MCH regulates SIRT1/FoxO1 and reduces POMC neuronal activity to induce hyperphagia, adiposity and glucose intolerance

Al-Massadi, Omar and Quiñones, Mar and Clasadonte, Jerome and Bautista, René H. and Romero-Picó, Amparo and Kalló, Imre and Liposits, Zsolt (2019) MCH regulates SIRT1/FoxO1 and reduces POMC neuronal activity to induce hyperphagia, adiposity and glucose intolerance. DIABETES, 68 (10). pp. 1-56. ISSN 0012-1797 (print); 1939-327X (online)

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Abstract

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 and genetic approaches to show that the SIRT1/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity and glucose intolerance. MCH reduces POMC neuronal activity and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of AgRP neurons because inhibition of GABA-R in the ARC did not prevent the orexigenic action of MCH; and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild type mice, however, these effects were abolished in mice over-expressing SIRT1 fed a high fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity.

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