MCH Regulates SIRT1/FoxO1 and Reduces POMC Neuronal Activity to Induce Hyperphagia, Adiposity, and Glucose Intolerance

• DOI: 10.2337/db19-0029
• Publication Date: 2019-09-17T07:35:13Z
• Authors: Omar Al-Massadi; Mar Quiñones; Jerome Clasadonte; René Hernandez-Ba...; Amparo Romero-Picó; Cintia Folgueira; Donald A. Morgan; Imre Kalló; Violeta Heras; Ana Senra; Samuel C. Funderburk; Michael J. Krashes; Yara Souto; Miguel Fidalgo; Serge Luquet; Melissa J. Chee; Monica Imbernon; Daniel Beiroa; Lucía García-Caba...; Rosalia Gallego; Brian Y.H. Lam; Giles Yeo; Miguel Lopez; Zsolt Liposits; Kamal Rahmouni; Vincent Prevot; Carlos Dieguez; Ruben Nogueiras
• Keywords: Orexigenic; Proopiomelanocortin; Hypophagia; Melanin-concentrating hormone; FOXO1; Sirtuin 1; Apelin

Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological genetic approaches to show that sirtuin 1 (SIRT1)/FoxO1 signaling pathway in hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, SIRT1/FoxO1 regulates inhibitory effect on POMC expression. Remarkably, metabolic are compromised mice lacking SIRT1 specifically neurons. Of note, independent agouti-related peptide (AgRP) neurons because inhibition γ-aminobutyric acid receptor ARC did not prevent orexigenic action MCH, hypophagic silencing was maintained after chemogenetic stimulation AgRP Central required for weight gain through its sympathetic nervous system. The central knockdown causes hypophagia loss diet-induced obese wild-type mice; however, effects were abolished overexpressing fed a high-fat diet. These data reveal basis body weight, metabolism highlight relevance obesity.