Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction.

Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-α (ERα). However, ERα-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERα in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERα in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERα from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ERα in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERα inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERα neurons to regulate different aspects of energy homeostasis and reproduction.

Sexual dimorphism in body fat distribution and risk for cardiovascular diseases.

The prevalence of obesity has dramatically increased over the past decade along with the cardiovascular and other health risks it encompasses. Adipose tissue, which is distributed in the abdominal viscera, carries a greater risk for cardiovascular disorders than adipose tissue subcutaneously. There is a sex difference in the regional fat distribution. Women have more subcutaneous fat, whereas men have more visceral fat. Therefore, obesity-related metabolic disorders are much lower in premenopausal women than men. Peripheral metabolic signals like leptin and insulin are involved in the food intake, body weight, body fat distribution, and cardiovascular disease. Key areas in the brain, including the hypothalamus, integrates these peripheral adiposity signals to maintain overall adiposity levels, and these brain regions are directly influenced by sex hormones. Therefore, differences in cardiovascular disease may be under the influence of sex hormones either directly in the brain or through their influence of body fat distribution. The role of estrogen in mediating body fat distribution and cardiovascular disease is the focus of this review.