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Molecular mechanisms mediating metabolic benefits of glucagon-like peptide-1 receptor agonists

Award Number: R01DK132852
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: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Molecular mechanisms mediating metabolic benefits of glucagon-like peptide-1 receptor agonists - PROJECT SUMMARY Although the ability of glucagon-like peptide-1 receptor (Glp1r) agonists to stimulate insulin secretion and reduce caloric intake has been recognized for over two decades, surprisingly little is known about the molecular mechanisms behind these effects. We have previously shown that activation of the hypothalamic Glp1r reduces food intake by engaging key nutrient sensing mechanisms such as mechanistic Target of Rapamycin Complex-1 (mTORC1). Since mTORC1 is also an important regulatory component of -cell function, this suggests that elucidating how Glp1r agonists regulate mTORC1 and its downstream targets will address a key knowledge gap about the mechanism of action of an important class of diabetes and obesity drugs. We have identified a novel interaction stimulated by the clinically relevant Glp1r agonist liraglutide (Lira) whereby the canonical target of Glp1r signaling, cAMP-dependent protein kinase A (PKA), phosphorylates the mTORC1 regulatory protein Raptor resulting in increased mTORC1 signaling. We have also identified the transcription factor Hypoxia- Inducible Factor (HIF) as a target of Glp1r signaling. This is relevant since HIF stimulates glycolysis, a mechanism necessary for the anorectic and insulinotropic effects of Glp1r agonists, and increased HIF expression in the hypothalamus and -cells reduces food intake and stimulates insulin secretion, respectively. We also provide preliminary data showing that Lira no longer reduces body weight or glucose levels in novel knockin mice replacing endogenous Raptor with a PKA-resistant Raptor. Our preliminary data, therefore, lead us to hypothesize that a Glp1r-PKA-mTORC1-HIF-glycolysis axis in the hypothalamus and -cells mediates the ability of Lira to reduce body weight (Aim 1) and stimulate insulin secretion (Aim 2), respectively. The clinical relevance of this is further emphasized by our preliminary data showing that two variants of the Glp1r found in humans that are associated with improved cardiometabolic outcomes and improved responsiveness to Lira also stimulate mTORC1 signaling to a greater degree than wild-type Glp1r. We will, therefore, use mice expressing these human Glp1r variants to test the hypothesis that Lira promotes greater weight loss and improved glucose tolerance in these mice via enhanced mTORC1 signaling (Aim 3). We will complete these Aims by leveraging our extensive expertise in assessing metabolic phenotypes in mice, including real-time measurements of energy balance parameters as well as pancreatic function in isolated islets and in vivo using hyperglycemic clamps. We will apply these approaches to a suite of novel mouse models that allow us to modulate or measure the expression and activity of target proteins in specific cell types. Accomplishing these Aims will delineate specific molecular mechanisms that can be leveraged towards either the improvement of the effectiveness of Lira or the design of more efficient weight-lowering drugs.


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 = $532,979 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/8/2025	NON-COMPETING CONTINUATION	$532,979
														Subtotal = $532,979

Issue Date FY: 2025 ( Subtotal = $532,979 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/13/2024	NON-COMPETING CONTINUATION	$479,681
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$53,298
														Subtotal = $532,979

Issue Date FY: 2024 ( Subtotal = $528,514 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/15/2024	NON-COMPETING CONTINUATION	$33,033
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/15/2023	NON-COMPETING CONTINUATION	$495,481
														Subtotal = $528,514

Issue Date FY: 2023 ( Subtotal = $550,534 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/30/2022	NEW	$550,534
														Subtotal = $550,534

Grand Total All Awards = $2,145,006

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Molecular mechanisms mediating metabolic benefits of glucagon-like peptide-1 receptor agonists

Award Number: R01DK132852

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: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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