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Elucidating Novel Regulations of Energy Metabolism by GLP-1 Receptor Agonism

Award Number: R56DK148870
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Elucidating Novel Regulations of Energy Metabolism by GLP-1 Receptor Agonism - ABSTRACT Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide and semaglutide, have revolutionized the treatment of diabetes and obesity, due to their functions on insulin secretion and appetite suppression. However, these drugs exhibit effects beyond these known mechanisms, notably in cardiovascular disease, fatty liver disease, and neurodegenerative conditions. The underlying regulatory and metabolic pathways responsible for these effects remain unclear, demonstrating important knowledge gaps in our understanding of what these drugs are doing to our body. There is a critical need to fill this gap given the widespread and growing use of GLP-1 receptor agonists. Our preliminary studies have revealed novel metabolic actions of GLP-1 receptor agonism that are independent of insulin levels or body weight loss. In fasted mice treated with a single dose of liraglutide, we observed a ~50% reduction in circulating glucose and a ~30% increase in the ketone body 3-hydroxybutyrate (3-HB) without changes in insulin levels or food intake. These findings point to unknown regulatory mechanisms of glucose and lipid metabolism mediated by GLP-1 receptor activation. The overall objective of this proposal is to elucidate the novel metabolic actions of GLP-1 receptor agonism on systemic glucose and lipid metabolism. We hypothesize that GLP-1 receptor agonists regulate hepatic ketogenesis and brown adipose tissue (BAT) glucose uptake via central nervous system (CNS) pathways. In this project, we will start testing the hypothesis through two specific aims. Aim 1 will focus on flux studies and determine the acute GLP-1 receptor agonism on utilization of glucose and production of 3-HB. Aim 2 will focus on mechanistic tests and determine the role of BAT and CNS in regulating glucose consumption flux upon acute GLP-1 receptor agonism. The results will serve as critical tests on our central hypothesis and move us closer to identifying the causes of decreased glucose levels and elevated 3-HB levels under acute GLP-1 receptor agonism, which is important as it can potentially lead to new therapies that mimic the acute metabolic effects of GLP-1 receptor agonism.


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 = $456,000 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/21/2026	NEW	$456,000
														Subtotal = $456,000

Grand Total All Awards = $456,000

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Elucidating Novel Regulations of Energy Metabolism by GLP-1 Receptor Agonism

Award Number: R56DK148870

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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