PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice

Authors: SAITO, KENJI - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); ZHU, LIANGRU - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); XU, PINGWEN - Children'S Nutrition Research Center (CNRC); HINTON, ANTENTOR - Children'S Nutrition Research Center (CNRC); YAN, XIAOFENG - Children'S Nutrition Research Center (CNRC); ZHAO, JEAN - Harvard Medical School; FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC); TONG, QINGCHUN - University Of Texas Health Science Center; CLEGG, DEBORAH - Cedars-Sinai Medical Center; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2016
Publication Date: 3/18/2016
Citation: Saito, K., He, Y., Yang, Y., Zhu, L., Wang, C., Xu, P., Hinton, A.O., Yan, X., Zhao, J., Fukuda, M., Tong, Q., Clegg, D.J., Xu, Y. 2016. PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Scientific Reports. 6:23459.

Interpretive Summary: Obesity and diabetes are serious global health problems. Here we showed that the female sex hormone, estrogen, can substantially reduce food intake and glucose in female mice. These findings highlighted estrogen signals as a potential therapeutic target for treatment of obesity and diabetes at least in women.

Technical Abstract: Estrogens act in the ventromedial hypothalamic nucleus (VMH) to regulate body weight homeostasis. However, the molecular mechanisms underlying these estrogenic effects are unknown. We show that activation of estrogen receptor-a (ERa) stimulates neural firing of VMH neurons expressing ERa, and these effects are blocked with intracellular application of a pharmacological inhibitor of the phosphatidyl inositol 3-kinase (PI3K). Further, we demonstrated that mice with genetic inhibition of PI3K activity in VMH neurons showed a sexual dimorphic obese phenotype, with only female mutants being affected. In addition, inhibition of VMH PI3K activity blocked effects of 17Beta-estradiol to stimulate energy expenditure, but did not affect estrogen-induced anorexia. Collectively, our results indicate that PI3K activity in VMH neurons plays a physiologically relevant role in mediating estrogenic actions on energy expenditure in females.