IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure [ChIP-Seq]. IL-10 signaling remodels adipose chromatin architecture to limit thermogenesis and energy expenditure [ChIP-Seq]

Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the physiologic limiters of energy expenditure are largely unknown. Here we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and mature adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to cold, obesity and aging. ATAC-seq and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and PGC-1alpha recruitment to key enhancer regions. These findings identify the IL-10 axis as a critical and potentially targetable regulator of thermogenesis, and expand our understanding of the links between inflammatory signaling and adipose tissue function in the setting of obesity. Overall design: D5 differentiated cells treated with and without IL10. Input served as a control for C/EBPβ enrichment. ChIP-Seq libraries were prepared using the Kapa LTP Library Preparation Kit (Kapa Biosystems). ChIP-Seq was performed as described (Tong et al., 2016).