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This Article Full Text Full Text (PDF) All Versions of this Article: 294/5/E833    most recent 00627.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tsunoda, M. Articles by Murakami, K. Search for Related Content PubMed PubMed Citation Articles by Tsunoda, M. Articles by Murakami, K.

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

Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan

Submitted 28 September 2007 ; accepted in final form 18 January 2008

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.

KRP-101; obesity; insulin resistance; muscle lipid oxidation