Enhancing the development and thermogenesis in brown and beige fat represents a potential treatment for obesity. In the present study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impairs the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice display increased fasting blood glucose levels and hepatic steatosis on a chow diet. Foxj3 deficiency inhibits the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduces the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhances the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and inguinal WAT increases energy expenditure and improves systemic metabolism on either a chow diet or a high-fat diet. Finally, Foxj3 deletion in fat inhibits the β3 agonist–mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulates the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. The present study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24515020.

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