Skeletal muscle adaptation to fatty acid depends on coordinated actions of the PPARs and PGC1 alpha: implications for metabolic disease.
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 1 alpha (PGC1 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, PGC1 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.
Department of Medicine, Duke University, Durham, NC 27710, USA. muoio@duke.edu
Deborah M
DM
Muoio
Timothy R
TR
Koves
D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism*; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D005227:Fatty Acids; D047492:Peroxisome Proliferator-Activated Receptors; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1