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

Abstract

The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha 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 PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.

PPARs and adipocyte function

“…PPAR agonist treatment also lowered hyper-insulinaemia and when present hyperglycaemia [94]. Conflicting these findings, however, transgenic over-expression of PPAR in muscle whilst also protecting from obesity, was associated with peripheral insulin resistance and glucose intolerance [92].…”

“…However, these animals display spontaneous, sexually dimorphic, late onset obesity (despite stable caloric intake) which is associated with adipocyte hypertrophy [91]. Furthermore, they are prone to diet-induced obesity which paradoxically is associated with enhanced insulin sensitivity [92]. In contrast, clofibrate treatment was shown to lead to a "browning" of retroperitoneal WAT as evidenced by enhanced UCP1 expression [93].…”

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

“…Activation of PPAR-a represses GLUT4 gene transcription (130). Indeed, 2-deoxyglucose uptake significantly increases in skeletal muscle of PPARa 7/7 mice compared to PPARa þ/þ controls (130). Exact mechanisms for the regulation of GLUT4 gene in muscle and adipose tissue are not known.…”

“…PPAR-a deficient mice shows hypoglycemia, hypertriglyceridemia, and hepatic steatosis (128,129). Activation of PPAR-a represses GLUT4 gene transcription (130). Indeed, 2-deoxyglucose uptake significantly increases in skeletal muscle of PPARa 7/7 mice compared to PPARa þ/þ controls (130).…”

“…Exact mechanisms for the regulation of GLUT4 gene in muscle and adipose tissue are not known. It was suggested that the repression of GLUT4 gene by PPAR-a is related to downregulation of MEF2A and PGC-1a gene expression via indirect mechanisms which may be associated with cellular energy status (130).…”