cell Biol. 14:999–1012 [Google Scholar]
  40. Kokoeva MV, Yin H, Flier JS. 40.  2005. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310:679–83 [Google Scholar]
  41. Gouazé A, Brenachot X, Rigault C, Krezymon A, Rauch C. 41.  et al. 2013. Cerebral cell renewal in adult mice controls the onset of obesity. PLOS ONE 8:e72029 [Google Scholar]
  42. McNay DEG, Briançon N, Kokoeva MV, Maratos-Flier E, Flier JS. 42.  2012. Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J. Clin. Investig. 122:142–52 [Google Scholar]
  43. Li J, Tang Y, Purkayastha S, Yan J, Cai D. 43.  2014. Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus. Mol. Metab. 3:313–24 [Google Scholar]
  44. Czupryn A, Zhou Y-D, Chen X, McNay D, Anderson MP. 44.  et al. 2011. Transplanted hypothalamic neurons restore leptin signaling and ameliorate obesity in db/db mice. Science 334:1133–37 [Google Scholar]
  45. Swanson LW, Kuypers HG. 45.  1980. A direct projection from the ventromedial nucleus and retrochiasmatic area of the hypothalamus to the medulla and spinal cord of the rat. Neurosci. Lett. 17:307–12 [Google Scholar]
  46. Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS. 46.  et al. 1998. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21:1375–85 [Google Scholar]
  47. Baker RA, Herkenham M. 47.  1995. Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat. J. Comp. Neurol. 358:518–30 [Google Scholar]
  48. Sohn J-W, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK. 48.  2011. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron 71:488–97 [Google Scholar]
  49. Williams KW, Margatho LO, Lee CE, Choi M, Lee S. 49.  et al. 2010. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J. Neurosci. 30:2472–79 [Google Scholar]
  50. Jarvie BC, Hentges ST. 50.  2012. Expression of GABAergic and glutamatergic phenotypic markers in hypothalamic proopiomelanocortin neurons. J. Comp. Neurol. 520:3863–76 [Google Scholar]
  51. Dennison CS, King CM, Dicken MS, Hentges ST. 51.  2016. Age-dependent changes in amino acid phenotype and the role of glutamate release from hypothalamic proopiomelanocortin neurons. J. Comp. Neurol. 524:1222–35 [Google Scholar]
  52. Hu J, Jiang L, Low MJ, Rui L. 52.  2014. Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons. PLOS ONE 9:e105080 [Google Scholar]
  53. Ciccotosto GD, Schiller MR, Eipper BA, Mains RE. 53.  1999. Induction of integral membrane PAM expression in AtT-20 cells alters the storage and trafficking of POMC and PC1. J. Cell Biol. 144:459–71 [Google Scholar]
  54. Cool DR, Normant E, Shen F, Chen HC, Pannell L. 54.  et al. 1997. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpefat mice. Cell 88:73–83 [Google Scholar]
  55. Jeong JK, Diano S. 55.  2014. Prolyl carboxypeptidase mRNA expression in the mouse brain. Brain Res 1542:85–92 [Google Scholar]
  56. Jeong JK, Szabo G, Raso GM, Meli R, Diano S. 56.  2012. Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity. Am. J. Physiol. Endocrinol. Metab. 302:E1502–10 [Google Scholar]
  57. Wallingford N, Perroud B, Gao Q, Coppola A, Gyengesi E. 57.  et al. 2009. Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents. J. Clin. Investig. 119:2291–303 [Google Scholar]
  58. Jeong JK, Szabo G, Kelly K, Diano S. 58.  2012. Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis. Endocrinology 153:683–89 [Google Scholar]
  59. Wardlaw SL. 59.  2011. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur. J. Pharmacol. 660:213–19 [Google Scholar]
  60. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L. 60.  et al. 1997. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Genet. 16:303–6 [Google Scholar]
  61. Diano S, Horvath TL. 61.  2012. Mitochondrial uncoupling protein 2 (UCP2) in glucose and lipid metabolism. Trends Mol. Med. 18:52–58 [Google Scholar]
  62. Kim JD, Leyva S, Diano S. 62.  2014. Hormonal regulation of the hypothalamic melanocortin system. Front. Physiol. 5:480 [Google Scholar]
  63. Toda C, Diano S. 63.  2014. Mitochondrial UCP2 in the central regulation of metabolism. Best Pract. Res. Clin. Endocrinol. Metab. 28:757–64 [Google Scholar]
  64. Jeong JK, Diano S. 64.  2013. Prolyl carboxypeptidase and its inhibitors in metabolism. Trends Endocrinol. Metab. 24:61–67 [Google Scholar]
  65. Dagon Y, Hur E, Zheng B, Wellenstein K, Cantley LC, Kahn BB. 65.  2012. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab 16:104–12 [Google Scholar]
  66. Minokoshi Y, Alquier T, Furukawa N, Kim Y-B, Lee A. 66.  et al. 2004. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–74 [Google Scholar]
  67. Aguilar V, Alliouachene S, Sotiropoulos A, Sobering A, Athea Y. 67.  et al. 2007. S6 kinase deletion suppresses muscle growth adaptations to nutrient availability by activating AMP kinase. Cell Metab 5:476–87 [Google Scholar]
  68. Shi H, Sorrell JE, Clegg DJ, Woods SC, Seeley RJ. 68.  2010. The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis. Physiol. Behav. 100:165–72 [Google Scholar]
  69. Chun SK, Jo YH. 69.  2010. Loss of leptin receptors on hypothalamic POMC neurons alters synaptic inhibition. J. Neurophysiol. 104:2321–28 [Google Scholar]
  70. do Carmo JM, da Silva AA, Cai Z, Lin S, Dubinion JH, Hall JE. 70.  2011. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57:918–26 [Google Scholar]
  71. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S. 71.  et al. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480–84 [Google Scholar]
  72. Könner AC, Janoschek R, Plum L, Jordan SD, Rother E. 72.  et al. 2007. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5:438–49 [Google Scholar]
  73. Huo L, Gamber K, Greeley S, Silva J, Huntoon N. 73.  et al. 2009. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9:537–47 [Google Scholar]
  74. Berglund ED, Vianna CR, Donato J Jr., Kim MH, Chuang JC. 74.  et al. 2012. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Investig. 122:1000–9 [Google Scholar]
  75. Pinto S, Roseberry AG, Liu H, Diano S, Shanabrough M. 75.  et al. 2004. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110–15 [Google Scholar]
  76. Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P. 76.  et al. 2014. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat. Neurosci. 17:908–10 [Google Scholar]
  77. Konner AC, Janoschek R, Plum L, Jordan SD, Rother E. 77.  et al. 2007. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5:438–49 [Google Scholar]
  78. Lin HV, Plum L, Ono H, Gutiérrez-Juárez R, Shanabrough M. 78.  et al. 2010. Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes 59:337–46 [Google Scholar]
  79. Plum L, Ma X, Hampel B, Balthasar N, Coppari R. 79.  et al. 2006. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity. J. Clin. Investig. 116:1886–901 [Google Scholar]
  80. Qiu J, Zhang C, Borgquist A, Nestor CC, Smith AW. 80.  et al. 2014. Insulin excites anorexigenic pro-opiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab 19:682–93 [Google Scholar]
  81. Belgardt BF, Husch A, Rother E, Ernst MB, Wunderlich FT. 81.  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. 7:291–301 [Google Scholar]
  82. Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED. 82.  et al. 2010. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab 11:286–97 [Google Scholar]
  83. Cone RD, Cowley MA, Butler AA, Fan W, Marks DL, Low MJ. 83.  2001. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 25:Suppl. 5S63–67 [Google Scholar]
  84. Riediger T, Traebert M, Schmid HA, Scheel C, Lutz TA, Scharrer E. 84.  2003. Site-specific effects of ghrelin on the neuronal activity in the hypothalamic arcuate nucleus. Neurosci. Lett. 341:151–55 [Google Scholar]
  85. Andrews ZB, Liu Z-W, Walllingford N, Erion DM, Borok E. 85.  et al. 2008. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454:846–51 [Google Scholar]
  86. Willesen MG, Kristensen P, Romer J. 86.  1999. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70:306–16 [Google Scholar]
  87. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N. 87.  et al. 2003. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–61 [Google Scholar]
  88. Yang Y, Atasoy D, Su HH, Sternson SM. 88.  2011. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146:992–1003 [Google Scholar]
  89. Tong Q, Ye C-P, Jones JE, Elmquist JK, Lowell BB. 89.  2008. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11:998–1000 [Google Scholar]
  90. Kwon Jeong J, Dae Kim J, Diano S. 90.  2013. Ghrelin regulates hypothalamic prolyl carboxypeptidase expression in mice. Mol. Metab. 2:23–30 [Google Scholar]
  91. Dallman MF, Akana SF, Strack AM, Scribner KS, Pecoraro N. 91.  et al. 2004. Chronic stress-induced effects of corticosterone on brain: direct and indirect. Ann. N.Y. Acad. Sci.1018141–50
  92. Gyengesi E, Liu Z-W, D'Agostino G, Gan G, Horvath TL. 92.  et al. 2010. Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology 151:5395–402 [Google Scholar]
  93. DiPatrizio NV, Piomelli D. 93.  2012. The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci 35:403–11 [Google Scholar]
  94. DiPatrizio NV, Piomelli D. 94.  2015. Intestinal lipid-derived signals that sense dietary fat. J. Clin. Investig. 125:891–98 [Google Scholar]
  95. Parsons LH, Hurd YL. 95.  2015. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci. 16:579–94 [Google Scholar]
  96. Tasker JG. 96.  2006. Rapid glucocorticoid actions in the hypothalamus as a mechanism of homeostatic integration. Obesity 14:Suppl. 5S259–65 [Google Scholar]
  97. Bakkali-Kassemi L, El Ouezzani S, Magoul R, Merroun I, Lopez-Jurado M, Errami M. 97.  2011. Effects of cannabinoids on neuropeptide Y and β-endorphin expression in the rat hypothalamic arcuate nucleus. Br. J. Nutr. 105:654–60 [Google Scholar]
  98. Hentges ST, Low MJ, Williams JT. 98.  2005. Differential regulation of synaptic inputs by constitutively released endocannabinoids and exogenous cannabinoids. J. Neurosci. 25:9746–51 [Google Scholar]
  99. Ho J, Cox JM, Wagner EJ. 99.  2007. Cannabinoid-induced hyperphagia: correlation with inhibition of proopiomelanocortin neurons?. Physiol. Behav. 92:507–19 [Google Scholar]
  100. Dutia R, Meece K, Dighe S, Kim AJ, Wardlaw SL. 100.  2012. β-Endorphin antagonizes the effects of α-MSH on food intake and body weight. Endocrinology 153:4246–55 [Google Scholar]
  101. Mineur YS, Abizaid A, Rao Y, Salas R, DiLeone RJ. 101.  et al. 2011. Nicotine decreases food intake through activation of POMC neurons. Science 332:1330–32 [Google Scholar]
  102. Huang H, Xu Y, van den Pol AN. 102.  2011. Nicotine excites hypothalamic arcuate anorexigenic proopiomelanocortin neurons and orexigenic neuropeptide Y neurons: similarities and differences. J. Neurophysiol. 106:1191–202 [Google Scholar]
  103. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ. 103.  et al. 2002. Activation of central melanocortin pathways by fenfluramine. Science 297:609–11 [Google Scholar]
  104. Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD. 104.  et al. 2007. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 6:398–405 [Google Scholar]
  105. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE. 105.  et al. 2008. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582–89 [Google Scholar]
  106. Xu Y, Berglund ED, Sohn J-W, Holland WL, Chuang J-C. 106.  et al. 2010. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat. Neurosci. 13:1457–59 [Google Scholar]
  107. Berglund ED, Liu C, Sohn J-W, Liu T, Kim MH. 107.  et al. 2013. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J. Clin. Investig. 123:5061–70 [Google Scholar]
  108. Kiss J, Leranth C, Halasz B. 108.  1984. Serotoninergic endings on VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci Lett. 44:119–24 [Google Scholar]
  109. Parton LE, Ye CP, Coppari R, Enriori PJ, Choi B. 109.  et al. 2007. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449:228–32 [Google Scholar]
  110. Diano S, Liu Z-W, Jeong JK, Dietrich MO, Ruan H-B. 110.  et al. 2011. Peroxisome proliferation-associated control of reactive oxygen species sets melanocortin tone and feeding in diet-induced obesity. Nat. Med. 17:1121–27 [Google Scholar]
  111. Long L, Toda C, Jeong JK, Horvath TL, Diano S. 111.  2014. PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding. J. Clin. Investig. 124:4017–27 [Google Scholar]
  112. Campanucci V, Krishnaswamy A, Cooper E. 112.  2010. Diabetes depresses synaptic transmission in sympathetic ganglia by inactivating nAChRs through a conserved intracellular cysteine residue. Neuron 66:827–34 [Google Scholar]
  113. Lu M, Sarruf DA, Talukdar S, Sharma S, Li P. 113.  et al. 2011. Brain PPAR-γ promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat. Med. 17:618–22 [Google Scholar]
  114. Ryan KK, Li B, Grayson BE, Matter EK, Woods SC, Seeley RJ. 114.  2011. A role for central nervous system PPAR-γ in the regulation of energy balance. Nat. Med. 17:623–26 [Google Scholar]
  115. Sena LA, Chandel NS. 115.  2012. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48:158–67 [Google Scholar]
  116. Finkel T. 116.  2012. From sulfenylation to sulfhydration: what a thiolate needs to tolerate. Sci. Signal. 5:10 [Google Scholar]
  117. Jo Y-H, Su Y, Gutierrez-Juarez R, Chua S. 117.  2009. Oleic acid directly regulates POMC neuron excitability in the hypothalamus. J. Neurophysiol. 101:2305–16 [Google Scholar]
  118. Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P. 118.  et al. 2010. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. PNAS 107:14875–80 [Google Scholar]
  119. Ito Y, Banno R, Shibata M, Adachi K, Hagimoto S. 119.  et al. 2013. GABA type B receptor signaling in pro-opiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. J. Neurosci. 33:17166–73 [Google Scholar]
  120. Cota D, Proulx K, Smith KAB, Kozma SC, Thomas G. 120.  et al. 2006. Hypothalamic mTOR signaling regulates food intake. Science 312:927–30 [Google Scholar]
  121. Blouet C, Jo Y-H, Li X, Schwartz GJ. 121.  2009. Mediobasal hypothalamic leucine sensing regulates food intake through activation of a hypothalamus-brainstem circuit. J. Neurosci. 29:8302–11 [Google Scholar]
  122. Mori H, Inoki K, Münzberg H, Opland D, Faouzi M. 122.  et al. 2009. Critical role for hypothalamic mTOR activity in energy balance. Cell Metab 9:362–74 [Google Scholar]
  123. Yang S-B, Tien A-C, Boddupalli G, Xu AW, Jan YN, Jan LY. 123.  2012. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 75:425–36 [Google Scholar]
  124. Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ. 124.  et al. 1998. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173–77 [Google Scholar]
  125. de Rooij SR, Roseboom TJ, Painter RC. 125.  2014. Famines in the last 100 years: implications for diabetes. Curr. Diab. Rep. 14:536 [Google Scholar]
  126. Breton C, Lukaszewski M-A, Risold P-Y, Enache M, Guillemot J. 126.  et al. 2009. Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring. Am. J. Physiol. Endocrinol. Metab. 296:E462–72 [Google Scholar]
  127. Delahaye F, Breton C, Risold P-Y, Enache M, Dutriez-Casteloot I. 127.  et al. 2008. Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups. Endocrinology 149:470–75 [Google Scholar]
  128. Coupé B, Amarger V, Grit I, Benani A, Parnet P. 128.  2010. Nutritional programming affects hypothalamic organization and early response to leptin. Endocrinology 151:702–13 [Google Scholar]
  129. Chen H, Morris MJ. 129.  2009. Differential responses of orexigenic neuropeptides to fasting in offspring of obese mothers. Obesity 17:1356–62 [Google Scholar]
  130. Fuente-Martín E, García-Cáceres C, Granado M, de Ceballos ML, Sánchez-Garrido . 130.  et al. 2012. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J. Clin. Investig. 122:3900–13 [Google Scholar]
  131. Steculorum SM, Bouret SG. 131.  2011. Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring. Endocrinology 152:4171–79 [Google Scholar]
  132. Sun B, Purcell RH, Terrillion CE, Yan J, Moran TH, Tamashiro KLK. 132.  2012. Maternal high-fat diet during gestation or suckling differentially affects offspring leptin sensitivity and obesity. Diabetes 61:2833–41 [Google Scholar]
  133. Vogt MC, Paeger L, Hess S, Steculorum SM, Awazawa M. 133.  et al. 2014. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156:495–509 [Google Scholar]
  134. Wellen KE, Hotamisligil GS. 134.  2005. Inflammation, stress, and diabetes. J. Clin. Investig. 115:1111–19 [Google Scholar]
  135. Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH. 135.  et al. 2012. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Investig. 122:153–62 [Google Scholar]
  136. Waise TMZ, Toshinai K, Naznin F, NamKoong C, Md Moin AS. 136.  et al. 2015. One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice. Biochem. Biophys. Res. Commun. 464:1157–62 [Google Scholar]
  137. Banks WA. 137.  2001. Anorectic effects of circulating cytokines: role of the vascular blood-brain barrier. Nutrition 17:434–37 [Google Scholar]
  138. Szelényi J. 138.  2001. Cytokines and the central nervous system. Brain Res. Bull. 54:329–38 [Google Scholar]
  139. Langlet F, Levin BE, Luquet S, Mazzone M, Messina A. 139.  et al. 2013. Tanycytic VEGF-A boosts blood-hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab 17:607–17 [Google Scholar]
  140. Amaral ME, Barbuio R, Milanski M, Romanatto T, Barbosa HC. 140.  et al. 2006. Tumor necrosis factor-α activates signal transduction in hypothalamus and modulates the expression of pro-inflammatory proteins and orexigenic/anorexigenic neurotransmitters. J. Neurochem. 98:203–12 [Google Scholar]
  141. Romanatto T, Cesquini M, Amaral ME, Roman EA, Moraes JC. 141.  et al. 2007. TNF-α acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient—effects on leptin and insulin signaling pathways. Peptides 28:1050–58 [Google Scholar]
  142. Arruda AP, Milanski M, Coope A, Torsoni AS, Ropelle E. 142.  et al. 2011. Low-grade hypothalamic inflammation leads to defective thermogenesis, insulin resistance, and impaired insulin secretion. Endocrinology 152:1314–26 [Google Scholar]
  143. Romanatto T, Roman EA, Arruda AP, Denis RG, Solon C. 143.  et al. 2009. Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis. J. Biol. Chem. 284:36213–22 [Google Scholar]
  144. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. 144.  1997. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389:610–14 [Google Scholar]
  145. Shi X, Wang X, Li Q, Su M, Chew E. 145.  et al. 2013. Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter. Diabetologia 56:925–36 [Google Scholar]
  146. Purkayastha S, Zhang G, Cai D. 146.  2011. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17:883–87 [Google Scholar]
  147. Milanski M, Degasperi G, Coope A, Morari J, Denis R. 147.  et al. 2009. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29:359–70 [Google Scholar]
  148. Wallenius V, Wallenius K, Ahrén B, Rudling M, Carlsten H. 148.  et al. 2002. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8:75–79 [Google Scholar]
  149. Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson J-O. 149.  2002. Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem. Biophys. Res. Commun. 293:560–65 [Google Scholar]
  150. Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR. 150.  et al. 2010. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin sensitivity through IKKβ and ER stress inhibition. PLOS Biol 8:e1000465 [Google Scholar]
  151. Nakata M, Yamamoto S, Okada T, Gantulga D, Okano H. 151.  et al. 2016. IL-10 gene transfer upregulates arcuate POMC and ameliorates hyperphagia, obesity and diabetes by substituting for leptin. Int. J. Obes. 40:425–33 [Google Scholar]
  152. Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ. 152.  1999. Leptin actions on food intake and body temperature are mediated by IL-1. PNAS 96:7047–52 [Google Scholar]
  153. Wisse BE, Ogimoto K, Schwartz MW. 153.  2006. Role of hypothalamic interleukin-1β (IL-1β) in regulation of energy homeostasis by melanocortins. Peptides 27:265–73 [Google Scholar]
  154. Reyes TM, Sawchenko PE. 154.  2002. Involvement of the arcuate nucleus of the hypothalamus in interleukin-1-induced anorexia. J. Neurosci. 22:5091–99 [Google Scholar]
  155. Scarlett JM, Jobst EE, Enriori PJ, Bowe DD, Batra AK. 155.  et al. 2007. Regulation of central melanocortin signaling by interleukin-1β. Endocrinology 148:4217–25 [Google Scholar]
  156. Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J. 156.  et al. 2009. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–59 [Google Scholar]
  157. Ehses JA, Meier DT, Wueest S, Rytka J, Boller S. 157.  et al. 2010. Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia 53:1795–806 [Google Scholar]
  158. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. 158.  2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Investig. 116:3015–25 [Google Scholar]
  159. Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. 159.  1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–22 [Google Scholar]
  160. Shechter R, London A, Kuperman Y, Ronen A, Rolls A. 160.  et al. 2013. Hypothalamic neuronal Toll-like receptor 2 protects against age-induced obesity. Sci. Rep. 3:1254 [Google Scholar]
  161. Cnop M, Foufelle F, Velloso LA. 161.  2012. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol. Med. 18:59–68 [Google Scholar]
  162. Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S. 162.  et al. 2009. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:35–51 [Google Scholar]
  163. Williams KW, Liu T, Kong X, Fukuda M, Deng Y. 163.  et al. 2014. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab 20:471–82 [Google Scholar]
  164. de Brito OM, Scorrano L. 164.  2008. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–10 [Google Scholar]
  165. Schneeberger M, Dietrich MO, Sebastián D, Imbernón M, Castaño C. 165.  et al. 2013. Mitofusin 2 in POMC neurons connects ER stress with leptin resistance and energy imbalance. Cell 155:172–87 [Google Scholar]
  166. Klionsky DJ. 166.  2007. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell. Biol. 8:931–37 [Google Scholar]
  167. Meng Q, Cai D. 167.  2011. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase β (IKKβ)/NF-κB pathway. J. Biol. Chem. 286:32324–32 [Google Scholar]
  168. Quan W, Kim H-K, Moon E-Y, Kim SS, Choi CS. 168.  et al. 2012. Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153:1817–26 [Google Scholar]
  169. Kaushik S, Arias E, Kwon H, Lopez NM, Athonvarangkul D. 169.  et al. 2012. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 13:258–65 [Google Scholar]
  170. Malhotra R, Warne JP, Salas E, Xu AW, Debnath J. 170.  2015. Loss of Atg12, but not Atg5, in pro-opiomelanocortin neurons exacerbates diet-induced obesity. Autophagy 11:145–54 [Google Scholar]
  171. Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E. 171.  et al. 2016. Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metab 23:113–27 [Google Scholar]
  172. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S. 172.  et al. 2011. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab 14:173–83 [Google Scholar]
/content/journals/10.1146/annurev-physiol-022516-034110
Loading
/content/journals/10.1146/annurev-physiol-022516-034110
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error