title: Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis.
abstract: Testosterone deficiency is epidemic in obese ageing males with type 2 diabetes, but the direction of causality remains unclear. Testosterone-deficient males and global androgen receptor (AR) knockout mice are insulin resistant with increased fat, but it is unclear whether AR signaling in adipose tissue mediates body fat redistribution and alters glucose homoeostasis. To investigate this, mice with selective knockdown of AR in adipocytes (fARKO) were generated. Male fARKO mice on normal diet had reduced perigonadal fat but were hyperinsulinemic and by age 12 months, were insulin deficient in the absence of obesity. On high-fat diet, fARKO mice had impaired compensatory insulin secretion and hyperglycemia, with increased susceptibility to visceral obesity. Adipokine screening in fARKO mice revealed a selective increase in plasma and intra-adipose retinol binding protein 4 (RBP4) that preceded obesity. AR activation in murine 3T3 adipocytes downregulated RBP4 mRNA. We conclude that AR signaling in adipocytes not only protects against high-fat diet-induced visceral obesity but also regulates insulin action and glucose homeostasis, independently of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes, with early insulin resistance and evolving insulin deficiency.
authors.affiliation: Endocrinology Unit, University/British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, Scotland, UK. kerry.mcinnes@ed.ac.uk
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: McInnes
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Hunger
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose; D004041:Dietary Fats / Q000009:adverse effects; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D018149:Glucose Intolerance; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism
chemical_list: D054392:Adipokines; D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C502487:Rbp4 protein, mouse; D011944:Receptors, Androgen; D054839:Retinol-Binding Proteins, Plasma; D013739:Testosterone; D005947:Glucose