It's ALL in the Hypothalamus! Sex, Reproduction, and Obesity.

Recent observations from our own and other labs have demonstrated that the ovarian steroid estrogen, acting at specific estrogen receptor-a (ERa) in distinct regions of the in the central nervous system (CNS), is responsible for normal body weight regulation. The ventral hypothalamus (VMH) contains two key nuclei, the arcuate (ARC ) which contains populations of neurons that regulate food intake and body weight, and the ventral medial nucleus (VMN), which alone has not been found to have a prominent role in the regulation of food intake and body weight but does influence energy expenditure. When portions of both the VMN and the ARC are destroyed in a typical VMH lesion, animals, and especially female animals, eat more, burn less energy and become obese. Further, animals devoid of ERa are obese. Collectively, these findings implicate ERa in the regulation of energy balance in females. The mechanisms by which the estrogen/ERa system regulates energy homeostasis, however, are yet fully understood. To tackle this issue, we first generated mice lacking Ea in the CNS. These mutant mice display increased body weight and adiposity, which result from both hyperphagia and decreased energy expenditure. Further, we generated mice with ERa selectively deleted in the hypothalamic pro-opiomelanocortin (POMC) neurons in the ARC and SF1 neurons in the VMN, respectively. Remarkably, we found that while deletion of ERa only in POMC neurons leads to hyperphagia, mice lacking ERa in SF1 neurons show decreased energy expenditure but normal food intake. These results demonstrate that ERa expressed in the CNS and is required for the coordinated control of food intake and energy expenditure. Further, the effects of estrogen on food intake and energy expenditure are mediated by distinct hypothalamic neurons.