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Elucidating the Transcriptional Brakes on Adipocyte Thermogenesis

Award Number: F30DK136168
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: 04/06/2023
PERIOD OF PERFORMANCE END DATE: 04/05/2028

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Elucidating the Transcriptional Brakes on Adipocyte Thermogenesis - PROJECT ABSTRACT/SUMMARY The ability of brown adipose tissue (BAT) to expend energy through a process called adaptive thermogenesis makes it an attractive target for intervention in obesity; however, the observation that BAT mass diminishes in human obesity raises concerns about its ability to clinically impact body weight when fully activated. Energy-storing white adipose tissue (WAT) can also adopt a “brown-like” thermogenic phenotype; however, there are potent molecular brakes on thermogenic gene program in white adipocytes that help maintain its energy- storing phenotype. Since WAT is present in far greater mass than BAT, activation of the thermogenic gene program in white adipocytes may be a more viable strategy for intervention in obesity; however, the mechanisms controlling the establishment and maintenance of the energy-burning vs. energy-storing adipocyte lineages remain undefined. ZFP423, a member of the C2H2 family of zinc finger proteins, is a physiologically regulated transcription factor that functions to maintain the energy-storing white adipocyte phenotype by suppressing the thermogenic gene program characteristic of brown/beige fat cells. ZFP423 physically interacts with the brown adipocyte determination factor, EBF2, in white adipocytes to prevent EBF2-dependent chromatin remodeling and PPARg occupancy at key thermogenic genes. The experiments that I propose to conduct as part of my PhD training in the Duke University Medical Scientist Training Program will utilize advanced approaches in biochemistry, molecular biology, and mouse genetics. This work, conducted under the mentorship of Dr. Rana Gupta at the Duke Molecular Physiology Institute, is designed to 1) address the hypothesis that the ability of ZFP423 to directly recruit the NuRD complex to EBF2 is essential for its ability to suppress thermogenesis in white adipocytes (Aim1), and 2) test the hypothesis that genetic disruption of the ZFP423-EBF complex in mice is sufficient to permit thermogenic WAT remodeling and prevent the development of obesity and metabolic dysfunction. The overall goal of my proposed research is to further define the critical protein-protein interactions leading to the suppression of the thermogenic gene program by ZFP423 in white adipocytes. Successful completion of this work will highlight the importance of transcriptional “brakes” on thermogenic gene expression in adipocytes and may suggest a strategy to unlock the thermogenic capacity of WAT to promote weight loss and/or improve nutrient homeostasis.


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 = $55,114 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/1/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/30/2025	NON-COMPETING CONTINUATION	$564
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/2/2025	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/21/2024	NON-COMPETING CONTINUATION	$52,694
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/8/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/18/2023	NEW	$0
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/6/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $216,320

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Elucidating the Transcriptional Brakes on Adipocyte Thermogenesis

Award Number: F30DK136168

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: 04/06/2023

PERIOD OF PERFORMANCE END DATE: 04/05/2028

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