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

被引：32

作者：

Al-Massadi, Omar ^{[1
,2
]}

Quinones, Mar ^{[1
,2
,3
]}

Clasadonte, Jerome ^{[4
,5
]}

Hernandez-Bautista, Rene ^{[1
]}

Romero-Pico, Amparo ^{[1
,2
]}

Folgueira, Cintia ^{[1
,2
]}

Morgan, Donald A. ^{[6
,7
]}

Kallo, Imre ^{[8
]}

Heras, Violeta ^{[1
,2
]}

Senra, Ana ^{[1
]}

Funderburk, Samuel C. ^{[9
]}

Krashes, Michael J. ^{[9
]}

Souto, Yara ^{[1
]}

Fidalgo, Miguel ^{[1
]}

Luquet, Serge ^{[3
]}

Chee, Melissa J. ^{[10
]}

Imbernon, Monica ^{[1
,2
,4
]}

Beiroa, Daniel ^{[1
,2
]}

Garcia-Caballero, Lucia ^{[11
]}

Gallego, Rosalia ^{[11
]}

Lam, Brian Y. H. ^{[12
,13
]}

Yeo, Giles ^{[12
,13
]}

Lopez, Miguel ^{[1
,2
]}

Liposits, Zsolt ^{[8
]}

Rahmouni, Kamal ^{[6
,7
]}

Prevot, Vincent ^{[4
,5
]}

Dieguez, Carlos ^{[1
,2
]}

Nogueiras, Ruben ^{[1
,2
]}

机构：

[1] Univ Santiago de Compostela, Dept Physiol, CIMUS, Inst Invest Sanitaria, Santiago De Compostela, Spain

[2] CIBER Fisiopatol Obes & Nutr, Santiago De Compostela, Spain

[3] Univ Paris Diderot, Unite Biol Fonct & Adaptat, CNRS UMR 8251, Sorbonne Paris Cite, Paris, France

[4] Jean Pierre Aubert Res Ctr, INSERM, U1172, Lab Dev & Plast Neuroendocrine Brain, Lille, France

[5] Univ Lille, Sch Med, FHU 1000 Days Hlth, Lille, France

[6] Univ Iowa, Dept Pharmacol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA

[7] Iowa City VA Hlth Care Syst, Iowa City, IA USA

[8] Hungarian Acad Sci, Inst Expt Med, Lab Endocrine Neurobiol, Budapest, Hungary

[9] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD 20892 USA

[10] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Endocrinol, Boston, MA 02115 USA

[11] Univ Santiago de Compostela, Sch Med, Dept Morphol Sci, Inst Invest Sanitaria, Santiago De Compostela, Spain

[12] Univ Cambridge, Metab Res Labs, Wellcome MRC Inst Metab Sci, MRC Metab Dis Unit, Cambridge, England

[13] Addenbrookes Hosp, Cambridge, England

来源：

DIABETES | 2019年 / 68卷 / 12期

基金：

美国国家科学基金会; 欧盟地平线“2020”; 美国国家卫生研究院;

关键词：

MELANIN-CONCENTRATING-HORMONE; DIET-INDUCED OBESITY; BODY-WEIGHT; ENERGY-BALANCE; TISSUE THERMOGENESIS; MELANOCORTIN SYSTEM; AGRP NEURONS; MICE; SIRT1; PEPTIDE;

D O I：

10.2337/db19-0029

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (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 agouti-related peptide (AgRP) neurons because inhibition of gamma-aminobutyric acid receptor 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 overexpressing 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.

引用

页码：2210 / 2222

页数：13

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[1] Late-onset leanness in mice with targeted ablation of melanin concentrating hormone neurons [J].