Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice

Author:

Dubois Vanessa1,Laurent Michaël R.12,Jardi Ferran13,Antonio Leen3,Lemaire Katleen4,Goyvaerts Lotte4,Deldicque Louise5,Carmeliet Geert3,Decallonne Brigitte3,Vanderschueren Dirk3,Claessens Frank1

Affiliation:

1. Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium

2. Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium

3. Clinical and Experimental Endocrinology (F.J., L.A., G.C., B.D., D.V.), Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium

4. Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium

5. Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium

Abstract

Abstract Androgen deficiency is associated with obesity, metabolic syndrome, and type 2 diabetes mellitus in men, but the mechanisms behind these associations remain unclear. In this study, we investigated the combined effects of androgen deficiency and high-fat diet (HFD) on body composition and glucose homeostasis in C57BL/6J male mice. Two models of androgen deficiency were used: orchidectomy (ORX) and androgen receptor knockout mice. Both models displayed higher adiposity and serum leptin levels upon HFD, whereas no differences were seen on a regular diet. Fat accumulation in HFD ORX animals was accompanied by increased sedentary behavior and occurred in spite of reduced food intake. HFD ORX mice showed white adipocyte hypertrophy, correlated with decreased mitochondrial content but not function as well as increased lipogenesis and decreased lipolysis suggested by the up-regulation of fatty acid synthase and the down-regulation of hormone-sensitive lipase. Both ORX and androgen receptor knockout exacerbated HFD-induced glucose intolerance by impairing insulin action in liver and skeletal muscle, as evidenced by the increased triglyceride and decreased glycogen content in these tissues. In addition, serum IL-1β levels were elevated, and pancreatic insulin secretion was impaired after ORX. Testosterone but not dihydrotestosterone supplementation restored the castration effects on body composition and glucose homeostasis. We conclude that sex steroid deficiency in combination with HFD exacerbates adiposity, insulin resistance, and β-cell failure in 2 preclinical male mouse models. Our findings stress the importance of a healthy diet in a clinical context of androgen deficiency and may have implications for the prevention of metabolic alterations in hypogonadal men.

Publisher

The Endocrine Society

Subject

Endocrinology

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