GDF15 Expression in Thermogenic Adipocytes Regulates Energy Homeostasis in a Sex-dependent Manner

Diet-induced obesity (DIO) induces growth differentiation factor 15 (GDF15) in various tissues, leading to increased GDF15 serum levels. The liver is the primary source of circulating GDF15 during DIO, but other tissues are also required. We investigated whether brown adipose tissue (BAT) contributes to GDF15 circulating levels and whether Gdf15 induction in BAT regulates systemic metabolism during DIO. We generated mice with selective Gdf15 deletion in thermogenic adipocytes (KO) and subjected them to 12 weeks of high-fat diet (HFD) feeding. Although in ad-libitum fed conditions GDF15 serum levels were unchanged between genotypes regardless of sex, female KO mice demonstrated reduced food intake, increased mitochondrial fatty acid oxidation in BAT, and were resistant to DIO, which was prevented by ovariectomy. Conversely, male KO mice demonstrated increased food intake, reduced mitochondrial respiratory capacity, and increased fibro-inflammation in BAT, resulting in increased body weight and fat mass accrual. Together, our data show that Gdf15 expression in BAT is required to regulate energy metabolism in mice in a sex-dependent manner.