Up-regulation of PPARgamma coactivator-1alpha as a strategy for preventing and reversing insulin resistance and obesity.
Excessive accumulation of triglycerides and certain fatty acid derivatives in skeletal muscle and other tissues appears to mediate many of the adverse effects of insulin resistance syndrome. Although fatty diets and obesity can promote such accumulation, deficient capacity for fatty acid oxidation can also contribute in this regard. Indeed, in subjects who are insulin resistant, diabetic, and/or obese, fatty acid oxidation by skeletal muscle tends to be inefficient, reflecting decreased expression of mitochondria and mitochondrial enzymes in muscle. This phenomenon is not corrected by weight loss, is not simply reflective of subnormal physical activity, and is also seen in lean first-degree relatives of diabetics; thus, it appears to be primarily attributable to genetic factors. Recent studies indicate that decreased expression of PPARgamma coactivator-1alpha (PGC-1alpha), a "master switch" which induces mitochondrial biogenesis by supporting the transcriptional activity of the nuclear respiratory factors, may largely account for the diminished oxidative capacity of subjects prone to insulin resistance. Thus, feasible measures which up-regulate PGC-1alpha may be useful for preventing and treating insulin resistance and obesity. These may include exercise training, metformin and other agents which stimulate AMP-activated kinase, high-dose biotin, and PPARdelta agonists. Drugs which are specific agonists for PPARdelta show remarkable efficacy in rodent models of insulin resistance, diabetes, and obesity, and are currently being evaluated clinically. Phytanic acid, a branched-chain fatty acid found in omnivore diets, can also activate PPARdelta, and thus should be examined with respect to its impact on mitochondrial biogenesis and insulin sensitivity.
McCarty
Mark F
MF
NutriGuard Research, 1051 Hermes Ave., Encinitas, CA 92024, USA. mccarty@pantox.com
D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D024821:Metabolic Syndrome / Q000378:metabolism* / Q000517:prevention & control; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010831:Phytanic Acid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D005227:Fatty Acids; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D010831:Phytanic Acid