GPCRs in Hypothalamic Neurons and Their Roles in Controlling Food Intake and Metabolism

Overview

Journal Front Mol Neurosci

Specialty Molecular Biology

Date 2025 Feb 20

PMID 39974186

Authors

Tian Qiu

Ou Fu

Affiliations

Soon will be listed here.

Abstract

G-protein coupled receptor (GPCR) subtypes within the hypothalamus play a pivotal role in maintaining body homeostasis, particularly in the regulation of food intake and energy metabolism. This review provides an overview of classical loss and gain-of-function studies on GPCRs related to feeding and metabolism, with a focus on emerging cell-type-specific investigations. These studies reveal that diverse GPCR-expressing neuronal populations are intricately linked to feeding and energy balance. We also discuss recent findings that highlight the interaction of distinct peptide-GPCR systems in modulating complex feeding behaviors.

References

Kushi A, Sasai H, Koizumi H, Takeda N, Yokoyama M, Nakamura M . Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. Proc Natl Acad Sci U S A. 1998; 95(26):15659-64. PMC: 28100. DOI: 10.1073/pnas.95.26.15659. View

Zimmerman C, Knight Z . Layers of signals that regulate appetite. Curr Opin Neurobiol. 2020; 64:79-88. PMC: 7572475. DOI: 10.1016/j.conb.2020.03.007. View

Chen W, Mehlkop O, Scharn A, Nolte H, Klemm P, Henschke S . Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation. Cell Metab. 2023; 35(5):786-806.e13. PMC: 10173804. DOI: 10.1016/j.cmet.2023.03.019. View

Coutinho E, Okamoto S, Ishikawa A, Yokota S, Wada N, Hirabayashi T . Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues. Diabetes. 2017; 66(9):2372-2386. DOI: 10.2337/db16-1344. View

Ghamari-Langroudi M, Cakir I, Lippert R, Sweeney P, Litt M, Ellacott K . Regulation of energy rheostasis by the melanocortin-3 receptor. Sci Adv. 2018; 4(8):eaat0866. PMC: 6105298. DOI: 10.1126/sciadv.aat0866. View

Butiaeva L, Slutzki T, Swick H, Bourguignon C, Robins S, Liu X . Leptin receptor-expressing pericytes mediate access of hypothalamic feeding centers to circulating leptin. Cell Metab. 2021; 33(7):1433-1448.e5. DOI: 10.1016/j.cmet.2021.05.017. View

Lingvay I, Cohen R, le Roux C, Sumithran P . Obesity in adults. Lancet. 2024; 404(10456):972-987. DOI: 10.1016/S0140-6736(24)01210-8. View

Sayar-Atasoy N, Laule C, Aklan I, Kim H, Yavuz Y, Ates T . Adrenergic modulation of melanocortin pathway by hunger signals. Nat Commun. 2023; 14(1):6602. PMC: 10587058. DOI: 10.1038/s41467-023-42362-8. View

Clement K, van den Akker E, Argente J, Bahm A, Chung W, Connors H . Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020; 8(12):960-970. DOI: 10.1016/S2213-8587(20)30364-8. View

10.

Clement K, Biebermann H, Farooqi I, van der Ploeg L, Wolters B, Poitou C . MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018; 24(5):551-555. DOI: 10.1038/s41591-018-0015-9. View

11.

Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, Nishimori K . Oxytocin receptor-deficient mice developed late-onset obesity. Neuroreport. 2008; 19(9):951-5. DOI: 10.1097/WNR.0b013e3283021ca9. View

12.

. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet. 2016; 387(10026):1377-1396. PMC: 7615134. DOI: 10.1016/S0140-6736(16)30054-X. View

13.

Chen A, Marsh D, Trumbauer M, Frazier E, Guan X, Yu H . Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet. 2000; 26(1):97-102. DOI: 10.1038/79254. View

14.

Li C, Navarrete J, Liang-Guallpa J, Lu C, Funderburk S, Chang R . Defined Paraventricular Hypothalamic Populations Exhibit Differential Responses to Food Contingent on Caloric State. Cell Metab. 2018; 29(3):681-694.e5. PMC: 6402975. DOI: 10.1016/j.cmet.2018.10.016. View

15.

Huang Z, Liu L, Zhang J, Conde K, Phansalkar J, Li Z . Glucose-sensing glucagon-like peptide-1 receptor neurons in the dorsomedial hypothalamus regulate glucose metabolism. Sci Adv. 2022; 8(23):eabn5345. PMC: 9177072. DOI: 10.1126/sciadv.abn5345. View

16.

Xu S, Yang H, Menon V, Lemire A, Wang L, Henry F . Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles. Science. 2020; 370(6514). DOI: 10.1126/science.abb2494. View

17.

Bonaz B, Rivest S . Effect of a chronic stress on CRF neuronal activity and expression of its type 1 receptor in the rat brain. Am J Physiol. 1998; 275(5):R1438-49. DOI: 10.1152/ajpregu.1998.275.5.R1438. View

18.

Liu J, Conde K, Zhang P, Lilascharoen V, Xu Z, Lim B . Enhanced AMPA Receptor Trafficking Mediates the Anorexigenic Effect of Endogenous Glucagon-like Peptide-1 in the Paraventricular Hypothalamus. Neuron. 2017; 96(4):897-909.e5. PMC: 5729931. DOI: 10.1016/j.neuron.2017.09.042. View

19.

Butler A, Kesterson R, Khong K, Cullen M, Pelleymounter M, Dekoning J . A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology. 2000; 141(9):3518-21. DOI: 10.1210/endo.141.9.7791. View

20.

Gui Y, Dahir N, Wu Y, Downing G, Sweeney P, Cone R . Melanocortin-3 receptor expression in AgRP neurons is required for normal activation of the neurons in response to energy deficiency. Cell Rep. 2023; 42(10):113188. PMC: 10728878. DOI: 10.1016/j.celrep.2023.113188. View