Review
Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity

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Because of increasing life expectancy, the contribution of age-related estrogen or androgen deficiency to obesity and type 2 diabetes will become a new therapeutic challenge. This review integrates current concepts on the mechanisms through which estrogen receptors (ERs) and androgen receptor (AR) regulate energy homeostasis in rodents and humans. In females, estrogen maintains energy homeostasis via ERα and ERβ, by suppressing energy intake and lipogenesis, enhancing energy expenditure, and ameliorating insulin secretion and sensitivity. In males, testosterone is converted to estrogen and maintains fuel homeostasis via ERs and AR, which share related functions to suppress adipose tissue accumulation and improve insulin sensitivity. We suggest that ERs and AR could be potential targets in the prevention of age-related metabolic disorders.

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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