Dramatic decline in circulating 17?-estradiol (E2) in post-menopausal women has been associated with development of obesity and glucose dysregulations. While E2 administration in post-menopausal women may correct these issues, the estrogen therapy is often associated with side effects, including reproductive endocrine toxicity and breast cancer. Targeting specific estrogen receptors (ERs) and ER-expressing populations may produce anti-obesity and anti-diabetes benefits with fewer side effects. We demonstrated that estrogen receptor-? (ER?) in the ventrolateral subdivision of the ventromedial hypothalamus (vlVMH) is essential to maintain body weight and glucose balance. Here we seek to unravel the molecular and neurocircuitry mechanisms for these ER? neurons by testing a general hypothesis that E2-sensitive ER?vlVMH neurons detect nutritional/glycemic fluctuations, and recruit multiple downstream neural circuits to maintain energy and glucose homeostasis. The first objective is to determine the glucose and energy-regulatory effects of the ER?vlVMH-originated projections to a few brain regions, including the dorsal Raphe nuclei (DRN) and medial posterior arcuate nucleus of the hypothalamus (mpARH). The second objective is to determine whether two ionic channel genes, namely, Abcc8 and Ano4, regulate the firing responses of ER?vlVMH neurons to various alterations in blood glucose and/or feeding states; we will also examine the physiological functions of these channels on whole-body energy/glucose balance. The third objective is to establish Clic1 as a novel ER? target gene, and to determine whether Clic1 in ER?vlVMH neurons mediates actions of E2 to maintain energy and glucose balance. Accomplishment of these studies will unravel ionic mechanisms by which ER?vlVMH neurons detect dynamic changes in energy and glucose balance, and reveal the ER?vlVMH-originated neural networks that respond to these changes and therefore restore energy/glucose homeostasis. We will also delineate molecular mechanisms by which E2 regulates ER?vlVMH neuron functions and energy/glucose balance, and may identify potential targets for treatment of metabolic disorders associated with menopause.
The female sex hormone, estrogen, acts in the brain to prevent obesity and metabolic disorders. We found that a group of estrogen-responsive neurons in the brain hypothalamus, namely ER?vlVMH neurons, can sense fluctuations in blood glucose and nutrient levels, and we will examine how these ER?vlVMH neurons integrate estrogen signals and metabolic/nutritional signals to regulate glucose and energy balance.
