Enhancing the development of and thermogenesis in brown and beige fat represents a potential treatment for obesity. In this study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impaired the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice displayed increased fasting blood glucose levels and hepatic steatosis while on a chow diet. Foxj3 deficiency inhibited the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduced 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 enhanced the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and iWAT increased energy expenditure and improved systemic metabolism on either a chow or high-fat diet. Finally, Foxj3 deletion in fat inhibited the β3-agonist–mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulated the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. This 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.

Article Highlights
  • Foxj3 is highly induced in brown adipose tissue and inguinal white adipose tissue of wild-type mice in response to cold exposure or β3-adrenergic agonist CL316,243 treatment and is dysregulated in db/db and high-fat diet–induced obese mice.

  • Adipose-specific Foxj3 knockout mice displayed obesity and a fatty liver phenotype on a chow diet; Foxj3 deficiency reduced brown fat thermogenesis.

  • Adeno-associated virus–mediated Foxj3 overexpression in fat increased energy expenditure and improved systemic metabolism on either a chow diet or high-fat diet.

  • Mechanistically, cold-inducible Foxj3 directly binds to and activates the promoter of PGC-1α and UCP1, thereby promoting energy expenditure.

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

J.H., Yu.Z., and X.Zho. contributed equally to this work.

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