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.