A novel PPAR agonist ameliorates insulin resistance in dogs fed a high-fat diet

Tsunoda M, Kobayashi N, Ide T, Utsumi M, Nagasawa M, Murakami K. A novel PPAR agonist ameliorates insulin resistance in dogs fed a high-fat diet. Am J Physiol Endocrinol Metab 294: E833–E840, 2008. First published January 22, 2008; doi:10.1152/ajpendo.00627.2007.—Agonism of peroxisome proliferator-activated receptor (PPAR) , a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPAR agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPAR agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg kg 1 day 1 KRP-101 (n 5) or vehicle (n 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPAR agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.