Transcriptomic profiling of adipocytes in response to cold reveals unique properties of Cxcl12 as a brown adipocyte secreted chemokine

Beyond its thermogenic potential, brown adipose tissue (BAT) performs important endocrine functions that regulate metabolism. However, the BAT microenvironment and the factors involved in BAT homeostasis and adaptation to cold remain poorly characterized. We therefore aimed to study secreted factors from active brown adipocytes that may be involved in adipocyte function and/or may orchestrate inter-cellular communications. For this, mRNA levels in mature adipocytes of brown, beige and white adipose depots from mice exposed to 21 days of cold were evaluated using RNA sequencing, and bioinformatic analysis was used to predict for potentially secreted factors. Cxcl12 was found to be the most cold-induced C-X-C chemokine in BAT, and Cxcl12 mRNA expression analysis by qPCR and fluorescence in-situ hybridization revealed its enrichment in brown adipocytes upon cold. Cold increased CXCL12 secretion from BAT, yet its level in plasma remained unchanged indicating a potential local action. Cxcl12 knockdown in mature brown adipocytes impaired thermogenesis, estimated by norepinephrine (NE)-induced Ucp1 gene expression, glycerol release and mitochondrial respiration despite unaltered β-adrenergic signaling, suggesting Cxcl12 regulates adipocyte function independently from the β-adrenergic pathway. Importantly, unaltered adipocyte characteristics upon Cxcl12 loss may indicate CXCL12 primarily regulates the NE-induced adipocyte activation. Furthermore, CXCL12 might exert inter-cellular crosstalk via its capacity to promote macrophage chemotaxis and neurite outgrowth. Here we present CXCL12 as a novel brown adipocyte, cold-induced secreted factor involved in adipocyte function and inter-cellular crosstalk within BAT.