Adipose-specific knockout of androgen receptors in mice results in hyperinsulinaemia without obesity
Kerry McInnes, Lee Smith, Philippa Saunders, Ruth Andrew & Brian Walker
Background: Visceral fat is a key factor underlying type 2 diabetes. The amount and distribution of body fat is strongly influenced by sex steroids. Androgen receptors (ARs) are present in adipose tissue and are abundant in the detrimental visceral bed. Here, we sought to determine the contribution of the AR in adipose tissue to the pathophysiology of visceral obesity and type 2 diabetes.
Methods: Male fat-specific AR-knockout (fARKO) mice (12 weeks; n=12 each group) were created by breeding floxed-AR mice with adipose-specific FABP4-Cre mice. Glucose homeostasis was assessed by intraperitoneal glucose tolerance test (IPGTT, 2 mg glucose/g body weight) following a 6 h fast. At cull, tissues were weighed and biochemical indices of insulin resistance assessed. Data are mean±S.E.M.
Results: AR mRNA expression was significantly decreased in fARKO adipose tissue compared to floxed controls (0.29±0.06 vs 0.76±0.2 Arbitrary Units, P<0.05). fARKO mice were lighter (27.9±0.38 vs 30.1±0.28 g, P<0.001), had decreased gonadal fat (9.9±0.5 vs 11.97±0.8 mg/g body weight, P<0.05) and increased brown adipose tissue (5.1±0.27 vs 4.1±0.28 mg/g body weight, P<0.05) compared to floxed controls. fARKO mice had normal fasting plasma glucose levels, glucose tolerance and NEFA suppression but showed elevated fasting (0.73±0.06 vs 0.54±0.04 ng/ml, P<0.05) and 90-min post-IP glucose bolus plasma insulin levels (0.81±0.07 vs 0.6±0.06 ng/ml, P<0.05). Liver triglycerides (11.77±0.39 vs 11.27±0.4 nmol/mg) and plasma testosterone levels (0.79±0.19 vs 0.82±0.22 ng/ml) were unchanged in fARKO mice.
Conclusions: Ablation of adipose AR in mice produces hyperinsulinaemia without obesity. These findings highlight a specific role for androgen action in adipose in the pathophysiology of insulin resistance and we anticipate that therapeutic manipulation of androgen action at the level of the adipose tissue may improve insulin sensitivity.