Metabolic Remodeling of Human Skeletal Myocytes by Cocultured Adipocytes Depends on the Lipolytic State of the System
- Jean-Paul Kovalik1,
- Dorothy Slentz1,
- Robert D. Stevens1,
- William E. Kraus2,
- Joseph A. Houmard3,
- James B. Nicoll4,
- Y. Renee Lea-Currie4,
- Karen Everingham5,
- C. Lawrence Kien5,6,
- Benjamin M. Buehrer4 and
- Deborah M. Muoio1,7,8⇓
- 1Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina
- 2Department of Cardiology, Duke University, Durham, North Carolina
- 3Human Performance Laboratory, Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina
- 4Zen-Bio, Research Triangle Park, North Carolina
- 5Department of Medicine, University of Vermont, Burlington, Vermont
- 6Department of Pediatrics, University of Vermont, Burlington, Vermont
- 7Department of Medicine, Duke University, Durham, North Carolina
- 8Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
- Corresponding author: Deborah M. Muoio, .
OBJECTIVE Adipocyte infiltration of the musculoskeletal system is well recognized as a hallmark of aging, obesity, and type 2 diabetes. Intermuscular adipocytes might serve as a benign storage site for surplus lipid or play a role in disrupting energy homeostasis as a result of dysregulated lipolysis or secretion of proinflammatory cytokines. This investigation sought to understand the net impact of local adipocytes on skeletal myocyte metabolism.
RESEARCH DESIGN AND METHODS Interactions between these two tissues were modeled using a coculture system composed of primary human adipocytes and human skeletal myotubes derived from lean or obese donors. Metabolic analysis of myocytes was performed after coculture with lipolytically silent or activated adipocytes and included transcript and metabolite profiling along with assessment of substrate selection and insulin action.
RESULTS Cocultured adipocytes increased myotube mRNA expression of genes involved in oxidative metabolism, regardless of the donor and degree of lipolytic activity. Adipocytes in the basal state sequestered free fatty acids, thereby forcing neighboring myotubes to rely more heavily on glucose fuel. Under this condition, insulin action was enhanced in myotubes from lean but not obese donors. In contrast, when exposed to lipolytically active adipocytes, cocultured myotubes shifted substrate use in favor of fatty acids, which was accompanied by intracellular accumulation of triacylglycerol and even-chain acylcarnitines, decreased glucose oxidation, and modest attenuation of insulin signaling.
CONCLUSIONS The effects of cocultured adipocytes on myocyte substrate selection and insulin action depended on the metabolic state of the system. These findings are relevant to understanding the metabolic consequences of intermuscular adipogenesis.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-0427/-/DC1.
- Received March 28, 2010.
- Accepted April 2, 2011.
- © 2011 by the American Diabetes Association.
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