A potential link between muscle peroxisome proliferator-activated receptor-α signaling and obesity-related diabetes

The role of the peroxisome proliferator-activated receptor-alpha (PPAR alpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPAR alpha in muscle (MCK-PPAR alpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPAR alpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPAR alpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPAR alpha on GLUT4 expression and glucose homeostasis. These results identify PPAR alpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.