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Histone methyltransferase SUV420H2 regulates brown/beige adipocyte thermogenesis and energy homeostasis

Award Number: R01DK107544
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): Obesity is now considered as an epidemic problem, which is associated with a panel of metabolic disorders, including insulin resistance/type 2 diabetes, dyslipidemia and cardiovascular diseases. While white adipose tissue (WAT) is involved in energy storage, that of brown adipose tissue (BAT) is to dissipate energy as heat due to the unique expression of uncoupling protein 1 (UCP1). In rodents, there exist two types of brown adipocytes. Traditional brown adipocytes are located in discrete areas; whereas "inducible" beige adipocytes are dispersed in WAT, and can be induced by cold exposure or ß3-adrenergic receptor activation. Activation of brown/beige adipocyte thermogenic function alleviates obesity and its associated metabolic diseases. Recent discovery of functional brown and beige adipocytes in humans suggest that increasing brown/beige cell function may be a novel approach in treating obesity. Epigenetic mechanisms play an important role in the regulation of complex diseases, including obesity. Suppressor of variegation 4-20 homolog 2 (Drosophila) (SUV420H2) is a histone methyltransferase that is important for the tri-methylation at histone H4 lysine 20 (H4K20). Our preliminary data suggest that SUV420H2 is important in the regulation of brown and beige adipocyte development. SUV420H2 expression parallels that of UCP1 expression in brown and beige adipocytes; knocking down of SUV420H2 significantly reduces, whereas overexpressing SUV420H2 significantly increases UCP1 levels. Therefore, we hypothesize that the histone H4K20 methyltransferase SUV420H2 is important in the regulation of brown and beige adipocyte development, and further regulates energy homeostasis in animal models. We will use brown/beige adipocyte specific SUV420H2 deficient mice and adipocyte-specific SUV420H2 transgenic mice to address the following specific aims. In Aim 1, we will test the importance of adipocyte SUV420H2 in the regulation of cold- and diet-induced brown and beige adipocyte thermogenesis. We will test: 1) whether brown/beige adipocyte-deletion of SUV420H2 impairs, whereas adipocyte-specific overexpression of SUV420H2 enhances brown and beige adipocyte thermogenesis during cold exposure; and 2) whether mice with brown/beige adipocyte-deletion of SUV420H2 are prone to; whereas mice with adipocyte-specific overexpression of SUV420H2 are resistant to high fat diet-induced obesity. In Aim 2, we will test the importance of SUV420H2-mediated H4K20 trimethylation at 4E-BP1 promoter in the regulation of PGC1a protein translation and SUV420H2-regulated brown/beige adipocyte thermogenesis. In Aim 3, we will test SUV420H2/H4K20me3-targeted cellular and molecular pathways in brown/beige adipocytes during cold exposure and in diet-induced thermogenesis using a combination of H4K20me3 ChIP-Seq and RNA-Seq approaches.


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: 2021 ( Subtotal = $0 )
2021	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $340,913 )
2019	2019	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/23/2019	NON-COMPETING CONTINUATION	$340,913
														Subtotal = $340,913

Issue Date FY: 2018 ( Subtotal = $340,913 )
2018	2018	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/25/2018	NON-COMPETING CONTINUATION	$34,092
2018	2018	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/17/2018	NON-COMPETING CONTINUATION	$306,821
														Subtotal = $340,913

Issue Date FY: 2017 ( Subtotal = $346,601 )
2017	2017	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE SE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/25/2017	NON-COMPETING CONTINUATION	$311,940
2017	2017	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/15/2017	NON-COMPETING CONTINUATION	$34,661
														Subtotal = $346,601

Issue Date FY: 2016 ( Subtotal = $345,859 )
2016	2016	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	33 GILMER STREET SOUTHEAST	ATLANTA	GA	30303	FULTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/11/2016	NEW	$345,859
														Subtotal = $345,859

Grand Total All Awards = $1,374,286

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Histone methyltransferase SUV420H2 regulates brown/beige adipocyte thermogenesis and energy homeostasis

Award Number: R01DK107544

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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