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.

Abstract

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 PPARalpha/gamma 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 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.

KEY 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.

CONCLUSION AND IMPLICATIONS:

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.

• Authors: Wei Chen, Xin-Bo Zhou, Hong-Ying Liu, Cheng Xu, Li-Li Wang, Song Li
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 157 Issue 5 Pg. 724-35 (Jul 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19422369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(4-(2-Fluoro-benzenesulphonyl)-piperazin-1-yl)-3-(4-(2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy)phenyl)propionic acid
• Blood Glucose
• Fabp4 protein, mouse
• Fatty Acid-Binding Proteins
• Fatty Acids, Nonesterified
• Hypoglycemic Agents
• Insulin
• PPAR alpha
• PPAR gamma
• Phenylpropionates
• RNA, Messenger
• Sulfonamides
• Triglycerides
• Acyl-CoA Oxidase

Topics

• 3T3-L1 Cells
• Acyl-CoA Oxidase (genetics)
• Adipocytes (drug effects, metabolism, pathology)
• Animals
• Blood Glucose (drug effects)
• Cell Differentiation (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy, metabolism, physiopathology)
• Disease Models, Animal
• Dyslipidemias (drug therapy, metabolism, physiopathology)
• Fatty Acid-Binding Proteins (genetics)
• Fatty Acids, Nonesterified (blood)
• Female
• Gene Expression Regulation (drug effects)
• Gluconeogenesis (drug effects)
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• Hypoglycemic Agents (adverse effects, pharmacology)
• Insulin (blood)
• Insulin Resistance
• Male
• Mice
• Mice, Inbred C57BL
• PPAR alpha (agonists, genetics, metabolism)
• PPAR gamma (agonists, genetics, metabolism)
• Pancreas (drug effects, metabolism, pathology)
• Phenylpropionates (adverse effects, pharmacology)
• RNA, Messenger (metabolism)
• Sulfonamides (adverse effects, pharmacology)
• Time Factors
• Transcriptional Activation (drug effects)
• Transfection
• Triglycerides (blood)