Journal
APPLIED PHYSIOLOGY NUTRITION AND METABOLISM
Volume 32, Issue 5, Pages 874-883Publisher
CANADIAN SCIENCE PUBLISHING
DOI: 10.1139/H07-083
Keywords
fatty acids; skeletal muscle; nuclear receptors; energy metabolism; insulin resistance; obesity; exercise; mitochondria
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Funding
- NIA NIH HHS [R01AG028930-01] Funding Source: Medline
- NIDDK NIH HHS [K01DK56112] Funding Source: Medline
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Dyslipidemia and intramuscular accumulation of fatty acid metabolites are increasingly recognized as core features of obesity and type 2 diabetes. Emerging evidence suggests that normal physiological adaptations to a heavy lipid load depend on the coordinated actions of broad transcriptional regulators such as the peroxisome proliferator activated receptors (PPARs) and PPAR gamma coactivator la (PGCl alpha). The application of transcriptomics and targeted metabolic profiling tools based on mass spectrometry has led to our finding that lipid-induced insulin resistance is a condition in which upregulation of PPAR-targeted genes and high rates of (beta-oxidation are not supported by a commensurate upregulation of tricarboxylic acid (TCA) cycle activity. In contrast, exercise training enhances mitochondrial performance, favoring tighter coupling between (beta-oxidation and the TCA cycle, and concomitantly restores insulin sensitivity in animals fed a chronic high-fat diet. The exercise-activated transcriptional coactivator, PGCl alpha, plays a key role in coordinating metabolic flux through these 2 intersecting metabolic pathways, and its suppression by overfeeding may contribute to diet-induced mitochondrial dysfunction. Our emerging model predicts that muscle insulin resistance arises from a mitochondrial disconnect between (beta-oxidation and TCA cycle activity. Understanding of this disconnect and its molecular basis may lead to new therapeutic approaches to combatting metabolic disease.
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