The Effects of Ppar Delta and Alpha Agonist on Fatty Acid and Glucose Metabolism in Vivo and in Mouse Isolated Soleus Muscle

Abstract

The peroxisome proliferator-activated receptors of the nuclear receptor superfamily are het-erodimers with the 9-cis retinoic acid receptor and bind to specific peroxisome proliferators re-sponse elements to regulate the transcription of their target genes resulting in the regulation of lipid, metabolism, glucose homeostasis and inflammation. Activation of these receptors by their agonists has since been shown to play critical and unique roles in lipid homeostasis. This work was designed to study the effects of PPAR-õ agonists and PPAR-α agonist on lipid and glucose homeostasis in models of diabetes and obesity in C57B1/6 mice. The effect of PPAR-õ agonist, GW610742, and PPAR-α agonist GW649003 on lipid and glucose metabolism were studied in C57B1/6 lean and obese mice. GW610742 was administered, p.o at 3mg/kg body weight and 10mg/kg body weight at 09.00h and 17.00h in two separate groups of lean mice in an acute study. The dosing was repeated over seven days in another two groups of mice in the chronic study. C57B1/6 obese and lean mice were also dosed with GW800644 (10mg/kg) and GW649003 (1mg/kg) p.o at 09.00h and 17.00h for 14 days. At the end of study, glucose, lactate, and NEFA were measured. Animals were killed; whole organs were removed and weighed. The soleus mus-cles were isolated and used to determine 2-deoxyglucose uptake and palmitate oxidation. GW610742 did not show any significant metabolic changes in lean mice in both the acute and chronic studies. However, chronic treatment with GW800644 and GW649003 in ob/ob mice, resulted in an increase uptake of 2-deoxyglucose and palmitate oxidation in mouse isolated so-leus muscle and decreased plasma glucose and insulin levels. However, GW649003 also induced hepatomegaly in lean mice but not in the obese. The fact that both PPAR-δ agonist GW800644 and PPAR-α agonist GW649003 showed a positive lipid, glucose and insulin homeostasis only in mice with these metabolic defects shows they have the potentials to be developed into drugs for management of diabetes and obesity.