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Mechanism of autophagy activation in exercise-induced anti-diabetic benefits

Award Number: R01DK113170
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: 09/12/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Mechanism of autophagy activation in exercise-induced anti-diabetic benefits - Modified Project Summary / Abstract Section This is a renewal application for R01 DK113170 to investigate the role and mechanism of autophagy activation in the regulation of exercise-induced metabolic benefits against type 2 diabetes (T2D). T2D is a sedentarism-associated disease affecting glucose metabolism and a risk factor for other disorders. Physical exercise has been widely recognized to exert beneficial effects against T2D. However, the mechanisms by which exercise elicits systemic metabolic benefits are unclear, which limits the development of therapeutic interventions. Autophagy is an essential intracellular degradation pathway, in which damaged or unnecessary cargos are transported to and broken down in lysosomes. It occurs at a low basal level under normal conditions, and can be induced by stressors such as fasting. We found that exercise is a potent inducer of autophagy, not only in contracting muscle tissues but also systemically in non-contractile tissues such as the liver. The mechanism and metabolic importance of autophagy activation by exercise in non-contractile tissues have never been addressed. Our preliminary data reveal that systemic autophagy activation may be mediated by exercise-induced circulating factors. By proteomic studies we discovered that fibronectin (Fn1), generally considered as an extracellular matrix protein under normal (resting) conditions, is significantly increased in the circulation after acute exercise. Importantly, muscle-specific depletion of fibronectin (FN1[delta]muscle mice) abolishes exercise-induced circulating fibronectin levels, autophagy activation in the liver, and systemic insulin sensitization, suggesting that muscle-secreted fibronectin is an essential regulator of exercise-induced systemic autophagy and metabolic benefits. In addition, knockdown of the fibronectin receptor, α5β1 integrin, abolishes the ability of exercised mouse serum in activating autophagy in cultured cells, further supporting the key role of the fibronectin-α5β1 integrin pathway in exercise-induced autophagy. Based on these data, we propose our overall hypothesis that autophagy activation in non-contractile tissues drives exercise-induced metabolic benefits against T2D, through a fibronectin-α5β1 integrin-IKK-JNK1 pathway. Using a combination of genetic, metabolic, biochemical, and cell biology approaches, we propose two aims: Aim 1 is to determine whether exercise activates autophagy systemically in non-contractile tissues via the fibronectin-α5β1 integrin-IKK-JNK1 pathway; and Aim 2 is to determine whether autophagy activation by the fibronectin-α5β1 integrin-JNK pathway in non-contractile tissues mediates exercise-induced metabolic benefits against T2D. Overall, our studies will establish the physiological importance of exercise-activated autophagy in non-contractile tissues in the prevention of T2D, and will demonstrate the previously uncharacterized function and mechanism of the fibronectin-integrin signaling pathway in regulating muscle-liver communication and whole-body metabolism.


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 = $385,877 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	7/11/2024	NON-COMPETING CONTINUATION	$385,877
														Subtotal = $385,877

Issue Date FY: 2023 ( Subtotal = $401,955 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	6/23/2023	NON-COMPETING CONTINUATION	$401,955
2023	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	6/21/2023	COMPETING CONTINUATION	$37,251
2023	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/21/2023	NON-COMPETING CONTINUATION	-$37,251
														Subtotal = $401,955

Issue Date FY: 2022 ( Subtotal = $461,464 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	9/13/2022	COMPETING CONTINUATION	$461,464
														Subtotal = $461,464

Issue Date FY: 2021 ( Subtotal = $385,982 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/9/2021	NON-COMPETING CONTINUATION	$385,982
														Subtotal = $385,982

Issue Date FY: 2020 ( Subtotal = $386,132 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/7/2020	NON-COMPETING CONTINUATION	$386,132
														Subtotal = $386,132

Issue Date FY: 2019 ( Subtotal = $386,277 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/5/2019	NON-COMPETING CONTINUATION	$386,277
														Subtotal = $386,277

Issue Date FY: 2018 ( Subtotal = $392,580 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/19/2018	NON-COMPETING CONTINUATION	$392,580
														Subtotal = $392,580

Issue Date FY: 2017 ( Subtotal = $395,000 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/12/2017	NEW	$395,000
														Subtotal = $395,000

Grand Total All Awards = $3,195,267

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Mechanism of autophagy activation in exercise-induced anti-diabetic benefits

Award Number: R01DK113170

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: 09/12/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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