Growth and differentiation factor 15 (GDF15) is induced in brown adipocytes in response to thermogenic stimuli, as well as high-fat feeding in mice. However, whether brown adipose tissue (BAT) -derived GDF15 is required to regulate BAT thermogenesis or energy homeostasis is unclear. In the present study, we sought to test the hypothesis that BAT-derived GDF15 is necessary to mediate thermogenesis and systemic adaptations to diet-induced obesity (DIO) . We generated mice lacking GDF15 specifically in BAT by crossing Gdf15 floxed mice with mice harboring the Cre recombinase under the control of the Ucp1 promoter (GDF15 BAT KO) . GDF15 BAT KO mice were treated with the beta adrenoreceptor agonist CL316,243 (CL) for 5 days to induce thermogenesis, or fed a high-fat diet (60% fat content) for 12 weeks to induce DIO. CL treatment promoted a significant induction in Gdf15 mRNA levels in the BAT of WT mice, which, as expected, was prevented in KO mice. Nonetheless, serum GDF15 levels were similarly induced by CL in both WT and KO mice. CL-induced activation of thermogenic genes in BAT, such as Ucp1 and Dio2, was comparable between genotypes, and core body temperature was unchanged between WT and KO mice. After 12 weeks of high-fat feeding, KO mice had significantly increased body weight and fat mass relative to WT mice. However, food intake, locomotor activity and energy expenditure were unchanged between groups. Respiratory exchange ratio was significantly higher in KO mice, indicating a relative preference for carbohydrate as fuel. Although glucose tolerance was unchanged between genotypes, insulin sensitivity was impaired in KO mice. Taken together, our data indicates that BAT-derived GDF15 does not contribute to GDF15 circulating levels in response to CL treatment and is largely dispensable for CL-induced BAT thermogenesis. However, BAT-derived GDF15 seems to be required to regulate diet-induced weight gain and insulin sensitivity. Disclosure J.Jena: None. K.Kato: None. A.A.Marti: None. R.Pereira: None. Funding NIHDK125405