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Reprogramming metabolism to support alternative modes of adipocyte thermogenesis

Award Number: R56DK127175
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: 08/04/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Reprogramming metabolism to support alternative modes of adipocyte thermogenesis - Obesity remains one of the most pressing public health challenges of our time. While recent pharmacological advances, such as GLP-1 receptor agonists, have delivered unprecedented clinical benefits, they also underscore the need for complementary strategies that address the complex metabolic dysfunctions underlying obesity and related chronic metabolic diseases. One promising approach is to activate thermogenic brown and beige adipocytes to increase energy expenditure. However, translating this strategy to human obesity requires a deeper understanding of the metabolic pathways that fuel thermogenesis. Two fundamental and unresolved questions guide this proposal: (1) which circulating fuels are preferentially used by thermogenic adipocytes in vivo, and what are the bioenergetic consequences of shifting substrate use; and (2) whether uncoupled respiration through UCP1 is uniquely required for thermogenesis, or whether alternative, UCP1-independent pathways can provide comparable or even superior energy dissipation under certain physiological or pathological conditions. This proposal specifically aims to define the metabolic circuitry underlying UCP1-dependent versus UCP1-indepenent modes of thermogenesis in brown fat, focusing on their relative energetic efficiency and potential physiological trade-offs. Using unique innovative genetic models and in vivo metabolic tracing approaches developed by our team during the previous funding period, we will evaluate how fuel selection and mitochondrial function differ between these different modes of thermogenesis. In parallel, we will investigate how thermogenic adipocytes use glucose not simply as a fuel source, but as an essential substrate for anaplerotic input to the TCA cycle, which may be critical for sustaining key biosynthetic and energy-dissipating pathways. These studies will uncover new fundamental principles of thermogenic metabolism and identify mechanisms that can be leveraged to improve energy expenditure in metabolically unhealthy individuals. The new insights gained from this work have high relevance to combating obesity, aging, and chronic metabolic disease.


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 = $206,000 )
2026	2026	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	8/27/2026	COMPETING CONTINUATION	$206,000
														Subtotal = $206,000

Grand Total All Awards = $206,000

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Reprogramming metabolism to support alternative modes of adipocyte thermogenesis

Award Number: R56DK127175

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: 08/04/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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