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The role of intestinal SCD1 in regulating metabolic health

Award Number: R01DK126963
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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The role of intestinal SCD1 in regulating metabolic health - The intestine is emerging as a regulatory and signaling organ, enabling diet-derived nutrients to perform essential actions. A better understanding of intestinal regulation of systemic lipid metabolism has direct implications to multiple human metabolic pathologies, including cardiovascular disease, fatty liver, and insulin resistance. The delta-9 desaturase, stearoyl-CoA desaturase-1 (SCD1), converts saturated fatty acids to monounsaturated products and has been shown to regulate lipid esterification in liver and skin. However, virtually nothing is known about the role of SCD1 in the intestine, where lipid esterification is crucial for its eventual absorption and secretion into chylomicrons (CMs). To address this gap in knowledge, we generated mice with a targeted deletion of SCD1 only in intestinal epithelial cells (iKO mice). Remarkably, we find that iKO animals have significant reductions not only in intestinal lipids, but also in circulating and hepatic lipid levels, particularly in levels of monounsaturated fatty acids. iKO mice also have significant increases in both energy expenditure and glucose tolerance, accompanied by increased thermogenic markers in brown adipose tissue and increased plasma GLP-1 levels. Unexpectedly, intestinal SCD1 deletion elevates plasma and hepatic bile acids (BAs) and alters markers of hepatobiliary BA efflux and ileal BA reuptake. Supported by these and other compelling preliminary data, this application will assess the role of intestinal SCD1 in integrating metabolic signals originating in the gut. The central hypothesis of this application is that intestinal SCD1 regulates metabolic health by altering secreted lipid content and composition, TGR5 signaling in BAT and the gut, and enterohepatic BA metabolism. This hypothesis will be tested by our two related but independent Specific Aims. In Aim 1, we will test the relevance of intestinal SCD1 inhibition to energy balance in the context of hypercaloric and hyperlipidemic diets. We will also evaluate a mechanistic role for TGR5 in mediating the improved metabolic phenotypes of iKO mice. In Aim 2, we will evaluate a role for SCD1-derived MUFAs in regulating hepatic BA efflux and intestinal BA reuptake . We will also utilize a) an inhibitor of intestinal BA reuptake, b) a gut-restricted FXR agonist, and c) dietary MUFAs to restore hepatic and plasma BA levels in iKO mice.


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 = $391,632 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/7/2025	NON-COMPETING CONTINUATION	$391,632
														Subtotal = $391,632

Issue Date FY: 2024 ( Subtotal = $375,967 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$375,967
														Subtotal = $375,967

Issue Date FY: 2023 ( Subtotal = $391,632 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/18/2023	NON-COMPETING CONTINUATION	$391,632
														Subtotal = $391,632

Issue Date FY: 2022 ( Subtotal = $391,632 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/25/2022	NON-COMPETING CONTINUATION	$391,632
														Subtotal = $391,632

Issue Date FY: 2021 ( Subtotal = $391,632 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/15/2021	NEW	$391,632
														Subtotal = $391,632

Grand Total All Awards = $1,942,495

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The role of intestinal SCD1 in regulating metabolic health

Award Number: R01DK126963

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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