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Post-translational control of adipose tissue remodeling and metabolic health

Award Number: R01DK127575
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: 09/14/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Post-translational control of adipose tissue remodeling and metabolic health - Adipose tissue remodeling, involving adipogenesis, lipogenesis, lipolysis, extracellular matrix (EM) remodeling, and thermogenesis, plays a central role in regulating energy homeostasis. A notable adaptive process within adipose tissues is the “browning” or “beiging” of white adipose tissue (WAT): enhanced brown/beige fat function is accompanied by a substantial improvement in metabolic health, including increased glucose tolerance and insulin sensitivity as well as reduced adipose tissue inflammation and fibrosis. Reciprocally, dysregulation in the processes is tightly associated with obesity and type 2 diabetes. As such, a better understanding of the brown/beige fat biogenesis continues to be a significant area of research in the field of metabolic disorders. The best-known stimuli of brown/beige fat biogenesis are cold and PPARγ: cold exposure via activation of β-adrenoceptor (β-AR) or chronic treatment with synthetic PPARγ ligands (e.g., thiazolidinediones) activate the brown/beige fat-selective genetic program. However, chronic activation of these pathways often causes multiple side effects, such as cardiovascular diseases. Thus, identifying alternative pathways that selectively stimulate brown/beige fat biogenesis, while avoiding the detrimental effects of the conventional pathways, may promise new approaches that improve metabolic health with minimal side effects. In this regard, our recent finding may offer a new opportunity: we identified a previously uncharacterized cell-intrinsic post-translational pathway that activates brown/beige fat biogenesis – e.g., enhanced mitochondrial biogenesis, fatty acid oxidation, thermogenesis, as well as reduced adipose tissue inflammation and fibrosis – without activating the canonical PPARγ transcription pathway. We found the first ubiquitin E3-ligase complex that controls the protein stability of PRDM16, a dominant transcriptional co-activator of the brown/beige fat gene program. Notably, inhibition of the ubiquitin E3-ligase complex is sufficient to activate the brown/beige fat program through extending the half-life of PRDM16 protein. Accordingly, this proposal aims to determine the post-translational mechanisms through which the newly identified E3-ligase complex for PRDM16 regulateswhole-body energy metabolism.


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: 2025 ( Subtotal = $516,250 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/18/2025	NON-COMPETING CONTINUATION	$516,250
														Subtotal = $516,250

Issue Date FY: 2024 ( Subtotal = $495,599 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/5/2024	NON-COMPETING CONTINUATION	$495,599
														Subtotal = $495,599

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $516,250 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/14/2022	NON-COMPETING CONTINUATION	$516,250
														Subtotal = $516,250

Issue Date FY: 2021 ( Subtotal = $516,250 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/19/2021	NON-COMPETING CONTINUATION	$516,250
														Subtotal = $516,250

Issue Date FY: 2020 ( Subtotal = $516,250 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/14/2020	NEW	$516,250
														Subtotal = $516,250

Grand Total All Awards = $2,560,599

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Post-translational control of adipose tissue remodeling and metabolic health

Award Number: R01DK127575

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: 09/14/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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