# Interleukin-10 Signaling in Adipose Tissue Thermogenesis and Energy expenditure

> **NIH NIH R00** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $248,145

## Abstract

PROJECT DESCRIPTION
 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 man...

## Key facts

- **NIH application ID:** 9996685
- **Project number:** 5R00DK114571-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Prashant Rajbhandari
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,145
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996685

## Citation

> US National Institutes of Health, RePORTER application 9996685, Interleukin-10 Signaling in Adipose Tissue Thermogenesis and Energy expenditure (5R00DK114571-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996685. Licensed CC0.

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