Brown Adipocytes Secrete GDF15 in Response to Thermogenic Activation

Abstract

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 β‐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.

New insights into the secretory functions of brown adipose tissue

“…It has been reported that brown adipocytes are able to dampen the inflammatory responses in macrophages (Dowal et al 2017). We have confirmed that the conditioned medium from brown adipocyte cultures represses the pro-inflammatory activity of M1-activated macrophages (Cereijo et al 2018, Campderros et al 2019. However, identifying the molecular actors involved in the signalling from brown/ beige adipocyte to immune cells has unveiled a complex scenario.…”

“…Recently, GDF15 has been reported to exert anorexigenic effects through its action at the brainstem and to contribute towards controlling the energy balance (Breit et al 2017. GDF15 is intensely secreted by brown fat upon exposure to cold conditions and by brown adipocytes after noradrenergic stimulation (Verdeguer et al 2015, Campderros et al 2019 and exerts mostly autocrine effects on macrophages, tuning down their pro-inflammatory responses (Campderros et al 2019). Whether these signalling capacities of brown adipokines towards immune cells are restricted to the local cross-talk between immune cells and adipocytes at adipose depots or have consequences on the systemic immune status of the organism are challenging possibilities that remain to be ascertained in further researches.…”

Expression and Secretion of an Atrial Natriuretic Peptide in Beige-Like 3T3-L1 Adipocytes

“…Brown adipose tissue also secretes hormones called batokines. Several researchers have studied the hormones released when adipose tissues are browned [11,[25][26][27][28]. For example, fibroblast growth factor 21 (FGF21) is a secreted factor induced by noradrenergic cAMP-mediated mechanisms in brown adipocytes [26].…”

“…FGF21 increases the expression of PGC-1α and UCP1 in adipocytes and promotes thermogenesis [11]. In addition, growth and differentiation factor 15 (GDF15) is secreted from brown and beige adipocytes that undergo noradrenergic, cAMP-mediated thermogenic activation [27]. This targets macrophages and downregulates the expression of proinflammatory genes.…”

“…This targets macrophages and downregulates the expression of proinflammatory genes. The treatment of FGF21 with brown adipocytes increases GDF15 secretion [27]. In humans, interleukin-6 (IL-6) is secreted from beige adipocytes more than white adipocytes [28].…”