KRP-101: A Potent PPARα Agonist Ameliolates Fat-Induced Insulin Resistance with Suppression of Adiposity in Dogs.

Tsunoda, Masaki; Kobayashi, Naoki; Utsumi, Mari; Nagasawa, Michiaki; Ide, Tomohiro; Murakami, Koji

Anti-diabetic effects in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were not pronounced. We hypothesized that the lower effects may have been due to the weak PPARα agonism of Fenofibrate and/or a lower expression of hepatic PPARα in humans than in rodents. To further clarify the insulin-sensitizing actions of PPARα agonism, dogs fed a high fat diet (HFD) were administered KRP-101 (KRP), a novel potent PPARα agonist. Dogs fed a HFD for 12 wk exhibited mild hyperglycemia (1.3-fold), hyperinsulinemia (3.2-fold), and hypertriglycemia (3.6-fold), compared to dogs fed a standard diet. KRP (0.03 mg/kg/day) decreased serum levels of glucose (-36%) and insulin (-70%) as well as triglyceride (TG, -80%). KRP improved glucose intolerance on OGTT. HFD caused TG accumulation and impairment of fatty acid oxidation (FAO; CO[sub 2] production from [[sup 14]C]-palmitic acid) in the liver and skeletal muscle. KRP decreased hepatic TG concentration (-57%) and increased FAO in the liver (2.6-fold). In skeletal muscle, KRP decreased the TG concentration (-19%) and increased FAO (1.8-fold). In contrast to PPARγ agonists, KRP significantly decreased the white adipose tissue weight (omental; -31%, mesenteric; -39%, perirenal; -55%) of HFD-fed dogs. Hyperleptinemia and hypoadiponectinemia in HFD-fed dogs were consistently improved by KRP treatment. In white adipose tissue of HFD-fed dogs, a macrophage marker CD68 was slightly increased, but inflammatory markers, TNFα and MCP-1, were not significantly increased, suggesting that adipose inflammation may be less responsible for the development of insulin resistance in HFD-fed dogs. KRP did not significantly affect mRNA levels of CD68, TNFα, and MCP-1. In conclusion, a potent PPARalpha; agonist prevented fat-induced insulin resistance through inhibition of lipid accumulation in insulin target tissues in dogs. This effect was accompanied by reduced adiposity. These findings suggest that strong PPARα activation is a potential new therapeutic strategy for diabetic dyslipidemia associated with obesity and metabolic syndrome.

NUCLEAR receptors (Biochemistry); HYPERGLYCEMIA; INSULIN; DIABETES; BLOOD sugar; TRIGLYCERIDES; FATTY acids; OBESITY

Diabetes, 2007, Vol 56, pA137

0012-1797

Academic Journal