Abstract Body (Do not enter title and authors here): Introduction/Background: Brown adipose tissue (BAT) can exert beneficial cardiometabolic effects via the secretion of endocrine factors known as batokines. One such batokine is growth differentiation factor-15 (GDF15), a stress response cytokine known to regulate energy homeostasis, and recently suggested to be cardioprotective. GDF15 exerts its actions on energy balance through its only validated receptor, GDNF family receptor α–like (GFRAL) located in the hindbrain, but whether GFRAL is required for cardioprotection has not been tested. Noteworthy, our preliminary data showed that in response to myocardial infarction (MI), GDF15 levels are induced in BAT and in the serum of wild type (MI) mice.

Research Questions/Hypothesis: The present study tested the hypothesis that BAT-derived GDF15 is required to promote cardioprotection and to improve survival following MI via GFRAL-mediated mechanisms.

Methods/Approach: To test our hypothesis, we generated mice lacking GDF15 in thermogenic adipocytes (KO) by crossing Gdf15 floxed mice with mice harboring the Cre recombinase under the control the Ucp1 promoter (Gdf15^BKO). We also used Gfral global KO (Gfral^-/-) and their WT littermate controls. Ten to twelve-week-old male Gdf15^BKO, Gfral^-/- and their respective WT littermate controls were subjected to MI or sham surgeries. GDF15 circulating levels, markers of inflammation and fibrosis, systolic function, and post-MI survival were assessed.

Results: Gdf15 deletion in BAT significantly lowered GDF15 serum levels after MI, whereas GDF15 serum levels remained elevated in Gfral^-/- after MI. Strikingly, Gdf15^BKO mice had reduced post-MI survival, whereas Gfral^-/- mice had similar survival rates as their WT controls. Contractile function and infarct size remained similar between Gdf15^BKO, Gfral^-/- and their respective WT controls. Interestingly, markers of inflammation and fibrosis were exacerbated in Gdf15^BKO relative to their WT controls, but were unchanged between Gfral^-/- and their WT control mice 3 days following MI.

Conclusions: BAT secreted GDF15 is required for cardioprotection and improves post-MI survival. Importantly, GDF15 signaling through Gfral is likely dispensable to promote these cardioprotective properties.