P633H, a novel dual agonist at peroxisome proliferator-activated receptors alpha and gamma, with different anti-diabetic effects in db/db and KK-Ay mice.
OBJECTIVE
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 PPARalpha/gamma dual agonist, was investigated for its very different effects on insulin resistance and dyslipidemia in db/db and KK-A(y) mice.


METHODS
The action of P633H at PPARalpha/gamma was characterized by using transactivation assays. Functional activation of PPARalpha/gammain 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.


RESULTS
P633H activated both PPARalpha and PPAR gamma, (with EC(50) values of 0.012 micromol and 0.032 micromol 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.


CONCLUSIONS
Although P633H was a high-potency PPARalpha/gamma dual agonist, with good functional activity in vitro, it produced opposing anti-diabetic effects in db/db and KK-A(y) mice.
Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Wei
W
Chen
Xin-Bo
XB
Zhou
Hong-Ying
HY
Liu
Cheng
C
Xu
Li-Li
LL
Wang
Song
S
Li
D041721:3T3-L1 Cells; D042962:Acyl-CoA Oxidase / Q000235:genetics; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010666:Phenylpropionates / Q000009:adverse effects / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014280:Triglycerides / Q000097:blood
C544179:2-(4-(2-Fluoro-benzenesulphonyl)-piperazin-1-yl)-3-(4-(2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy)phenyl)propionic acid; D001786:Blood Glucose; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D012333:RNA, Messenger; D013449:Sulfonamides; D014280:Triglycerides; D042962:Acyl-CoA Oxidase