Cell types of the immune system residing within adipose tissue have been postulated to act as critical regulators of metabolic homeostasis. Obesity-induced chronic inflammation in adipose tissue is associated with metabolic abnormalities. It has therefore been widely assumed that anti-inflammatory factors are beneficial in areas of insulin resistance and diabetes. Unexpectedly, we find that ablation of interleukin-10 (IL-10) anti- inflammatory signaling in mice improves insulin sensitivity and glucose tolerance, protects against diet-induced obesity, and elicits browning of white adipose tissue. This phenotype is associated with increased mitochondrial respiration and energy expenditure despite increased food consumption. Reconstitution of wild-type bone marrow into IL-10 knockout mice reversed the thermogenic phenotype, pointing to a hematopoietic origin of the IL-10 signal regulating adipose tissue function. IL-10 receptor (IL10R?) is highly expressed in mature adipocytes and iWAT-specific acute knockdown of IL10R? using antisense oligonucleotide decreases fat mass and increases thermogenesis. IL-10 treatment directly antagonizes the expression of thermogenic genes in a cell autonomous manner. Furthermore, genome-wide Assay for Transposase-Accessible Chromatin (ATAC)-seq and RNA-seq demonstrated that IL-10 represses the transcription of thermogenic genes by altering chromatin configuration at key enhancer and promoter regions. These findings identify IL-10 axis as a novel regulator of a thermogenic transcriptional program in adipose tissue and challenge the conventional assumptions regarding the links between immune and inflammatory signaling and adipose tissue function in the setting of obesity. To further test the hypothesis that adipose-specific IL10R? directly senses IL-10 in the microenvironment to limit adipose thermogenesis, I have proposed two interrelated aims to examine i) metabolic consequences of adipocyte-specific ablation of IL10R? in mice, and ii) mechanisms underlying IL-10 inhibition of thermogenic gene transcription in vitro and in vivo. The proposal details a five-year integrated plan consisting of a two-year of mentored training program (K99 Phase) followed by a three-year independent program (R00 Phase) for my development into an independent academic science research career. I have significant experience studying immune-adipose interaction and metabolic diseases and plan to extend my scientific training in genome-wide sequencing and data analysis during the mentored phase. I will achieve my project goals with mentorship from my advisor, Dr. Peter Tontonoz, an internationally recognized expert in lipid metabolism, and Drs. Stephen Smale, Karen Reue, and Orian Shirihai who will serve as my key advisors to provide relevant scientific mentorship and career guidance. Overall, the proposal is designed to advance my training in key scientific areas, develop critical skills (grant-writing, presentation, lab management, and others) to become a well-rounded scientific investigator, and foster my transition to an independent faculty position where I will setup an interdisciplinary research program focused on mechanisms of obesity and metabolic disorders.
Pathological increase in white adiposity is associated with type 2 diabetes and cardiovascular diseases whereas brown adipose tissue has potential anti-obesity properties. White adipose tissue has an inherent plasticity to turn on brown gene program to increase energy expenditure. Therefore, understanding the biological program contributing to distinct adipose phenotype might have therapeutic potential to combat obesity, insulin resistance, and heart diseases.
|Seldin, Marcus M; Koplev, Simon; Rajbhandari, Prashant et al. (2018) A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism. Cell Metab 27:1138-1155.e6|