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P633H, a novel dual agonist at peroxisome proliferator‐activated receptors α and γ, with different anti‐diabetic effects in db/db and KK‐A y mice
Author(s) -
Chen Wei,
Zhou XinBo,
Liu HongYing,
Xu Cheng,
Wang LiLi,
Li Song
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00231.x
Subject(s) - endocrinology , medicine , peroxisome proliferator activated receptor , agonist , adipocyte , receptor , insulin resistance , chemistry , adipose tissue , dyslipidemia , insulin , diabetes mellitus , biology
Background and purpose: Peroxisome proliferator‐activated receptors (PPARs) are attractive targets for the treatment of type 2 diabetes and the metabolic syndrome. P633H (2‐[4‐(2‐Fluoro‐benzenesulphonyl)‐piperazin‐1‐yl]‐3‐{4‐[2‐(5‐methyl‐2‐phenyl‐oxazol‐4‐yl)‐ethoxy]‐phenyl}‐propionic acid), a novel PPARα/γ dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK‐A y mice. Experimental approach: The action of P633H at PPARα/γ was characterized by using transactivation assays. Functional activation of PPARα/γ in vitro was confirmed by pre‐adipocyte differentiation and regulation of target gene expression. Anti‐diabetic studies were performed in two different diabetic mice models in vivo . Key results: P633H activated both PPARα and PPAR γ, (with EC 50 values of 0.012 µmol and 0.032 µmol respectively). Additionally, P633H promoted pre‐adipocyte differentiation, up‐regulated expression of adipose specific transport protein (aP2) mRNA (3T3‐Ll cells) and acyl‐CoA oxidase mRNA (LO2 cells). In db/db mice, P633H reduced serum glucose, insulin, triglycerides, non‐esterified fatty acids and liver triglycerides. It also improved glucose intolerance without affecting food intake and body weight after 15 days of treatment. However in KK‐A y mice, hyperglycaemia, dyslipidemia and impaired glucose tolerance were not relieved even after a 25 day treatment with P633H. Further studies with real‐time PCR and electron microscopy revealed that P633H promoted progression of diabetes in KK‐A y mice by increasing hepatic gluconeogenesis and exacerbating pancreatic pathology. Conclusion and implications: Although P633H was a high‐potency PPARα/γ dual agonist, with good functional activity in vitro , it produced opposing anti‐diabetic effects in db/db and KK‐A y mice.