Thursday, May 29, 2025
5/29/2025
Interleukin-10 mediated immune cell-adipocyte crosstalk in adipose thermogenesis - Project Description Immune cells are an integral part of the white adipose tissue 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. We 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. Yet, several questions remain about the mechanisms that mediate the metabolic actions of IL10: i) how does IL10 block adipose thermogenesis? ii) what are the fates of adipocytes deficient in IL10 signaling? and, iii) since IL10 is produced by multiple immune cell types, which adipose-resident immune cell is responsible for IL10 production? Our proposal builds upon our comprehensive data to address the crosstalk between immune cells and adipocytes within adipose tissue depots in regulating systemic metabolism and adipose thermogenesis. Our published and pilot studies show that interfering with IL10 activity in adipocytes is associated with increased mitochondrial respiration and energy expenditure. Reconstitution of wild-type bone marrow into IL10 knockout mice reversed the thermogenic phenotype. 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 (IL10Ra) is highly expressed in mature adipocytes, and adipocyte-specific knockdown of IL10Ra decreases fat mass and increases adipose thermogenesis and energy expenditure. Conversely, IL10 treatment directly antagonizes the expression of thermogenic 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 through STAT3. Our findings identify the “IL10-IL10Ra-STAT3 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 adipocyte-specific IL10Ra directly “senses” IL10 in the microenvironment to limit adipose thermogenesis and energy expenditure, I propose three Specific Aims to define: i) mechanisms underlying IL10 inhibition of thermogenic gene transcription and beige adipocyte formation; ii) the fates of adipocytes in the presence and absence of IL10Ra, and iii) adipose resident immune cells responsible for anti-thermogenic activities.
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