Paradoxical Coupling of Triglyceride Synthesis and Fatty Acid Oxidation in Skeletal Muscle Overexpressing DGAT1
- Li Liu1,
- Xiaojing Shi1,
- Cheol Soo Choi2,
- Gerald I. Shulman2,
- Katherine Klaus3,
- K. Sreekumaran Nair3,
- Gary J. Schwartz4,
- Yiying Zhang5,
- Ira J. Goldberg1 and
- Yi-Hao Yu1
- 1Department of Medicine, Preventive Medicine and Nutrition, Columbia University, New York, New York;
- 2Departments of Internal Medicine and Cellular and Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut;
- 3Endocrine Research Unit and Department of Laboratory Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota;
- 4Department of Medicine & Neuroscience, Diabetes Research and Training Center, Albert Einstein College of Medicine, New York, New York;
- 5Department of Pediatrics, Naomi Berrie Diabetes Center, Columbia University, New York, New York.
- Corresponding author: Yi-Hao Yu, yy102{at}columbia.edu.
Abstract
OBJECTIVE Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride, a phenomenon similar to what is known as the “athlete paradox.” The primary objective of this study is to determine how DGAT1 affects muscle fatty acid oxidation in relation to whole-body energy metabolism and insulin sensitivity.
RESEARCH DESIGN AND METHODS We first quantified insulin sensitivity and the relative tissue contributions to the improved whole-body insulin sensitivity in muscle creatine kisase (MCK)-DGAT1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of DGAT1 overexpression in skeletal muscles were determined by quantifying triglyceride synthesis/storage (anabolic) and fatty acid oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in fatty acid metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states.
RESULTS MCK-DGAT1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting triglyceride synthesis, DGAT1 overexpression also led to increased muscle mitochondrial fatty acid oxidation efficiency, as compared with wild-type muscles. On a high-fat diet, MCK-DGAT1 mice displayed higher basal metabolic rates and 5–10% lower body weights compared with wild-type littermates, whereas food consumption was not different.
CONCLUSIONS DGAT1 overexpression in skeletal muscle led to parallel increases in triglyceride synthesis and fatty acid oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin-sensitive myofibers and suggests that DGAT1 plays an active role in metabolic “remodeling” of skeletal muscle coupled with insulin sensitization.
Footnotes
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C.S.C. is currently affiliated with the Laboratory of Cellular & Molecular Physiology and Metabolism, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received August 11, 2008.
- Accepted July 16, 2009.
- © 2009 American Diabetes Association
