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Interleukin-10 mediated immune cell-adipocyte crosstalk in adipose thermogenesis

Award Number: R01DK136035
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $618,621 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/16/2026	NON-COMPETING CONTINUATION	$618,621
														Subtotal = $618,621

Issue Date FY: 2025 ( Subtotal = $618,621 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/12/2025	NON-COMPETING CONTINUATION	$61,861
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$556,760
														Subtotal = $618,621

Issue Date FY: 2024 ( Subtotal = $618,621 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/30/2024	NEW	$618,621
														Subtotal = $618,621

Grand Total All Awards = $1,855,863

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Interleukin-10 mediated immune cell-adipocyte crosstalk in adipose thermogenesis

Award Number: R01DK136035

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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