title: Androgen Deficiency Exacerbates High-Fat Diet-Induced Metabolic Alterations in Male Mice.
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.
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Dubois
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Michaël R
authors.initials: MR
authors.lastname: Laurent
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Ferran
authors.initials: F
authors.lastname: Jardi
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Antonio
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: Lemaire
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Goyvaerts
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Louise
authors.initials: L
authors.lastname: Deldicque
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Decallonne
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Vanderschueren
authors.affiliation: Molecular Endocrinology Laboratory (V.D., M.R.L., L.A., F.C.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Gerontology and Geriatrics (M.R.L.), KU Leuven, 3000 Leuven, Belgium; 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; Gene Expression Unit (K.L., L.G.), Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium; Exercise Physiology Research Group (L.D.), Department of Kinesiology, KU Leuven, 3000 Leuven, Belgium; and Institute of Neuroscience (L.D.), Université Catholique de Louvain, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Claessens
mesh_terms: D050154:Adiposity / Q000235:genetics; D000728:Androgens / Q000172:deficiency*; D000818:Animals; D001823:Body Composition / Q000235:genetics; D059305:Diet, High-Fat; D018450:Disease Progression; D018149:Glucose Intolerance / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007006:Hypogonadism / Q000150:complications / Q000235:genetics / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: D000728:Androgens; D011944:Receptors, Androgen