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Deciphering the Function of the CCL22-CCR4 Axis in Adipose Beiging and Obesity

Award Number: R01DK144044
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: 08/24/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Deciphering the Function of the CCL22-CCR4 Axis in Adipose Beiging and Obesity - Abstract: Obesity occurs when energy intake exceeds energy expenditure. Unlike white adipocytes, beige adipocytes within inguinal white adipose tissue (iWAT) are recruited thermogenic fat cells that have great anti-obesity and anti-diabetes potential. In both rodents and humans, beige adipocytes can be generated from tissue-residing perivascular beige adipocyte progenitor cells (APCs) in response to cold temperatures. However, the number of beige adipocytes found in WAT declines with aging and obesity, concomitant with loss of their energy-expending capacity. We have data to support the notion that one of the mechanisms accounting for this beige loss is a result of dysfunctional immunological niche signals that control beige APCs for adipose beiging and thermogenesis. Utilizing our fate mapping and genetic mouse model, we have developed various genetic tools for tracing and manipulating the beige lineage, placing us in a unique position to characterize the biological properties of APCs and their interactions with the immunological niche. Among these various niche signals, we find a critical role of local macrophage-derived chemokine CCL22 and its receptor CCR4 in facilitating beige APCs to generate beige adipocytes and maintain energy homeostasis. Specifically, injection of CCL22 into iWAT is sufficient to promote its beiging, and conversely, CCL22 neutralizing antibody treatment can block iWAT beiging. Mechanistically, CCL22 receptor CCR4 in eosinophils is required for CCL22-induced beige formation. Moreover, inguinal lymph node (iLNs) removal impairs beiging in the surrounding area, which can be fully restored by injecting CCL22 or its main cellular source, macrophages, into iWAT. Lastly, both mouse and human serum CCL22 levels are inversely correlated with body weight and fat mass, suggesting a potential role for CCL22 in preventing the development of obesity. These observations lead us to hypothesize that the CCL22- CCR4 axis acts downstream of iLNs to ensure cold-induced APC beiging by recruiting macrophages and eosinophils, thereby promoting energy expenditure and mitigating the development of obesity and related metabolic disorders. In this application, our overall objectives are to identify the cellular source and role of CCL22 (AIM 1), the cellular targets of its action (AIM 2), and to establish the role of LN-derived factors in adipose function, with a specific focus on the mechanisms driving CCL22 activation and APC beiging (AIM 3). Results from this project will pinpoint new biological pathways, including macrophage-derived chemokine CCL22, its receptor CCR4 in eosinophils and APCs, and the upstream influence of lymph nodes in the differentiation of APCs into beige adipocytes, as well as their role in maintaining whole-body energy balance and obesity prevention.


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 = $777,090 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/24/2026	NEW	$777,090
														Subtotal = $777,090

Grand Total All Awards = $777,090

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Deciphering the Function of the CCL22-CCR4 Axis in Adipose Beiging and Obesity

Award Number: R01DK144044

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: 08/24/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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