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.

The role of sex steroids in white adipose tissue adipocyte function

“…The differential effects of menopause, hypogonadism and PCOS on the function of adipose tissue underscore the important role that sex steroids play in the modulation of WAT metabolism. Interestingly, high-fat diet appears to interact with sex steroids to apply an additional layer of control over adipose tissue function (Floryk et al 2011, Gorres et al 2011, McInnes 2012, Metz et al 2016. As the obesity rate continues to rise worldwide, disproportionately affecting women (Flegal et al 2016), it is likely an increased importance will be placed upon understanding the mechanistic control of WAT function.…”

5α-Reductase Type 1 Deficiency or Inhibition Predisposes to Insulin Resistance, Hepatic Steatosis, and Liver Fibrosis in Rodents

“…These changes in adipose tissue may be indirect, mediated by altered prevailing insulin concentrations, or direct, mediated by altered local steroid signaling. Androgen deficiency in fat, exemplified in adipose-specific androgen receptor knockdown in mice (41), is characterized by increased obesity and insulin resistance, but is accompanied by increases in transcripts for Fas, Atgl, Lpl, and Hsl. These changes were not observed in 5aR1-KO mice, again supporting a role for glucocorticoids rather than androgens in their phenotype.…”

Testosterone and glucose metabolism in men: current concepts and controversies

“…However, studies that have reported thresholds for both fat mass and insulin sensitivity suggest that the testosterone level required to prevent fat accumulation may be higher than the level below which insulin resistance increases (Table 3). Studies in men with experimentally induced hypogonadism (Singh et al 2002) and in male mice lacking a functional androgen receptor either globally (Rana et al 2011) or selectively in fat (McInnes et al 2012) also show that effects of testosterone on body composition and glucose metabolism can be dissociated. In part, this may be due to the fact that the effects of testosterone therapy on visceral adiposity, the fat compartment most closely associated with insulin resistance, have been inconsistent: the (2013a)) showed that testosterone therapy does not reduce visceral fat.…”