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 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 and 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 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.

Glucocorticoid-Responsive Transcription Factor Krüppel-Like Factor 9 Regulates fkbp5 and Metabolism

“…While our gene expression results suggest that loss of klf9 function produces a metabolic shift toward glycolysis, those results were obtained in 5 dpf larvae, and may not be directly relatable to the differences in OCR observed at 1 dpf, given the significant development that occurs between 1 and 5 dpf. Our results are nonetheless consistent with evidence of cell autonomous metabolic regulation in mice, where over-expression of klf9 increased oxygen consumption and the number of mitochondria in cultured adipocytes (Fan et al, 2020). Similarly, elimination of fkbp5 elevates resting metabolic rate while protecting against obesity and increasing glucose tolerance (Balsevich et al, 2017).…”

Glycerol Monocaprylate Modulates Gut Microbiota and Increases Short-Chain Fatty Acids Production without Adverse Effects on Metabolism and Inflammation

“…Moreover, PRDM16, which is a transcriptional regulator in the differentiation of brown adipocyte, had a significantly higher expression in the 1600 mg kg −1 GMC group [ 35 ]. Meanwhile, UCP1, the regulatory gene of BAT-thermogenesis, also had a slightly increased level in the high-dose GMC treatment group [ 36 ]. These data indicate that 1600 mg kg −1 GMC may have a positive effect on stimulating the differentiation and thermogenesis of brown fat.…”

Thermogenic Fat: Development, Physiological Function, and Therapeutic Potential

“…Krüppel-like factor 9 (Klf9) in vitro and in vivo in mice regulates the cold-induced browning of WAT and thermogenic function of AT through enhancing the Pgc1α expression [ 113 ].…”