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Weight-cycling exacerbates obesity-induced inflammation through the reprogramming of hematopoietic stem and progenitor cells

Award Number: F31DK146719
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Weight-cycling exacerbates obesity-induced inflammation through the reprogramming of hematopoietic stem and progenitor cells - PROJECT SUMMARY Inflammation is a major culprit of obesity comorbidities including diabetes, cardiovascular disease, and infections, all of which are leading causes of death worldwide. Over 40% of adults in the United States are obese. The most common and effective treatment to alleviate obesity-related inflammation is weight loss. However, weight loss is difficult to maintain and over 60% of adults regain their weight, a process termed weight cycling (WC). WC has been associated with exacerbated inflammation and a greater risk of developing obesity complications such as diabetes and cardiovascular disease, compared to never losing weight, however, the mechanisms remain unknown. The proposed work aims to interrogate the origin of exacerbated inflammation during weight cycling to provide a novel mechanistic basis that can be used to treat obesity-induced inflammation, thus addressing a critical public need and adding fundamental knowledge about metabolic regulation of immunity. Hematopoietic stem and progenitor cells (HSPCs) are critical for the lifelong production of all blood cells. Their ability to self-renew, differentiate into all blood cells, and respond to pathogenic stimuli, places them as major determinants of immune responses. HSPCs are also known to harbor trained immunity, which results in the enhanced inflammatory and metabolic activity of progeny from HSPCs to non-specific stimuli. Studies from our lab show that WC promotes inflammation in a cardiovascular disease mouse model via the transfer of HSPCs that have been exposed to a WC environment. This indicates that WC may induce trained immunity. My preliminary data show that WC increases HSPC frequencies compares to stable-obese mice, illustrating HSPCs are being activated by WC. Additionally, challenging WC mice with stimuli to induce systemic inflammation results in a greater amounts of inflammatory myeloid cells within the bone marrow compared to stable-obesity. Lastly, ex vivo stimulation of mature immune cells from WC bone marrow and adipose tissue result in greater pro-inflammatory gene expression compared to stable-obese cells. The results of my data have led to my central hypothesis that weight cycling reprograms immune progenitors via epigenetic and metabolic changes to produce more myeloid progeny with greater inflammatory potential. To test my central hypothesis I have developed two specific aims: 1) Test the hypothesis that WC promotes myelopoiesis via metabolic alterations and, 2) Identify the mechanisms underlying the heightened inflammatory phenotype of myeloid progeny in WC. This project will uncover mechanisms driving increased inflammation during weight cycling that can be targeted to alleviate obesity-related inflammation. Furthermore, this project will train a highly motivated graduate student with the necessary skills to become an independent investigator and expert in the field of immunometabolism.


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 = $49,538 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/13/2026	NEW	$49,538
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/13/2026	NEW	$0
														Subtotal = $49,538

Grand Total All Awards = $49,538

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Weight-cycling exacerbates obesity-induced inflammation through the reprogramming of hematopoietic stem and progenitor cells

Award Number: F31DK146719

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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