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Cold-inducible Klf9 regulates thermogenesis of brown and beige fat

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posted on 29.09.2020 by Ada Admin, Heng Fan, Yujie Zhang, Jun Zhang, Qiyuan Yao, Yongfeng Song, Qiwei Shen, Jun Lin, Yuanxu Gao, Xiuyun Wang, Lei Zhang, Yinliang Zhang, Pingsheng Liu, Jiajun Zhao, Qinghua Cui, John Zhong Li, Yongsheng Chang
Promoting development and function of brown and beige fat may represent an attractive treatment of obesity. In the present study, we show that fat Klf9 expression is markedly induced by cold exposure and a β-adrenergic agonist. Moreover, Klf9 expression levels in human white adipose tissue (WAT) are inversely correlated with adiposity, and Klf9 overexpression in primary fat cells stimulates cellular thermogenesis, which is Ucp1-dependent. Fat-specific Klf9 transgenic mice gain less weight and have smaller fat pads due to increased thermogenesis of brown and beige fat. Moreover, Klf9 transgenic mice displayed lower fasting blood glucose levels, improved glucose tolerance and insulin sensitivity under the high-fat diet condition. Conversely, Klf9 mutation in brown adipocytes reduces the expression of thermogenic genes, causing a reduction in cellular respiration. Klf9-mutant mice exhibited obesity and cold sensitivity due to impairments in the thermogenic function of fat. Finally, fat Klf9 deletion inhibits the β3-agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, Cold-inducible Klf9 stimulates expression of PGC-1α, a master regulator of fat thermogenesis, by a direct binding to its gene promoter region, subsequently promoting energy expenditure. The present study reveals a critical role for Klf9 in mediating thermogenesis of brown and beige fat.

Funding

This work was supported by the National Key Research and Development Program of China (2018YFA0800601) and the National Natural Science Foundation of China (grants 81730024, 81825004, 81670749, 81471079) and Natural Science Foundation of NingXia (2020AAC03422).

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