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

Abstract

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.

AMPK in Health and Disease

“…However, a complicating factor in both the ArKO and ERKO mice is the finding of elevated circulating androgens. Recent studies by McInnes et al (326) have shown that dihydrotestosterone infusion inhibits AMPK signaling in adipocytes, suggesting that increased adiposity in ArKO mice is due at least in part to the increase in androgen-to-estrogen ratio resulting in the inhibition of AMPK signaling rather than solely a lack of estrogen. Interestingly, AMPK expression levels and activity are not altered in human skeletal muscle (414).…”

Sex Differences in Obesity-Related Glucose Intolerance and Insulin Resistance

“…Administration of aromatizable androgens such as testosterone (94,95), but not nonaromatizable dihydrotestostone (94), reduces total and abdominal fat in older men. In contrast, androgen administration to ovariectomized female mice significantly increases body adiposity and abdominal fat (96). Such obesity development is associated with reduced fatty acid oxidation, indicated by decreased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and acetyl-CoA carboxylase in abdominal visceral fat (96).…”

“…In contrast, androgen administration to ovariectomized female mice significantly increases body adiposity and abdominal fat (96). Such obesity development is associated with reduced fatty acid oxidation, indicated by decreased phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and acetyl-CoA carboxylase in abdominal visceral fat (96). In humans, women with higher circulating androgen levels (97) or exogenous androgen administration (98, 99) increase abdominal fat.…”

Estrogens, Obesity, Inflammation, and Breast Cancer—What Is the Link?

“…The AMP-activated protein kinase (AMPK) is now recognized to be a master regulator of energy homeostasis and the nexus for the convergence of endocrine signals including leptin, adiponectin, estradiol, androgens, and phytoestrogens. [19][20][21] AMPK activity is regulated primarily through phosphorylation at T172(α) by the upstream kinases LKB-1 and CaMKK; however, in most tissues LKB-1 appears to predominate. Furthermore, phosphorylation of the α-catalytic subunit of AMPK at S485 (α1) or S491 (α2) by PKA reduces its catalytic activity.…”

“…19 In mouse adipose tissue and in 3T3L1 cells, testosterone or dihydrotestosterone inhibits, and estradiol stimulates, LKB1 expression, and ERα binds to the LKB1 promoter in the presence of estradiol. 19 Thus, we predict that when the circulating ratio of testosterone to estradiol is high, as in the postmenopausal years, then aromatase expression in the breast is stimulated.…”