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

• Published in: Diabetes, obesity & metabolism Vol. 13; no. 5; pp. 455 - 464
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2011; Wiley Subscription Services, Inc
• Subjects: Acetates - pharmacology; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adrenergic receptors; Agonists; animal pharmacology; Animals; antidiabetic drug; Antidiabetics; antiobesity drug; Biological Transport; Body weight; Cardiac muscle; Deoxyglucose; Diabetes; Energy balance; Energy expenditure; energy regulation; Food intake; Glucose; Glucose - metabolism; Glucose tolerance; Glucose Tolerance Test; glucose utilization; Homeostasis; Insulin Resistance; Liver; Male; Mice; Mice, Obese; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; ob/ob mouse; obesity; Oxidation; Palmitic acid; peroxisome proliferator-activated receptor δ agonist; Peroxisome proliferator-activated receptors; Phenoxyacetates; PPAR delta - agonists; Pyridines - pharmacology; Skeletal muscle; Soleus muscle; Thermogenesis; Time Factors
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2011.01371.x

Aim: We investigated how GW800644, the first pharmacologically selective murine peroxisome proliferator‐activated receptor δ (PPARδ) agonist, affects energy balance, glucose homeostasis and fuel utilization by muscle in obese mice. 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 PPARδ (EC50 2 nM), but caused little to no activation of PPARα or PPARγ up to 10 µM. 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 β3‐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: PPARδ agonism reduced food intake and independently elicited metabolic effects that included increased responsiveness to β3‐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.