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Title: The ERa-PI3K cascade in proopiomelanocortin progenitor neurons regulates feeding and glucose balance in female mice

Author
item ZHU, LIANGRU - Children'S Nutrition Research Center (CNRC)
item XU, PINGWEN - Children'S Nutrition Research Center (CNRC)
item CAO, XUEHONG - Children'S Nutrition Research Center (CNRC)
item YANG, YONGJIE - Children'S Nutrition Research Center (CNRC)
item HINTON, ANTENTOR - Children'S Nutrition Research Center (CNRC)
item XIA, YAN - Children'S Nutrition Research Center (CNRC)
item SAITO, KENJI - Children'S Nutrition Research Center (CNRC)
item YAN, XIAOFENG - Children'S Nutrition Research Center (CNRC)
item ZOU, FANG - Children'S Nutrition Research Center (CNRC)
item DING, HONGFANG - Children'S Nutrition Research Center (CNRC)
item WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC)
item YAN, CHUNLING - Children'S Nutrition Research Center (CNRC)
item PRADIP, SAHA - Children'S Nutrition Research Center (CNRC)
item KHAN, SOHAIB - University Of Cincinnati
item ZHAO, JEAN - Harvard University
item FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)
item TONG, QINGCHUN - University Of Texas Health Science Center
item CLEGG, DEBORAH - Cedars-Sinai Medical Center
item CHAN, LAWRENCE - Children'S Nutrition Research Center (CNRC)
item XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/11/2015
Publication Date: 12/3/2015
Citation: Zhu, L., Xu, P., Cao, X., Yang, Y., Hinton, A., Xia, Y., Saito, K., Yan, X., Zou, F., Ding, H., Wang, C., Yan, C., Pradip, S., Khan, S.A., Zhao, J., Fukuda, M., Tong, Q., Clegg, D.J., Chan, L., Xu, Y. 2015. The ERa-PI3K cascade in proopiomelanocortin progenitor neurons regulates feeding and glucose balance in female mice. Endocrinology. 156(12):4474-4491.

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 the treatment of obesity and diabetes at least in women.

Technical Abstract: Estrogens act upon estrogen receptor (ER)a to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERa specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERa agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERa-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.