Trends in Endocrinology & Metabolism
ReviewEstrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity
Section snippets
Contribution of sex hormones to metabolic diseases
Increased food supply and decreased physical activity have resulted in a worldwide epidemic of obesity. As a consequence of these environmental changes, the incidence of type 2 diabetes (T2D) is on the rise [1]. In addition, a disorder involving increased visceral adipose tissue, hyperlipidemia, insulin resistance, and hypertension termed metabolic syndrome, has emerged [2].
There is a concerted interaction between sex/reproduction and energy metabolism [3]. First, extreme conditions of
Mechanism of ERs action
In healthy premenopausal women, 17β-estradiol (E2) is produced by the ovaries by the aromatization of androstenedione to estrone, followed by conversion to E2. In these women, E2 functions as a circulating hormone that acts on distant target tissues. However, in women after menopause (when the ovaries fail to produce E2) and in men, E2 is produced in extragonadal sites, mainly adipose tissue, bone, vessels and brain by local tissue aromatization from circulating testosterone [7]. Therefore, in
Mechanism of AR action
Androgens influence gene transcription through the activation of the AR, a ligand-activated transcription factor that subsequently binds as a homodimer with specific DNA motifs in its target genes [60]. These DNA motifs, called androgen response elements (AREs), can be categorized as classic AREs, which are recognized by glucocorticoid or progesterone receptors, and AR-specific AREs, which display selectivity for the AR [61]. As in the case of estrogens, over the past two decades evidence has
Conclusions and future perspectives
E2 and testosterone are crucial hormonal signals maintaining energy homeostasis in both sexes, and the effect of E2 treatment on obesity and the prevention of obesity and diabetes is one of the most powerful observations of rodent physiology. Although men have lower circulating E2 concentrations than do premenopausal women, aromatization of circulating testosterone to E2 in target metabolic tissues equilibrates cellular E2 concentrations, and ER activation is similarly crucial in both sexes in
Acknowledgements
This work was supported by grants from National Institutes of Health (P50 HD044405, RO1 DK074970-01), the Juvenile Diabetes Research Foundation (1-2006-837), and the March of Dimes (6-FY07-678) and by Northwestern University Institute for Women's Health Research Pioneer Award.
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