Metabolic cycles are a fundamental element of cellular and organismal function. Among the most critical in higher organisms is the Cori Cycle, the systemic cycling between lactate and glucose. Here, skeletal muscle-specific Mitochondrial Pyruvate Carrier (MPC) deletion in mice increased muscle glucose uptake but diverted pyruvate into the circulation as lactate, driving increased Cori Cycling and energy expenditure. Loss of muscle MPC activity evoked adaptive glutaminolysis, increased fatty acid oxidation, and resulted in a striking resistance to gains in fat mass with age with perfect sparing of muscle mass and strength. Furthermore, chronic and acute muscle MPC deletion accelerated fat mass loss on a normal diet after high fat diet-induced obesity. Our results illuminate the role of the skeletal muscle MPC as a central node for whole-body carbohydrate, fat, and amino acid metabolism. They highlight the potential utility of decreasing muscle pyruvate oxidation to ameliorate obesity and type 2 diabetes.
Dissertation
The role of the skeletal muscle mitochondrial pyruvate carrier in systemic glucose homeostasis and whole-body adiposity
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2018
DOI: 10.17077/etd.bgjn-khw1
Abstract
Details
- Title: Subtitle
- The role of the skeletal muscle mitochondrial pyruvate carrier in systemic glucose homeostasis and whole-body adiposity
- Creators
- Arpit Sharma - University of Iowa
- Contributors
- Eric B. Taylor (Advisor)Lori Wallrath (Committee Member)Brandon Davies (Committee Member)Peter Rubenstein (Committee Member)William Sivitz (Committee Member)Sheila Baker (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biochemistry
- Date degree season
- Autumn 2018
- DOI
- 10.17077/etd.bgjn-khw1
- Publisher
- University of Iowa
- Number of pages
- xv, 155 pages
- Copyright
- Copyright © 2018 Arpit Sharma
- Language
- English
- Date submitted
- 03/08/2019
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 139-155).
- Public Abstract (ETD)
More than two-thirds of American adults are overweight or obese. Previously, obesity was considered only a risk factor for other conditions such as heart failure, diabetes, stroke, and hypertension. The American Medical Association now classifies obesity as a disease.
Obesity results from an energy imbalance in which energy intake chronically exceeds energy expenditure. Such a chronic imbalance results in excess energy storage as fat. After a certain threshold of body fat is surpassed, fat tissue fails to store the excess energy, and excess fat accumulates in other tissues of the body such as heart and skeletal muscle. This excess deposition of fat in muscle tissue results in a deviation from normal muscle metabolism. The ability of the muscle to clear glucose from the blood after a meal becomes compromised. This can lead to type 2 diabetes.
My work focuses on understanding how carbohydrate metabolism in the muscle is controlled by a recently discovered protein complex called the mitochondrial pyruvate carrier (MPC). Understanding how carbohydrate metabolism in muscle is controlled can help us develop strategies to restore normal metabolism in obese and diabetic muscle. To understand the role of MPC in muscle carbohydrate metabolism, I used a mouse model in which a gene required for MPC complex formation, Mpc1, was specifically deleted in skeletal muscle (MPC SkmKO mice). Muscle in MPC SkmKO mice increased fat oxidation to compensate for decreased carbohydrate oxidation. Furthermore, MPC SkmKO mice had increased energy expenditure. Increased energy expenditure combined with increased muscle fat utilization allowed these mice to lose fat mass while they maintained their muscle mass. MPC SkmKO also showed improved recovery from diet-induced obesity after they were fed a 60% fat diet. My work is important because it highlights a way to alter energy expenditure and fat utilization to treat obesity. Interventions like the ones highlighted in this thesis may prove useful to increase fat clearance in obese states while simultaneously increasing energy expenditure.
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9983776639302771
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