Gdf15 expression in thermogenic adipocytes regulates diet-induced weight gain in a sex-dependent manner

Abstract Background Growth differentiation factor 15 (GDF15) is a stress-induced cytokine known to bind to its endogenous receptor GDNF-family α-like (GFRAL) in the hindbrain, thereby modulating energy homeostasis. In response to prolonged high-fat diet (HFD) feeding, Gdf15 expression is induced in various tissues, including liver and brown adipose tissue (BAT), leading to increased GDF15 serum levels. Although the liver is the primary source of circulating GDF15 during diet-induced obesity (DIO), other tissues are also required. We investigated whether BAT contributes to GDF15 circulating levels and if GDF15 induction in BAT regulates systemic metabolism during DIO. Methods We generated mice with selective Gdf15 deletion in thermogenic adipocytes (KO) and subjected them to 12 weeks of HFD feeding to determine the role of BAT-derived GDF15 on systemic metabolic homeostasis in both male and female mice. Results Unexpectedely, despite no changes in GDF15 serum levels in mice fed ad-libitum regardless of sex or genotype, female KO mice were resistant to DIO, had increased energy expenditure and improved mitochondrial fatty acid oxidation in BAT, which was prevented by ovariectomy. Conversely, male KO mice had increased body weight and adiposity upon HFD feeding, along with reduced respiratory capacity in BAT mitchondria, and increased markers of fibro-inflammation. Conclusions Together, our data reveal GDF15 induction in BAT is required to regulate weight gain in mice in a sex-dependent manner. Our results also suggest female sex hormones contribute to increase energy expenditure in female KO mice promoting leanness. Our study underscore the importance of rigorously addressing sex differences in GDF15 biology and pharmacology and suggests GDF15 might exert effects on energy balance and adiposity that are independent of signaling through GFRAL.