Obesity is a major risk factor for type II diabetes and cardiovascular disease and increased understanding of body weight regulation may lead to effective strategies to combat obesity and diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight and glucose balance as women show dramatically increased risks for developing obesity and diabetes when they enter menopause. Hormone replacement therapy may be a way to reduce these risks, but actions of estrogen via its receptors in the peripheral tissues cause unwanted effects, such as cancer and heart disease. Evidence indicates that estrogen acts in the brain to reduce body weight and improve glucose profile, but the mechanisms underlying these beneficial effects are not fully understood. To this end, three objectives will be pursued in the current grant. (1) It has been shown that estrogen suppresses food intake and improves glucose balance by acting upon one estrogen receptor isoforms, ER1, present in a subset of brain cells, namely POMC neurons. However, the downstream neural circuits recruited by these POMC neurons to mediate effects of estrogen remain unknown. Mouse models will be generated in which melanocortin 4 receptor (MC4R), the receptor for the POMC product, will be re-expressed in two distinct site of the brain at the null background. These models will be used to determine if MC4R in these sites is sufficient to mediate anorexigenic and anti-diabetic effects of estrogen. (2) Actions of ER1 in another population of brain cells (SF1 neurons) are shown to increase energy expenditure, but the intracellular signaling initiated by ER1 to achieve this regulation are unclear. Mice with FoxO1 deleted only in SF1 neurons will be used to determine if FoxO1 in SF1 neurons is required to mediate estrogenic effects on energy expenditure. (3) Finally, the functions of ER1 in other brain sites will be examined. Mice will be generated with ER1 deleted only in a forebrain structure, amygdala. These mice will be used to determine if ER1 in the amygdala provides redundant mechanisms to regulate energy and glucose balance. Thus, the proposed study will not only advance our understanding about the mechanisms by which sex hormone regulates brain functions to provide a coordinated regulation of body weight and glucose, but also help identify rational targets for developing more specific estrogen therapies that provide metabolic benefits with no or fewer side effects.
The hormone replacement therapy with estrogens may be used to greatly reduce risks of development of obesity and diabetes in women. However, due to the broad actions of estrogen in the body, the metabolic benefits by estrogens are often associated with unwanted side effects, such as breast cancer and heart disease. Using the state-of-art technology, we propose to identify the critical brain sites that express estrogen receptors, the downstream brain networks, and intracellular molecules that mediate the anti-obesity and anti-diabetic effects of estrogens, and therefore results from these studies will provide rational targets for the development of novel estrogen therapies that combat obesity and diabetes with no or fewer side effects.
|Lee, Jong Han; Lin, Ligen; Xu, Pingwen et al. (2016) Neuronal Deletion of Ghrelin Receptor Almost Completely Prevents Diet-Induced Obesity. Diabetes 65:2169-78|
|Saito, Kenji; He, Yanlin; Yan, Xiaofeng et al. (2016) Visualizing estrogen receptor-Î±-expressing neurons using a new ERÎ±-ZsGreen reporter mouse line. Metabolism 65:522-32|
|Xu, Yuanzhong; Chang, Jeffrey T; Myers Jr, Martin G et al. (2016) Euglycemia Restoration by Central Leptin in Type 1 Diabetes Requires STAT3 Signaling but Not Fast-Acting Neurotransmitter Release. Diabetes 65:1040-9|
|Sisley, Stephanie R; Arble, Deanna M; Chambers, Adam P et al. (2016) Hypothalamic Vitamin D Improves Glucose Homeostasis and Reduces Weight. Diabetes 65:2732-41|
|Hinton Jr, Antentor Othrell; He, Yanlin; Xia, Yan et al. (2016) Estrogen Receptor-Î± in the Medial Amygdala Prevents Stress-Induced Elevations in Blood Pressure in Females. Hypertension 67:1321-30|
|Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L et al. (2016) Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions. Cell Rep 16:3003-15|
|Saito, Kenji; He, Yanlin; Yang, Yongjie et al. (2016) PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Sci Rep 6:23459|
|Xu, Pingwen; He, Yanlin; Cao, Xuehong et al. (2016) Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice. Biol Psychiatry :|
|Meng, Fantao; Han, Yong; Srisai, Dollada et al. (2016) New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism. Proc Natl Acad Sci U S A 113:3645-50|
|Yan, Chunling; He, Yanlin; Xu, Yuanzhong et al. (2016) Apolipoprotein A-IV Inhibits AgRP/NPY Neurons and Activates Pro-Opiomelanocortin Neurons in the Arcuate Nucleus. Neuroendocrinology 103:476-88|
Showing the most recent 10 out of 28 publications