The Role of PDK4 in High Fat Diet - Induced Insulin Resistance

Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a potential main regulator of the metabolic program that is shown to be activated by exercise and down-regulated by high fat feeding and sedentary lifestyle. It is shown that PGC-1α coactivates the pyruvate dehydrogenase kinase (PDK4) gene expression via the estrogen related receptor (ERRα). The expression of PDK4 is shown to be elevated with diabetes, fasting and other conditions associated with the switch from the utilization of glucose to fatty acids as an energy source. PURPOSE: Our aim in this study was to investigate the effects of high fat (HF) diet and physical activity in the expression levels of the above mentioned genes in the skeletal muscles of C57BL/6J mice. METHODS: In this experiment we induced insulin resistance by feeding high fat diet for 19 weeks to C57BL/6J mice. After 9 and 18 weeks on the diet, the fasting glucose and insulin levels were measured. The total cholesterol, free fatty acids and triglycerides were measured after the 19 - week experiment. The expression levels of the genes PGC-1α, ERRα and PDK4 were measured with quantitative RT-PCR and by Western blotting from the quadriceps femoris muscle. RESULTS:The HF animals had significantly higher diet - induced fasting glucose and insulin levels compared to low fat (LF) fed animals. The HOMA index indicated that after 18 weeks HF mice were more insulin resistant than LF mice, but no running effect could be seen. The HF animals showed an altered blood lipid profile suggesting changes in the overall lipid metabolism. Chronic HF feeding and voluntary running training did not have significant effects on PGC-1α mRNA or protein levels. Upregulation of ERRα and PDK4 was seen after HF diet and this combined with running had even more profound effects on the expression levels. CONCLUSIONS: We observed an up-regulated PDK4 expression along with more modest changes in PGC-1α and ERRα expression in response to both high fat diet and voluntary exercise. We speculate that this increased PDK4 expression is due to previous increase of the PGC-1α and ERRα expression, which subsequently blunts cellular glucose oxidation. In this scenario, PGC-1α is the master regulator of energy metabolism by regulating the increase of fatty acid oxidation and decreasing glucose oxidation via PGC-1α/ERRα pathway. Our data further suggests that the inhibition of pyruvate dehydrogenase complex by PDK4 must be contemplated as a possible mechanism or contributor to insulin resistance. The research was funded by the Finnish Ministry of Education and Culture.