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Regulation of Adenosine 5',Monophosphate-Activated Protein Kinase and Lipogenesis by Androgens Contributes to Visceral Obesity in an Estrogen-Deficient State

Prince Henry’s Institute of Medical Research (K.J.M., A.C., E.R.S., M.E.J.), Clayton, Victoria 3168, Australia; and Departments of Anatomy and Cell Biology (K.J.M., M.E.J.) and Biochemistry (E.R.S.), Monash University, Clayton, Victoria 3800, Australia

Address all correspondence and requests for reprints to: Kerry McInnes, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton, Victoria 3168, Australia. E-mail: kerry.mcinnes{at}princehenrys.org.

Menopause is associated with an accumulation of visceral fat. An emerging concept suggests that relatively elevated levels of circulating androgens, compared with estrogens in postmenopausal women, underlie this shift in body fat distribution. In this study we administered dihydrotestosterone (DHT) to ovariectomized mice to examine the effect of relative androgen excess on adipose tissue distribution and function in estrogen-deficient mice. Compared with controls, DHT-treated mice exhibited increased body weight and visceral fat mass associated with triglyceride accumulation. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase was significantly decreased by DHT in visceral fat. In 3T3-L1 cells, DHT decreased phosphorylation of AMPK in a dose-dependent manner. In addition, DHT increased the expression of lipogenic genes (fatty acid synthase, sterol regulatory element binding protein-2, and lipoprotein lipase) in visceral fat. These data provide the first in vivo evidence that an increased androgen to estrogen ratio can promote visceral fat accumulation by inhibiting AMPK activation and stimulating lipogenesis.