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Identification of Muscle-Specific Biomarkers of Fatty Acid beta-Oxidation

Award Number: R01DK078328
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: 09/30/2008
PERIOD OF PERFORMANCE END DATE: 06/30/2015

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Identification of Muscle-Specific Biomarkers of Fatty Acid beta-Oxidation - DESCRIPTION (provided by applicant): Elevated fat levels within skeletal muscle cells (intramyocellular lipids) are highly correlated with muscle and whole-body insulin resistance, and more prevalent in obesity. The molecular links and metabolic shifts driving this association remain open to debate, but notably, reduced muscle mitochondrial fatty acid (FA) beta-oxidation is more prevalent among insulin-resistant/diabetic persons. Therefore, discovery of biomarkers reflective of the status of an individual's muscle FA beta-oxidation activity or capacity would have tremendous prognostic and diagnostic value in terms of diabetes. Furthermore, characterization of metabolites associated with muscle mitochondrial fat metabolism should uncover candidate signaling factors which tie FA beta-oxidation to insulin signaling. We propose to identify, for the first time, specific biomarkers of muscle FA beta- oxidation using multiple metabolomic analytical platforms to compare metabolite profiles in samples derived from biological systems displaying disparate muscle fat combustion, including: isolated mitochondrial organelles and muscle cells catabolizing FA at different rates, a UCP3 transgenic animal model, and human subjects harboring a UCP3 truncation polymorphism (Aims 1 & 2). Pilot validation studies in Aim 3 will test whether plasma metabolites and/or metabolite signatures that track muscular FA beta-oxidation (as identified in Aims 1 and 2) can be experimentally increased in obese, insulin-resistant subjects via a diet-exercise regimen designed to improve muscle fitness and FA combustion. Aim 1--Identify Metabolite Biomarkers of Muscle Fat Combustion in Organelle, Cell, and Animal Models Displaying Significantly Altered Fatty Acid beta-Oxidation. We will determine how metabolite profiles shift in models displaying increased muscle beta-oxidation (uncoupling protein 3-overexpressing muscle cell line and muscle UCP3-transgenic mice), and hypothesize that profiles in UCP3-overexpressing systems will reflect increased FA beta-oxidation. Complementary studies will identify tissue-specific metabolites generated by mitochondria in the course of palmitate catabolism in vitro, comparing muscle to liver and kidney preparations. Aim 2--Identify Metabolite Biomarkers of Muscle Fat Combustion in Humans Harboring a UCP3 Missense Polymorphic Allele. We predict that subjects with this polymorphism (which yields a truncated UCP3 and 50% decreased whole-body fat combustion) will display a distinctive plasma metabolite profile indicative of reduced muscle FA oxidation, when compared to subjects without the polymorphism. Aim 3--Determine Whether Metabolomic Profiles Reflective of Muscle Fat Combustion Predict Metabolic Health Changes Following Diet & Exercise Intervention in Obese Subjects. We hypothesize that biomarkers reflective of normal to increased muscle beta-oxidation will be increased, and markers indicative of poor muscle fat combustion reduced, in a cohort of sedentary obese subjects undergoing a 4 month diet- exercise protocol which will increase muscle fitness and improve insulin action. PUBLIC HEALTH RELEVANCE: A reduced ability of the pancreatic hormone insulin to trigger tissue uptake of blood sugar is an early event in the course of development of type 2 diabetes mellitus (T2DM), and the muscle beds are important sites for this phenomenon in many people. Relatively poor fat combustion by fasting muscle is often correlated with insulin resistance, even in the pre-diabetic state. Thus, the overarching aim of our research-- identification of clinically-relevant biomarkers of muscle fat metabolism--is critical to help identify at-risk persons, determine etiology of disease, and ultimately thwart development of T2DM through nutritional, physical activity, and pharmacological interventions.


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: 2015 ( Subtotal = $0 )
2015	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/25/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/15/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/26/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $221,573 )
2012	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	10/26/2012	NON-COMPETING CONTINUATION	$0
2012	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	8/21/2012	NON-COMPETING CONTINUATION	$0
2012	2012	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/27/2012	NON-COMPETING CONTINUATION	$221,573
2012	2011	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/31/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $221,573

Issue Date FY: 2011 ( Subtotal = $225,250 )
2011	2011	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/29/2011	NON-COMPETING CONTINUATION	$225,250
2011	2011	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	10/31/2011	NON-COMPETING CONTINUATION	$0
2011	2009	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Trans-NIH Recovery Act Research Support	001	2	8/9/2011	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $225,250

Issue Date FY: 2010 ( Subtotal = $262,561 )
2010	2010	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/28/2010	NON-COMPETING CONTINUATION	$262,561
														Subtotal = $262,561

Issue Date FY: 2009 ( Subtotal = $852,128 )
2009	2009	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Trans-NIH Recovery Act Research Support	003	2	9/22/2009	SUPPLEMENT FOR EXPANSION	$294,293
2009	2009	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/29/2009	NON-COMPETING CONTINUATION	$269,467
2009	2009	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Trans-NIH Recovery Act Research Support	002	2	9/16/2009	SUPPLEMENT FOR EXPANSION	$288,368
2009	2008	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/24/2008	NEW	$0
														Subtotal = $852,128

Issue Date FY: 2008 ( Subtotal = $261,933 )
2008	2008	US DEPARTMENT OF AGRICULTURE, SOIL CONSERVATION SERVICE	4601 LOCUST LANE	HARRISBURG	PA	17109	DAUPHIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/15/2008	NEW	$261,933
														Subtotal = $261,933

Grand Total All Awards = $1,823,445

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Identification of Muscle-Specific Biomarkers of Fatty Acid beta-Oxidation

Award Number: R01DK078328

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: 09/30/2008

PERIOD OF PERFORMANCE END DATE: 06/30/2015

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