Brown Adipocytes Secrete GDF15 in Response to Thermogenic Activation

Objective Transcriptomic analysis of gene expression in brown adipose tissue (BAT) from mice in response to cold revealed strong induction of growth and differentiation factor 15 (GDF15). This study aimed to characterize GDF15 as a brown adipokine released in response to thermogenic activation and to determine its target functions. Methods GDF15 expression was measured in adipose tissues from mice in response to physiological and pharmacological modulators of thermogenesis. Brown and beige cell cultures were used to dissect the mechanisms regulating GDF15 expression. Brown adipocyte cellular models of fibroblast growth factor 21 and beta-klotho invalidation were employed to identify the autocrine regulators of GDF15. RAW 264.7 macrophages were used to explore the targeting of GDF15 released by brown adipocytes. Results Cold exposure of mice strongly induced GDF15 expression in BAT. Norepinephrine and cyclic adenosine monophosphate induced GDF15 expression and release by cells through protein kinase A-mediated mechanisms. Noradrenergic regulation of GDF15 required the active fibroblast growth factor 21 pathway in brown adipocytes. GDF15 released by brown adipocytes targeted macrophages and downregulated the expression of proinflammatory genes. Conclusions GDF15 is a brown adipokine released by brown and beige cells in response to thermogenic activity. GDF15 released by BAT targets macrophages and may mediate downregulation of local inflammatory pathways.