Immune-adipocyte Crosstalk in Adipose-selective Thermogenic Program - Project Summary Immune cells are an integral part of the adipose microenvironment and have pronounced effects on the expansion and activation of thermogenic adipocytes, also known as beige/brite adipocytes. Anti-inflammatory factors are postulated to be beneficial for insulin resistance and diabetes. Our lab recently reported that ablation of interleukin-10 (IL10)-associated anti-inflammatory signaling in mice, surprisingly, improved insulin sensitivity and glucose tolerance, protected against diet-induced obesity, and elicited browning of white adipose tissue. My proposal builds upon comprehensive data to address the crosstalk between immune cells and adipocytes within adipose tissue depots in regulating adipose thermogenesis. Our published and pilot studies show that interfering with IL10 activity in adipocytes is associated with increased thermogenesis, mitochondrial respiration, and energy expenditure. Ablation of adipose T cells increased adipose thermogenesis, pointing to a hematopoietic origin of the IL-10 signal regulating adipose tissue function. The IL10 receptor alpha (IL10R) is highly expressed in mature adipocytes, and adipocyte-specific knockdown of IL10R decreases fat mass and increases adipose thermogenesis, energy expenditure, and lipolysis. Conversely, IL10 treatment directly antagonizes the expression of thermogenic and lipolytic genes in a cell-autonomous manner. Furthermore, genome-wide Assay for Transposase-Accessible Chromatin (ATAC)-seq, ChIP-seq, and RNA-seq demonstrated that IL-10 represses the transcription of thermogenic genes by altering chromatin configuration at key enhancer and promoter regions. Our findings identify the “IL10-IL10R axis” as a novel regulator of the thermogenic transcriptional program in adipose tissue and challenge conventional assumptions regarding links between immune and inflammatory signaling and adipose tissue function in obesity. To further test the hypothesis that adipose-specific IL10R directly “senses” IL10 in the microenvironment to limit adipose thermogenesis and promote obesity-related traits I propose three Specific Aims: i) to define the therapeutic potential of ablating IL10R in the adipocytes of adult obese mice; ii) to identify IL10 secreting immune cells, and iii) to determine the mechanism by which IL10 controls adipocyte thermogenic program. Immune cells are an integral part of the adipose microenvironment; thus, studying how IL10 modulates adipocyte regulatory processes should advance our knowledge beyond inflammation and anti-inflammation and inform future therapy for obesity and insulin resistance.
