Cold-Inducible Klf9 Regulates Thermogenesis of Brown and Beige Fat.

Promoting development and function of brownand beige fat may represent an attractive treatment of obesity. In the presentstudy, we show that fat Klf9 expression ismarkedly induced by cold exposure and a β-adrenergicagonist. Moreover, Klf9 expression levels in human white adipose tissue (WAT)are inversely correlated with adiposity, and Klf9 overexpression inprimary fat cells stimulates cellular thermogenesis, which is Ucp1-dependent. Fat-specific Klf9 transgenic mice gainless weight and have smaller fat pads due to increased thermogenesis of brownand beige fat. Moreover, Klf9 transgenic mice displayed lower fasting bloodglucose levels, improved glucose tolerance and insulin sensitivity under thehigh-fat diet condition. Conversely, Klf9 mutation in brown adipocytes reduces the expressionof thermogenic genes, causing a reduction in cellular respiration. Klf9-mutantmice exhibited obesity and cold sensitivity due to impairments in thethermogenic function of fat. Finally, fat Klf9 deletion inhibits the β3-agonist-mediatedinduction of WAT browning andbrownadipose tissue thermogenesis. Mechanistically, Cold-inducible Klf9 stimulates expression of PGC-1α,a master regulator of fat thermogenesis, by a direct binding to its genepromoter region, subsequently promoting energy expenditure. The present studyreveals a critical role for Klf9 in mediating thermogenesis of brown and beigefat.