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Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

Award Number: R01DK124329
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Excess lipids increase the total intramyocellular lipid content and the ectopic fat storage resulting in lipotoxicity and insulin resistance in skeletal muscles, which is one of the main targets of insulin and its action is central for the maintenance of glucose homeostasis. Consumption of a diet high in fat and refined sugars, a Western Diet (WD), activates mineralocorticoid receptors (MRs) to induce muscle lipid metabolic disorders and insulin resistance. Recent data further indicate that cell specific endothelial cell (EC) MR (ECMR) activation mediates WD-induced muscle lipid metabolism disorders, impaired insulin metabolic signaling, and tissue insulin resistance. In this regard, ECMR activation increase CD36 expression in skeletal muscle arterioles and tissues, which promotes excessive free fatty acid trafficking across the muscle vasculature, leading to skeletal muscle lipid accumulation, CD36 palmitoylation and insulin resistance. There is a relationship between microvascular endothelial dysfunction and muscle metabolic disorders and insulin resistance through exosomes. Recent data suggest that EC derived exosomal proteins, such as exosomal CD36, can promote lipid accumulation and metabolic disorders. Upon being released from ECs, exosomal CD36 can be up-taken by the neighboring skeletal muscle and thus promote muscle lipid accumulation. The hypothesis of this application is that activation of ECMRs induces EC CD36 expression and release of EC-derived exosomal CD36 which increases free fatty acid uptake in ECs and translocation to skeletal muscle cells, leading to skeletal muscle intramyocellular lipid deposits and insulin resistance. Objective 1 of this application is to understand the role and mechanisms of ECMR signaling on CD36 expression, free fatty acid uptake in ECs and skeletal muscle cells, and related muscle lipid deposition and insulin resistance. Objective 2 of this application is to investigate the role and mechanisms of enhanced ECMR signaling on the EC-derived exosomal CD36 release and its role in facilitating increased skeletal muscle cell CD36 to further promote muscle fatty acid uptake, IMC lipid deposition and insulin resistance. Accordingly, in vitro cell treated with free fatty acid and in vivo mice fed a WD will be used to set up a model of ECMR/ECCD36 activation, obesity and insulin resistance. The proposed work should provide a better understanding the role of ECMRs and EC exosomal CD36 in the development of skeletal muscle insulin resistance and provide an important biomarker for the early diagnosis and prevention of this increasing cause of diabetes.


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: 2024 ( Subtotal = $369,037 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/22/2023	NON-COMPETING CONTINUATION	$345,973
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/3/2024	NON-COMPETING CONTINUATION	$23,064
														Subtotal = $369,037

Issue Date FY: 2023 ( Subtotal = $390,837 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/9/2023	NON-COMPETING CONTINUATION	$39,084
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/28/2022	NON-COMPETING CONTINUATION	$351,753
														Subtotal = $390,837

Issue Date FY: 2022 ( Subtotal = $397,048 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/22/2021	NON-COMPETING CONTINUATION	$357,343
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/7/2022	NON-COMPETING CONTINUATION	$39,705
														Subtotal = $397,048

Issue Date FY: 2021 ( Subtotal = $400,858 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/26/2020	NEW	$400,858
														Subtotal = $400,858

Grand Total All Awards = $1,557,780

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Endothelial mineralocorticoid receptors in diet-induced skeletal muscle insulin resistance

Award Number: R01DK124329

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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