Network of hypothalamic neurons that control appetite

Jong-Woo Sohn, Jong-Woo Sohn

Abstract

The central nervous system (CNS) controls food intake and energy expenditure via tight coordinations between multiple neuronal populations. Specifically, two distinct neuronal populations exist in the arcuate nucleus of hypothalamus (ARH): the anorexigenic (appetite-suppressing) pro-opiomelanocortin (POMC) neurons and the orexigenic (appetite-increasing) neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. The coordinated regulation of neuronal circuit involving these neurons is essential in properly maintaining energy balance, and any disturbance therein may result in hyperphagia/obesity or hypophagia/starvation. Thus, adequate knowledge of the POMC and NPY/AgRP neuron physiology is mandatory to understand the pathophysiology of obesity and related metabolic diseases. This review will discuss the history and recent updates on the POMC and NPY/AgRP neuronal circuits, as well as the general anorexigenic and orexigenic circuits in the CNS.

Figures

Fig. 1.. POMC neurons and the central…
Fig. 1.. POMC neurons and the central melanocortin pathway. Two distinct populations of POMC neurons are present within the ARH; 5-HT2CR-expressing POMC neurons suppress food intake, and LepR-expressing POMC neurons increase energy expenditure. The effects of MC4Rs on energy balance are localized to different central nuclei; MC4Rs expressed by the PVH Sim1 neurons suppress food intake, and MC4Rs expressed by the IML sympathetic neurons increase energy expenditure. The solid black lines show possible connections between the specific POMC neurons and specific brain nuclei; the connections represented by the broken gray lines have not been ruled out. MC4R-expressing PVH glutamatergic neurons send axons to the neurons of the L-PBN. 3V: third ventricle, 5-HT2CR: serotonin 2C receptor, α-MSH: α-melanocyte stimulating hormone, ChAT: choline acetyltransferase, EE: energy expenditure, FI: food intake, IML: intermediolateral column of spinal cord, L-PBN: lateral parabrachial nucleus, LepR: leptin receotor, MC4R: melanocortin-4 receptor, ME: median eminence, POMC: pro-opiomelanocortin, PVH: paraventricular nucleus of hypothalamus, Sim1: single-minded 1.
Fig. 2.. NPY/AgRP neurons and the orexigenic…
Fig. 2.. NPY/AgRP neurons and the orexigenic pathway. NPY/AgRP neurons have axon terminals that release GABA (an inhibitory neurotransmitter) to suppress the POMC neurons, PVH OXT neurons, and neurons within the L-PBN. PVH neurons that express PACAP/TRH have axon terminals that release glutamate (an excitatory neurotransmitter) to activate NPY/AgRP neurons. Functional connections between NPY/AgRP neurons and PVH neurons that express CRH/AVP have not been established (dotted lines). AgRP: agouti-related peptide, AVP: arginine vasopressin, CRH: corticotropin-releasing hormone, L-PBN: lateral parabrachial nucleus, NPY: neuropeptide Y, OXT: oxytocin, PACAP: pituitary adenylate cyclase-activating peptide, POMC: pro-opiomelanocortin, PVH: paraventricular nucleus of hypothalamus, TRH: thyrotropin-releasing hormone.

References

    1. Hetherington AW, Ranson SW. Hypothalamic lesions and adiposity in the rat. Anat Rec. (1940);78:149–172. doi: 10.1002/ar.1090780203.
    1. Anand BK, Brobeck JR. Localization of a "feeding center" in the hypothalamus of the rat. Proc Soc Exp Biol Med. (1951);77:323–324. doi: 10.3181/00379727-77-18766.
    1. Cowley MA, Smart JL, Rubinstein M, et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. (2001);411:480–484. doi: 10.1038/35078085.
    1. Hill JW, Williams KW, Ye C, et al. Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest. (2008);118:1796–1805. doi: 10.1172/JCI32964.
    1. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nat Neurosci. (2004);7:493–494. doi: 10.1038/nn1226.
    1. Williams KW, Margatho LO, Lee CE, et al. Segregation of acute leptin and insulin effects in distinct populations of arcuate proopiomelanocortin neurons. J Neurosci. (2010);30:2472–2479. doi: 10.1523/JNEUROSCI.3118-09.2010.
    1. Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. (2003);37:649–661. doi: 10.1016/S0896-6273(03)00063-1.
    1. van den Pol AN, Yao Y, Fu LY, et al. Neuromedin B and gastrin-releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong Renilla green fluorescent protein in NPY neurons. J Neurosci. (2009);29:4622–4639. doi: 10.1523/JNEUROSCI.3249-08.2009.
    1. Yang Y, Atasoy D, Su HH, Sternson SM. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell. (2011);146:992–1003. doi: 10.1016/j.cell.2011.07.039.
    1. Qiu J, Zhang C, Borgquist A, et al. Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metab. (2014);19:682–693. doi: 10.1016/j.cmet.2014.03.004.
    1. Al-Qassab H, Smith MA, Irvine EE, et al. Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metab. (2009);10:343–354. doi: 10.1016/j.cmet.2009.09.008.
    1. Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. (1999);5:1066–1070. doi: 10.1038/12506.
    1. Aponte Y, Atasoy D, Sternson SM. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci. (2011);14:351–355. doi: 10.1038/nn.2739.
    1. Zhan C, Zhou J, Feng Q, et al. Acute and Long-Term Suppression of Feeding Behavior by POMC Neurons in the Brainstem and Hypothalamus, Respectively. J Neurosci. (2013);33:3624–3632. doi: 10.1523/JNEUROSCI.2742-12.2013.
    1. Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. (1997);88:131–141. doi: 10.1016/S0092-8674(00)81865-6.
    1. Balthasar N, Dalgaard LT, Lee CE, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. (2005);123:493–505. doi: 10.1016/j.cell.2005.08.035.
    1. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. (1997);385:165–168. doi: 10.1038/385165a0.
    1. Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. (1998);20:111–112. doi: 10.1038/2404.
    1. Farooqi IS, Keogh JM, Yeo GS, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. (2003);348:1085–1095. doi: 10.1056/NEJMoa022050.
    1. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. New Engl J Med. (1997);337:581–588. doi: 10.1056/NEJM199708283370901.
    1. Heisler LK, Cowley MA, Tecott LH, et al. Activation of central melanocortin pathways by fenfluramine. Science. (2002);297:609–611. doi: 10.1126/science.1072327.
    1. Xu Y, Jones JE, Kohno D, et al. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron. (2008);60:582–589. doi: 10.1016/j.neuron.2008.09.033.
    1. Berglund ED, Liu C, Sohn JW, et al. Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis. J Clin Invest. (2013);123:5061–5070. doi: 10.1172/JCI70338.
    1. Sohn JW, Xu Y, Jones JE, Wickman K, Williams KW, Elmquist JK. Serotonin 2C Receptor Activates a Distinct Population of Arcuate Pro-opiomelanocortin Neurons via TRPC Channels. Neuron. (2011);71:488–497. doi: 10.1016/j.neuron.2011.06.012.
    1. Roepke TA, Smith AW, Ronnekleiv OK, Kelly MJ. Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons. Am J Physiol Endocrinol Metab. (2012);302:E1399–1406. doi: 10.1152/ajpendo.00565.2011.
    1. Xu Y, Jones JE, Lauzon DA, et al. A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J Neurosci. (2010);30:14630–14634. doi: 10.1523/JNEUROSCI.5412-09.2010.
    1. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. New Engl J Med. (2010);363:245–256. doi: 10.1056/NEJMoa0909809.
    1. Balthasar N, Coppari R, McMinn J, et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron. (2004);42:983–991. doi: 10.1016/j.neuron.2004.06.004.
    1. Berglund ED, Vianna CR, Donato J, Jr, et al. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest. (2012);122:1000–1009. doi: 10.1172/JCI59816.
    1. Scott MM, Williams KW, Rossi J, Lee CE, Elmquist JK. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J Clin Invest. (2011);121:2413–2421. doi: 10.1172/JCI43703.
    1. Rossi J, Balthasar N, Olson D, et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. (2011);13:195–204. doi: 10.1016/j.cmet.2011.01.010.
    1. Michaud JL, Boucher F, Melnyk A, et al. Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet. (2001);10:1465–1473. doi: 10.1093/hmg/10.14.1465.
    1. Swaab DF, Purba JS, Hofman MA. Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases. J Clini Endocrin Metab. (1995);80:573–579.
    1. Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR. Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice. Mol Endocrinol. (2008);22:1723–1734. doi: 10.1210/me.2008-0067.
    1. Holder JL, Jr, Butte NF, Zinn AR. Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet. (2000);9:101–108. doi: 10.1093/hmg/9.1.101.
    1. Shah BP, Vong L, Olson DP, et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc Natl Acad Sci U S A. (2014);111:13193–13198. doi: 10.1073/pnas.1407843111.
    1. Krashes MJ, Shah BP, Madara JC, et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature. (2014);507:238–242. doi: 10.1038/nature12956.
    1. Wu Q, Clark MS, Palmiter RD. Deciphering a neuronal circuit that mediates appetite. Nature. (2012);483:594–597. doi: 10.1038/nature10899.
    1. Wu Q, Boyle MP, Palmiter RD. Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell. (2009);137:1225–1234. doi: 10.1016/j.cell.2009.04.022.
    1. Becskei C, Grabler V, Edwards GL, Riediger T, Lutz TA. Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Res. (2007);1162:76–84. doi: 10.1016/j.brainres.2007.06.016.
    1. Carter ME, Soden ME, Zweifel LS, Palmiter RD. Genetic identification of a neural circuit that suppresses appetite. Nature. (2013);503:111–114. doi: 10.1038/nature12596.
    1. Cai H, Haubensak W, Anthony TE, Anderson DJ. Central amygdala PKC-delta(+) neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci. (2014);17:1240–1248. doi: 10.1038/nn.3767.
    1. Qian S, Chen H, Weingarth D, et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. (2002);22:5027–5035. doi: 10.1128/MCB.22.14.5027-5035.2002.
    1. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. (2005);310:683–685. doi: 10.1126/science.1115524.
    1. Luquet S, Phillips CT, Palmiter RD. NPY/AgRP neurons are not essential for feeding responses to glucoprivation. Peptides. (2007);28:214–225. doi: 10.1016/j.peptides.2006.08.036.
    1. Gropp E, Shanabrough M, Borok E, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. (2005);8:1289–1291. doi: 10.1038/nn1548.
    1. Krashes MJ, Koda S, Ye C, et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J Clin Invest. (2011);121:1424–1428. doi: 10.1172/JCI46229.
    1. Sohn JW, Elmquist JK, Williams KW. Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. (2013);36:504–512. doi: 10.1016/j.tins.2013.05.003.
    1. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci. (2008);11:998–1000. doi: 10.1038/nn.2167.
    1. Atasoy D, Betley JN, Su HH, Sternson SM. Deconstruction of a neural circuit for hunger. Nature. (2012);488:172–177. doi: 10.1038/nature11270.

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