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- Title
PPARγ1 Stimulates Uptake and Oxidation of Fatty Acid in Myocytes.
- Authors
Yao, Jianrong; Hu, Shanming; Kahn, C. R.; Spector, Arthur A.; Norris, Andrew W.
- Abstract
Muscle-localized PPARγ1 protects against whole-body adiposity and insulin resistance via unknown means. Recently, we found impaired fatty acid uptake and oxidation in skeletal muscle of mice lacking muscle PPARγ suggesting a possible mechanism. To determine if this is a primary or secondary phenomenon, we have studied C2C12 myotubes transfected with adenovirus expressing PPARγ1 (adPPARγ1). PPARγ mRNA and protein could not be reliably detected in control myotubes transfected with adenovirus expressing green fluorescent protein, but were easily detected in adPPARγ1 transfected myotubes. Transfected myotubes retained differentiated morphology and expressed markers of muscle differentiation for at least 48 hours after transfection, the time used for these studies. As predicted by in vivo results, PPARγ1 increased cellular uptake and retention of radiolabeled oleic acid across a range of concentrations and incubation times, averaging a 24±6% (p < 0.01) increase compared to controls. The augmented uptake was observable within 2 minutes of incubation and became proportionally greater with time. Rosiglitazone, a pharmacological activator of PPARγ, produced no stimulation of oleic acid uptake in control myotubes, but enhanced fatty acid uptake to 50-±10% (p=0.001) above baseline in adPPARγ1 transfected myotubes with an EC50 of 0.1 µM. Importantly, non-mitochondrial cellular oxidation of oleic acid, as determined using 50 µM etomoxir, was stimulated 80% (p=0.02) by adPPARγ1 and an additional 95% (p<0.001) synergistically by adPPARgamma;1 plus 0.5 µM rosiglitazone. In summary, PPARγin differentiated myocytes stimulates uptake and non-mitochondrial oxidation of fatty acids. These findings are consistent with in vivo results and demonstrate that the regulation of muscle lipid metabolism by PPARγ1 is direct, since in culture there are no other tissue types present to mediate indirect effects. Hence, when muscle PPARγ1 is absent, the capacity of skeletal muscle to dispose of fatty acids is reduced, leading to excess lipid exposure of other tissues, and thus whole-body adiposity and insulin resistance.
- Publication
Diabetes, 2007, Vol 56, pA399
- ISSN
0012-1797
- Publication type
Academic Journal