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

Kenji Saito,Deborah J Clegg,Yanlin He,Chunmei Wang,Xiaofeng Yan,Pingwen Xu,Qingchun Tong,Yongjie Yang,Makoto Fukuda,Yong Xu,Antentor Othrell Hinton,Jean Zhao,Liangru Zhu

doi:10.1038/srep23459

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-α (ERα) stimulates neural firing of VMH neurons expressing ERα, 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 17β-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.

Highlights

The Phosphatidyl inositol 3-kinase (PI3K) activity in estrogenic actions is unclear
This interesting sexual dimorphism led to the hypothesis that estrogens may be one of the hormones that drive PI3K activity in VMH steroidogenic factor-1 (SF1) neurons in females to prevent body weight gain
We have previously reported that male mice lacking PI3K activity selectively in VMH SF1 neurons (SF1-p110α -KO) developed obesity when fed on a high fat diet (HFD), but they showed normal body weight when fed on regular chow[13]

Summary

Results

Dimorphic obesity in mice lacking PI3K activity in VMH SF1 neurons. We have previously reported that male mice lacking PI3K activity selectively in VMH SF1 neurons (SF1-p110α -KO) developed obesity when fed on a high fat diet (HFD), but they showed normal body weight when fed on regular chow[13]. While cumulative locomotor activities during the 24-hour period and the dark cycle were not significantly different between these two groups (Fig. 4K,L), OVX+ E SF1-p110α -KO mice showed significantly decreased light-cycle locomotor activity compared to OVX+ V SF1-p110α -KO mice (Fig. 4M) These results indicate that OVX SF1-p110α -KO females were partially resistant to body weight-lowering effects of chronic 17β -estradiol supplement, associated with blunted responses to estrogenic actions to stimulate energy expenditure. Gonad intact SF1-p110α -KO females, with normal circulating levels of 17β -estradiol, showed modest but significant increases in body weight compared to gonad intact wild type females, while the same mutation did not affect body weight in chow-fed male mice This sexual dimorphism further supports the notion that endogenous estrogens drive PI3K activity in VMH SF1 neurons in females to prevent obesity; lack of PI3K in VMH SF1 neurons would impair estrogenic actions on body weight regulation and lead to modest obesity in females, while the same mutation does not affect males. These findings provide potential targets for development of novel anti-obesity therapies, at least for women

Methods

Author Contributions

Additional Information