Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes

References

• Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas. Diabetes Res Clin Pract. 2019;157:107843. doi:10.1016/j.diabres.2019.107843
   PubMed Web of Science ®Google Scholar
• Sun H, Saeedi P, Karuranga S, et al. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119. doi:10.1016/j.diabres.2021.109119
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Ferrannini E, Groop L, et al. Type 2 diabetes mellitus. Nat Rev Dis Primers. 2015;1:15019. doi:10.1038/nrdp.2015.19
   PubMed Web of Science ®Google Scholar
• Labazi H, Trask AJ. Coronary microvascular disease as an early culprit in the pathophysiology of diabetes and metabolic syndrome. Pharmacol Res. 2017;123:114–121. doi:10.1016/j.phrs.2017.07.004
   PubMed Web of Science ®Google Scholar
• da Silva AA, Do Carmo JM, Hall JE. CNS regulation of glucose homeostasis: role of the leptin-melanocortin system. Curr Diab Rep. 2020;20(7):29. doi:10.1007/s11892-020-01311-1
   Web of Science ®Google Scholar
• Myers MG Jr, Olson DP. Central nervous system control of metabolism. Nature. 2012;491(7424):357–363. doi:10.1038/nature11705
   PubMed Web of Science ®Google Scholar
• Candler T, Kuhnen P, Prentice AM, Silver M. Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease. Front Neuroendocrinol. 2019;54:100773. doi:10.1016/j.yfrne.2019.100773
   Web of Science ®Google Scholar
• Zhan C. POMC neurons: feeding, energy metabolism, and beyond. Adv Exp Med Biol. 2018;1090:17–29.
   Web of Science ®Google Scholar
• Goit RK, Taylor AW, Lo ACY. The central melanocortin system as a treatment target for obesity and diabetes: a brief overview. Eur J Pharmacol. 2022;924:174956. doi:10.1016/j.ejphar.2022.174956
   Web of Science ®Google Scholar
• Hill JW, Elias CF, Fukuda M, et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 2010;11(4):286–297. doi:10.1016/j.cmet.2010.03.002
   PubMed Web of Science ®Google Scholar
• Myers MG Jr, Olson DP. SnapShot: neural pathways that control feeding. Cell Metab. 2014;19(4):732–732 e731. doi:10.1016/j.cmet.2014.03.015
   Web of Science ®Google Scholar
• Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism. 2015;64(1):24–34. doi:10.1016/j.metabol.2014.08.004
   PubMed Web of Science ®Google Scholar
• Nakano M, Asakawa A, Inui A. Long-term correction of type 1 and 2 diabetes by central leptin gene therapy independent of effects on appetite and energy expenditure. Indian J Endocrinol Metab. 2012;16(Suppl 3):S556–561. doi:10.4103/2230-8210.105572
   Google Scholar
• Shi H, Strader AD, Sorrell JE, Chambers JB, Woods SC, Seeley RJ. Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis. Am J Physiol Endocrinol Metab. 2008;294(3):E630–639. doi:10.1152/ajpendo.00704.2007
   PubMed Web of Science ®Google Scholar
• Munzberg H, Morrison CD. Structure, production and signaling of leptin. Metabolism. 2015;64(1):13–23. doi:10.1016/j.metabol.2014.09.010
   PubMed Web of Science ®Google Scholar
• Zhang Y, Scarpace PJ. Circumventing central leptin resistance: lessons from central leptin and POMC gene delivery. Peptides. 2006;27(2):350–364. doi:10.1016/j.peptides.2005.01.024
   Web of Science ®Google Scholar
• Wardlaw SL. Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol. 2011;660(1):213–219. doi:10.1016/j.ejphar.2010.10.107
   Web of Science ®Google Scholar
• Mizuno TM, Kleopoulos SP, Bergen HT, Roberts JL, Priest CA, Mobbs CV. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and [corrected] in ob/ob and db/db mice, but is stimulated by leptin. Diabetes. 1998;47(2):294–297. doi:10.2337/diab.47.2.294
   PubMed Web of Science ®Google Scholar
• Bray GA. The Zucker-fatty rat: a review. Fed Proc. 1977;36(2):148–153.
   Google Scholar
• Kim EM, O’Hare E, Grace MK, Welch CC, Billington CJ, Levine AS. ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean Zucker rats. Brain Res. 2000;862(1–2):11–16. doi:10.1016/S0006-8993(00)02060-6
   Web of Science ®Google Scholar
• Huo L, Gamber K, Greeley S, et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 2009;9(6):537–547. doi:10.1016/j.cmet.2009.05.003
   Web of Science ®Google Scholar
• Kahn BB, Minokoshi Y. Leptin, GABA, and glucose control. Cell Metab. 2013;18(3):304–306. doi:10.1016/j.cmet.2013.08.015
   Web of Science ®Google Scholar
• Faulkner LD, Dowling AR, Stuart RC, Nillni EA, Hill JW. Reduced melanocortin production causes sexual dysfunction in male mice with POMC neuronal insulin and leptin insensitivity. Endocrinology. 2015;156(4):1372–1385. doi:10.1210/en.2014-1788
   PubMed Web of Science ®Google Scholar
• Ernst MB, Wunderlich CM, Hess S, et al. Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. J Neurosci. 2009;29(37):11582–11593. doi:10.1523/JNEUROSCI.5712-08.2009
   Web of Science ®Google Scholar
• Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415–1421. doi:10.1126/science.8197455
   PubMed Web of Science ®Google Scholar
• Rahmouni K, Sigmund CD, Haynes WG, Mark AL. Hypothalamic ERK mediates the anorectic and thermogenic sympathetic effects of leptin. Diabetes. 2009;58(3):536–542. doi:10.2337/db08-0822
   PubMed Web of Science ®Google Scholar
• Hill JW, Xu Y, Preitner F, et al. Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis. Endocrinology. 2009;150(11):4874–4882. doi:10.1210/en.2009-0454
   Web of Science ®Google Scholar
• Belgardt BF, Husch A, Rother E, et al. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab. 2008;7(4):291–301. doi:10.1016/j.cmet.2008.01.006
   Web of Science ®Google Scholar
• Yang SB, Tien AC, Boddupalli G, Xu AW, Jan YN, Jan LY. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron. 2012;75(3):425–436. doi:10.1016/j.neuron.2012.03.043
   PubMed Web of Science ®Google Scholar
• Smith MA, Katsouri L, Irvine EE, et al. Ribosomal S6K1 in POMC and AgRP neurons regulates glucose homeostasis but not feeding behavior in mice. Cell Rep. 2015;11(3):335–343. doi:10.1016/j.celrep.2015.03.029
   Web of Science ®Google Scholar
• Yu Y, Wu Y, Szabo A, et al. Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice. Endocrinology. 2013;154(9):3130–3140. doi:10.1210/en.2013-1218
   PubMed Web of Science ®Google Scholar
• Marty N, Dallaporta M, Thorens B. Brain glucose sensing, counterregulation, and energy homeostasis. Physiology. 2007;22:241–251. doi:10.1152/physiol.00010.2007
   PubMed Web of Science ®Google Scholar
• Dodd GT, Tiganis T. Insulin action in the brain: roles in energy and glucose homeostasis. J Neuroendocrinol. 2017;29:10. doi:10.1111/jne.12513
   Web of Science ®Google Scholar
• Schwartz MW, Sipols A, Kahn SE, et al. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990;259(3 Pt 1):E378–383. doi:10.1152/ajpendo.1990.259.3.E378
   Web of Science ®Google Scholar
• Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra111. doi:10.1126/scitranslmed.3003748
   PubMed Web of Science ®Google Scholar
• Molnar G, Farago N, Kocsis AK, et al. GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J Neurosci. 2014;34(4):1133–1137. doi:10.1523/JNEUROSCI.4082-13.2014
   PubMed Web of Science ®Google Scholar
• Choi JH, Kim MS. Homeostatic regulation of glucose metabolism by the central nervous system. Endocrinol Metab. 2022;37(1):9–25. doi:10.3803/EnM.2021.1364
   Web of Science ®Google Scholar
• Lin HV, Plum L, Ono H, et al. Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons. Diabetes. 2010;59(2):337–346. doi:10.2337/db09-1303
   Web of Science ®Google Scholar
• Klockener T, Hess S, Belgardt BF, et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci. 2011;14(7):911–918. doi:10.1038/nn.2847
   Web of Science ®Google Scholar
• 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(4):682–693. doi:10.1016/j.cmet.2014.03.004
   PubMed Web of Science ®Google Scholar
• Shin AC, Filatova N, Lindtner C, et al. Insulin receptor signaling in POMC, but Not AgRP, neurons controls adipose tissue insulin action. Diabetes. 2017;66(6):1560–1571. doi:10.2337/db16-1238
   PubMed Web of Science ®Google Scholar
• Yan J, Zhang H, Yin Y, et al. Obesity- and aging-induced excess of central transforming growth factor-beta potentiates diabetic development via an RNA stress response. Nat Med. 2014;20(9):1001–1008. doi:10.1038/nm.3616
   Web of Science ®Google Scholar
• Jais A, Bruning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest. 2017;127(1):24–32. doi:10.1172/JCI88878
   PubMed Web of Science ®Google Scholar
• Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med. 2012;18(1):59–68. doi:10.1016/j.molmed.2011.07.010
   PubMed Web of Science ®Google Scholar
• Avalos Y, Hernandez-Caceres MP, Lagos P, et al. Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism. Cell Death Dis. 2022;13(7):659. doi:10.1038/s41419-022-05109-9
   Web of Science ®Google Scholar
• Yao T, Deng Z, Gao Y, et al. Ire1alpha in pomc neurons is required for thermogenesis and glycemia. Diabetes. 2017;66(3):663–673. doi:10.2337/db16-0533
   Web of Science ®Google Scholar
• Williams KW, Liu T, Kong X, et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 2014;20(3):471–482. doi:10.1016/j.cmet.2014.06.002
   Web of Science ®Google Scholar
• Lindtner C, Scherer T, Zielinski E, et al. Binge drinking induces whole-body insulin resistance by impairing hypothalamic insulin action. Sci Transl Med. 2013;5(170):170ra114. doi:10.1126/scitranslmed.3005123
   Web of Science ®Google Scholar
• Weissmann L, Quaresma PG, Santos AC, et al. IKKepsilon is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity. Diabetes. 2014;63(10):3334–3345. doi:10.2337/db13-1817
   Web of Science ®Google Scholar
• Wang Z, Do Carmo JM, da Silva AA, et al. Role of SOCS3 in POMC neurons in metabolic and cardiovascular regulation. Am J Physiol Regul Integr Comp Physiol. 2019;316(4):R338–R351. doi:10.1152/ajpregu.00163.2018
   Web of Science ®Google Scholar
• Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997;389(6651):631–635. doi:10.1038/39369
   PubMed Web of Science ®Google Scholar
• Yuan F, Yin H, Deng Y, et al. Overexpression of Smad7 in hypothalamic POMC neurons disrupts glucose balance by attenuating central insulin signaling. Mol Metab. 2020;42:101084. doi:10.1016/j.molmet.2020.101084
   Web of Science ®Google Scholar
• Gaspar JM, Velloso LA. Hypoxia inducible factor as a central regulator of metabolism - implications for the development of obesity. Front Neurosci. 2018;12:813. doi:10.3389/fnins.2018.00813
   PubMed Web of Science ®Google Scholar
• Gaspar JM, Mendes NF, Correa-da-Silva F, et al. Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity. Brain Behav Immun. 2018;73:550–561. doi:10.1016/j.bbi.2018.06.020
   Web of Science ®Google Scholar
• Wang Z, Khor S, Cai D. Age-dependent decline of hypothalamic HIF2alpha in response to insulin and its contribution to advanced age-associated metabolic disorders in mice. J Biol Chem. 2019;294(13):4946–4955. doi:10.1074/jbc.RA118.005429
   Web of Science ®Google Scholar
• Wu Z, Xi P, Zhang Y, et al. LKB1 up-regulation inhibits hypothalamic inflammation and attenuates diet-induced obesity in mice. Metabolism. 2021;116:154694. doi:10.1016/j.metabol.2020.154694
   Web of Science ®Google Scholar
• Wu Z, Han J, Xue J, et al. Deletion of liver kinase B1 in POMC neurons predisposes to diet-induced obesity. Life Sci. 2020;258:118204. doi:10.1016/j.lfs.2020.118204
   Web of Science ®Google Scholar
• Tang Q, Liu Q, Yang X, et al. Sirtuin 6 supra-physiological overexpression in hypothalamic pro-opiomelanocortin neurons promotes obesity via the hypothalamus-adipose axis. FASEB J. 2021;35(3):e21408. doi:10.1096/fj.202002607
   Web of Science ®Google Scholar
• Tang Q, Gao Y, Liu Q, et al. Sirt6 in pro-opiomelanocortin neurons controls energy metabolism by modulating leptin signaling. Mol Metab. 2020;37:100994. doi:10.1016/j.molmet.2020.100994
   Web of Science ®Google Scholar
• Yang Y, He Y, Liu H, et al. Hypothalamic steroid receptor coactivator-2 regulates adaptations to fasting and overnutrition. Cell Rep. 2021;37(10):110075. doi:10.1016/j.celrep.2021.110075
   Web of Science ®Google Scholar
• Koch CE, Lowe C, Legler K, et al. Central adiponectin acutely improves glucose tolerance in male mice. Endocrinology. 2014;155(5):1806–1816. doi:10.1210/en.2013-1734
   Web of Science ®Google Scholar
• Coope A, Milanski M, Araujo EP, et al. AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus. FEBS Lett. 2008;582(10):1471–1476. doi:10.1016/j.febslet.2008.03.037
   PubMed Web of Science ®Google Scholar
• Qi Y, Takahashi N, Hileman SM, et al. Adiponectin acts in the brain to decrease body weight. Nat Med. 2004;10(5):524–529. doi:10.1038/nm1029
   PubMed Web of Science ®Google Scholar
• Park S, Kim DS, Kwon DY, Yang HJ. Long-term central infusion of adiponectin improves energy and glucose homeostasis by decreasing fat storage and suppressing hepatic gluconeogenesis without changing food intake. J Neuroendocrinol. 2011;23(8):687–698. doi:10.1111/j.1365-2826.2011.02165.x
   Web of Science ®Google Scholar
• Guillod-Maximin E, Roy AF, Vacher CM, et al. Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons. J Endocrinol. 2009;200(1):93–105. doi:10.1677/JOE-08-0348
   Web of Science ®Google Scholar
• Thundyil J, Pavlovski D, Sobey CG, Arumugam TV. Adiponectin receptor signalling in the brain. Br J Pharmacol. 2012;165(2):313–327. doi:10.1111/j.1476-5381.2011.01560.x
   Web of Science ®Google Scholar
• Minokoshi Y, Alquier T, Furukawa N, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428(6982):569–574. doi:10.1038/nature02440
   PubMed Web of Science ®Google Scholar
• Suyama S, Maekawa F, Maejima Y, Kubota N, Kadowaki T, Yada T. Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. Sci Rep. 2016;6:30796. doi:10.1038/srep30796
   Web of Science ®Google Scholar
• Posey KA, Clegg DJ, Printz RL, et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab. 2009;296(5):E1003–1012. doi:10.1152/ajpendo.90377.2008
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Habener JF, Holst JJ. Discovery, characterization, and clinical development of the glucagon-like peptides. J Clin Invest. 2017;127(12):4217–4227. doi:10.1172/JCI97233
   PubMed Web of Science ®Google Scholar
• Amato A, Baldassano S, Mule F. GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity. J Endocrinol. 2016;229(2):R57–66. doi:10.1530/JOE-16-0035
   PubMed Web of Science ®Google Scholar
• Ten Kulve JS, van Bloemendaal L, Balesar R, et al. Decreased hypothalamic glucagon-like peptide-1 receptor expression in type 2 diabetes patients. J Clin Endocrinol Metab. 2016;101(5):2122–2129. doi:10.1210/jc.2015-3291
   Web of Science ®Google Scholar
• Guan X, Shi X, Li X, et al. GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility. Am J Physiol Endocrinol Metab. 2012;303(7):E853–864. doi:10.1152/ajpendo.00245.2012
   Web of Science ®Google Scholar
• Halawi H, Khemani D, Eckert D, et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial. Lancet Gastroenterol Hepatol. 2017;2(12):890–899. doi:10.1016/S2468-1253(17)30285-6
   PubMed Web of Science ®Google Scholar
• Roh E, Song DK, Kim MS. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp Mol Med. 2016;48:e216. doi:10.1038/emm.2016.4
   PubMed Web of Science ®Google Scholar
• Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest. 2014;124(10):4473–4488. doi:10.1172/JCI75276
   PubMed Web of Science ®Google Scholar
• Jones GL, Wittmann G, Yokosawa EB, et al. Selective restoration of pomc expression in glutamatergic POMC neurons: evidence for a dynamic hypothalamic neurotransmitter network. eNeuro. 2019;6:2. doi:10.1523/ENEURO.0400-18.2019
   Web of Science ®Google Scholar
• Bjorbaek C, Hollenberg AN. Leptin and melanocortin signaling in the hypothalamus. Vitam Horm. 2002;65:281–311.
   Web of Science ®Google Scholar
• Arora S. Role of neuropeptides in appetite regulation and obesity--a review. Neuropeptides. 2006;40(6):375–401. doi:10.1016/j.npep.2006.07.001
   Web of Science ®Google Scholar
• Baldassano S, Amato A, Mule F. Influence of glucagon-like peptide 2 on energy homeostasis. Peptides. 2016;86:1–5. doi:10.1016/j.peptides.2016.09.010
   PubMed Web of Science ®Google Scholar
• The GX. CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis. Am J Physiol Regul Integr Comp Physiol. 2014;307(6):R585–596. doi:10.1152/ajpregu.00096.2014
   Web of Science ®Google Scholar
• Shi X, Zhou F, Li X, et al. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons. Cell Metab. 2013;18(1):86–98. doi:10.1016/j.cmet.2013.06.014
   PubMed Web of Science ®Google Scholar
• Taher J, Baker C, Alvares D, Ijaz L, Hussain M, Adeli K. GLP-2 dysregulates hepatic lipoprotein metabolism, inducing fatty liver and VLDL overproduction in male hamsters and mice. Endocrinology. 2018;159(9):3340–3350. doi:10.1210/en.2018-00416
   Web of Science ®Google Scholar
• Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–756. doi:10.1016/j.cmet.2018.03.001
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696–1705. doi:10.1016/S0140-6736(06)69705-5
   PubMed Web of Science ®Google Scholar
• Girardet C, Butler AA. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim Biophys Acta. 2014;1842(3):482–494. doi:10.1016/j.bbadis.2013.05.004
   PubMed Web of Science ®Google Scholar
• Fan W, Dinulescu DM, Butler AA, Zhou J, Marks DL, Cone RD. The central melanocortin system can directly regulate serum insulin levels. Endocrinology. 2000;141(9):3072–3079. doi:10.1210/endo.141.9.7665
   PubMed Web of Science ®Google Scholar
• Hill JW, Faulkner LD. The role of the melanocortin system in metabolic disease: new developments and advances. Neuroendocrinology. 2017;104(4):330–346. doi:10.1159/000450649
   Web of Science ®Google Scholar
• Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88(1):131–141. doi:10.1016/S0092-8674(00)81865-6
   PubMed Web of Science ®Google Scholar
• Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev. 2010;31(4):506–543. doi:10.1210/er.2009-0037
   PubMed Web of Science ®Google Scholar
• Kievit P, Halem H, Marks DL, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes. 2013;62(2):490–497. doi:10.2337/db12-0598
   PubMed Web of Science ®Google Scholar
• Mark AL, Correia M, Morgan DA, Shaffer RA, Haynes WG. State-of-The-art-lecture: obesity-induced hypertension: new concepts from the emerging biology of obesity. Hypertension. 1999;33(1 Pt 2):537–541. doi:10.1161/01.HYP.33.1.537
   Web of Science ®Google Scholar
• Greenfield JR, Miller JW, Keogh JM, et al. Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med. 2009;360(1):44–52. doi:10.1056/NEJMoa0803085
   PubMed Web of Science ®Google Scholar
• Koch M, Varela L, Kim JG, et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015;519(7541):45–50. doi:10.1038/nature14260
   Web of Science ®Google Scholar
• Tsunematsu T, Yamanaka A. The role of orexin/hypocretin in the central nervous system and peripheral tissues. Vitam Horm. 2012;89:19–33.
   Web of Science ®Google Scholar
• Laburthe M, Voisin T, El Firar A. Orexins/hypocretins and orexin receptors in apoptosis: a mini-review. Acta Physiol. 2010;198(3):393–402. doi:10.1111/j.1748-1716.2009.02035.x
   Web of Science ®Google Scholar
• Yang D, Xu L, Guo F, Sun X, Zhang D, Wang M. Orexin-A and endocannabinoid signaling regulate glucose-responsive arcuate nucleus neurons and feeding behavior in obese rats. Neuropeptides. 2018;69:26–38. doi:10.1016/j.npep.2018.04.001
   Web of Science ®Google Scholar
• Morello G, Imperatore R, Palomba L, et al. Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling. Proc Natl Acad Sci U S A. 2016;113(17):4759–4764. doi:10.1073/pnas.1521304113
   Web of Science ®Google Scholar
• Nishimura Y, Mabuchi K, Taguchi S, et al. Involvement of orexin-A neurons but not melanin-concentrating hormone neurons in the short-term regulation of food intake in rats. J Physiol Sci. 2014;64(3):203–211. doi:10.1007/s12576-014-0312-0
   Web of Science ®Google Scholar
• Blais A, Drouin G, Chaumontet C, et al. Impact of Orexin-A treatment on food intake, energy metabolism and body weight in mice. PLoS One. 2017;12(1):e0169908. doi:10.1371/journal.pone.0169908
   Web of Science ®Google Scholar
• Griffond B, Risold PY. MCH and feeding behavior-interaction with peptidic network. Peptides. 2009;30(11):2045–2051. doi:10.1016/j.peptides.2009.07.008
   Web of Science ®Google Scholar
• Cheon HG. Antiobesity effects of melanin-concentrating hormone receptor 1 (MCH-R1) antagonists. Handb Exp Pharmacol. 2012;209:383–403.
   Google Scholar
• Shearman LP, Camacho RE, Sloan Stribling D, et al. Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats. Eur J Pharmacol. 2003;475(1–3):37–47. doi:10.1016/S0014-2999(03)02146-0
   PubMed Web of Science ®Google Scholar
• Al-Massadi O, Quinones M, Clasadonte J, et al. MCH Regulates SIRT1/FoxO1 and Reduces POMC neuronal activity to induce hyperphagia, adiposity, and glucose intolerance. Diabetes. 2019;68(12):2210–2222. doi:10.2337/db19-0029
   PubMed Web of Science ®Google Scholar
• Kong D, Vong L, Parton LE, et al. Glucose stimulation of hypothalamic MCH neurons involves K(ATP) channels, is modulated by UCP2, and regulates peripheral glucose homeostasis. Cell Metab. 2010;12(5):545–552. doi:10.1016/j.cmet.2010.09.013
   Web of Science ®Google Scholar
• Surwit RS, McCubbin JA, Kuhn CM, Cochrane C, Feinglos MN. Differential glycemic effects of morphine in diabetic and normal mice. Metabolism. 1989;38(3):282–285. doi:10.1016/0026-0495(89)90089-9
   Web of Science ®Google Scholar
• Benarroch EE. Endogenous opioid systems: current concepts and clinical correlations. Neurology. 2012;79(8):807–814. doi:10.1212/WNL.0b013e3182662098
   PubMed Web of Science ®Google Scholar
• Koekkoek LL, van der Gun LL, Serlie MJ, la Fleur SE. The clash of two epidemics: the relationship between opioids and glucose metabolism. Curr Diab Rep. 2022;22(7):301–310. doi:10.1007/s11892-022-01473-0
   Web of Science ®Google Scholar
• Lux F, Brase DA, Dewey WL. Differential effects of subcutaneous and intrathecal morphine administration on blood glucose in mice: comparison with intracerebroventricular administration. J Pharmacol Exp Ther. 1988;245(1):187–194.
   Web of Science ®Google Scholar
• Tzeng TF, Lo CY, Cheng JT, Liu IM. Activation of mu-opioid receptors improves insulin sensitivity in obese Zucker rats. Life Sci. 2007;80(16):1508–1516. doi:10.1016/j.lfs.2007.01.016
   Web of Science ®Google Scholar
• Giugliano D, Ceriello A, Salvatore T, Paolisso G, D’Onofrio F, Lefebvre P. Beta-endorphin infusion restores acute insulin responses to glucose in type-2 diabetes mellitus. J Clin Endocrinol Metab. 1987;64(5):944–948. doi:10.1210/jcem-64-5-944
   Web of Science ®Google Scholar
• Pennock RL, Hentges ST. Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the mu-opioid receptor. J Physiol. 2014;592(19):4247–4256. doi:10.1113/jphysiol.2014.275339
   Web of Science ®Google Scholar
• 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(12):5061–5070. doi:10.1172/JCI70338
   PubMed Web of Science ®Google Scholar
• Burke LK, Ogunnowo-Bada E, Georgescu T, et al. Lorcaserin improves glycemic control via a melanocortin neurocircuit. Mol Metab. 2017;6(10):1092–1102. doi:10.1016/j.molmet.2017.07.004
   PubMed Web of Science ®Google Scholar
• Zhou L, Sutton GM, Rochford JJ, et al. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab. 2007;6(5):398–405. doi:10.1016/j.cmet.2007.10.008
   PubMed Web of Science ®Google Scholar
• Wang D, He X, Zhao Z, et al. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front Neuroanat. 2015;9:40. doi:10.3389/fnana.2015.00040
   Web of Science ®Google Scholar
• Blits-Huizinga CT, Nelersa CM, Malhotra A, Liebl DJ. Ephrins and their receptors: binding versus biology. IUBMB Life. 2004;56(5):257–265. doi:10.1080/15216540412331270076
   Web of Science ®Google Scholar
• Gervais M, Labouebe G, Picard A, Thorens B, Croizier S. EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis. PLoS Biol. 2020;18(11):e3000680. doi:10.1371/journal.pbio.3000680
   Web of Science ®Google Scholar