title: A novel PPARalpha agonist ameliorates insulin resistance in dogs fed a high-fat diet.
abstract: Agonism of peroxisome proliferator-activated receptor (PPAR) alpha, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPARalpha 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 PPARalpha 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 x kg(-1) x 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 PPARalpha agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.
authors.affiliation: Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tsunoda
authors.forename: Naoki
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ide
authors.forename: Mari
authors.initials: M
authors.lastname: Utsumi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Koji
authors.initials: K
authors.lastname: Murakami
mesh_terms: D052242:Adiponectin / Q000096:biosynthesis / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D017930:Genes, Reporter / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009765:Obesity / Q000188:drug therapy; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D047494:PPAR delta / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D052242:Adiponectin; D002087:Butyrates; D018076:DNA, Complementary; D004041:Dietary Fats; D005227:Fatty Acids; D000960:Hypolipidemic Agents; C529595:KRP-101; D008055:Lipids; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; C006012:fenofibric acid; D008156:Luciferases; D011345:Fenofibrate