Cold-Inducible Klf9 Regulates Thermogenesis of Brown and Beige Fat

Abstract

Promoting development and function of brown and beige fat may represent an attractive treatment of obesity. In the current study, we show that fat <i>Klf9</i> expression is markedly induced by cold exposure and a β-adrenergic agonist. Moreover, <i>Klf9</i> expression levels in human white adipose tissue (WAT) are inversely correlated with adiposity, and <i>Klf9</i> overexpression in primary fat cells stimulates cellular thermogenesis, which is <i>Ucp1</i> dependent. Fat-specific <i>Klf9</i> transgenic mice gain less weight and have smaller fat pads due to increased thermogenesis of brown and beige fat. Moreover, <i>Klf9</i> transgenic mice displayed lower fasting blood glucose levels and improved glucose tolerance and insulin sensitivity under the high-fat diet condition. Conversely, <i>Klf9</i> mutation in brown adipocytes reduces the expression of thermogenic genes, causing a reduction in cellular respiration. <i>Klf9</i>-mutant mice exhibited obesity and cold sensitivity due to impairments in the thermogenic function of fat. Finally, fat <i>Klf9</i> deletion inhibits the β3 agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible <i>Klf9</i> stimulates expression of Pgc1α, a master regulator of fat thermogenesis, by a direct binding to its gene promoter region, subsequently promoting energy expenditure. The current study reveals a critical role for KLF9 in mediating thermogenesis of brown and beige fat.