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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093587-03
Application #
8516035
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
2011-09-27
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$344,620
Indirect Cost
$92,983
Name
Baylor College of Medicine
Department
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Chunmei; He, Yanlin; Xu, Pingwen et al. (2018) TAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis. Nat Commun 9:1544
Xu, Yong; López, Miguel (2018) Central regulation of energy metabolism by estrogens. Mol Metab 15:104-115
Mangieri, Leandra R; Lu, Yungang; Xu, Yuanzhong et al. (2018) A neural basis for antagonistic control of feeding and compulsive behaviors. Nat Commun 9:52
Zhu, Canjun; Xu, Pingwen; He, Yanlin et al. (2017) Heparin Increases Food Intake through AgRP Neurons. Cell Rep 20:2455-2467
Xu, Yuanzhong; Lu, Yungang; Xu, Pingwen et al. (2017) VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation. eNeuro 4:
Xu, Pingwen; He, Yanlin; Cao, Xuehong et al. (2017) Activation of Serotonin 2C Receptors in Dopamine Neurons Inhibits Binge-like Eating in Mice. Biol Psychiatry 81:737-747
Xu, Yong; O'Malley, Bert W; Elmquist, Joel K (2017) Brain nuclear receptors and body weight regulation. J Clin Invest 127:1172-1180
Duerrschmid, Clemens; He, Yanlin; Wang, Chunmei et al. (2017) Asprosin is a centrally acting orexigenic hormone. Nat Med 23:1444-1453
Kim, Eun Ran; Fan, Shengjie; Akhmedov, Dmitry et al. (2017) Red blood cell ?-adrenergic receptors contribute to diet-induced energy expenditure by increasing O2 supply. JCI Insight 2:
Bai, Juli; Cervantes, Christopher; Liu, Juan et al. (2017) DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proc Natl Acad Sci U S A 114:12196-12201

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