A new, highly selective murine peroxisome proliferator-activated receptor delta agonist increases responsiveness to thermogenic stimuli and glucose uptake in skeletal muscle in obese mice

作者：Ngala R A; Stocker C J; Roy A G; Hislop D; Wargent E; Bell R; Hassall D G; Harling J D; Billin A N; Willson T M; Arch J R S^*; Cawthorne M A

来源：Diabetes, Obesity and Metabolism, 2011, 13(5): 455-464.

DOI：10.1111/j.1463-1326.2011.01371.x

• animal pharmacology
• antidiabetic drug
• antiobesity drug
• diabetes
• energy regulation
• glucose metabolism
• glucose utilization
• ob
• ob mouse
• obesity
• peroxisome proliferator-activated receptor delta agonist
• soleus muscle
• thermogenesis

Methods: Potencies were determined in transactivation assays. Oral glucose tolerance was determined after 14 and 22 days' administration (10 mg/kg body weight, twice daily) to Lepob/Lepob mice. Food intake and energy expenditure were measured during a 26-day experiment, and plasma metabolites and 2-deoxyglucose uptake in vivo at termination. Palmitate oxidation and 2-deoxyglucose uptake by isolated soleus muscles were measured after 14 (in lean and obese mice) and 26 days.
Results: GW800644 activated murine PPAR delta (EC(50) 2 nM), but caused little to no activation of PPAR alpha or PPAR gamma up to 10 mu M. It did not increase liver weight. GW800644 reduced food intake and body weight in obese mice after 8 days. It did not affect resting energy expenditure, but, compared to pair-fed mice, it increased the response to a beta(3)-adrenoceptor agonist. It improved glucose tolerance. GW800644, but not pair-feeding, reduced plasma glucose, insulin and triglyceride concentrations. It increased 2-deoxyglucose uptake in vivo in adipose tissue, soleus muscle, heart, brain and liver, and doubled 2-deoxyglucose uptake and palmitate oxidation in isolated soleus muscle from obese but not lean mice.
Conclusions: PPAR delta agonism reduced food intake and independently elicited metabolic effects that included increased responsiveness to beta(3)-adrenoceptor stimulation, increased glucose utilization and fat oxidation in soleus muscle of Lepob/Lepob but not lean mice and increased glucose utilization in vivo in Lepob/Lepob mice.

• 出版日期2011-5