RESUMO
Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and insulin resistance. In this study we show that a novel compound, 3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}- 2-[2-(2-nitro-phenoxy)-acetyl amino]-propionic acid (O325H), is an agonist with dual effect on PPARalpha/gamma by using dual-luciferase reporter gene assay. By activating PPARalpha and PPARgamma simultaneously, O325H promotes pre-adipocyte differentiation and up-regulates the expression of glucose and lipid metabolic target genes. In diabetic mice, administration of O325H at 10 mg/kg decreases the blood lipid and glucose levels. Therefore, O325H has dual action on PPARalpha and PPARgamma and is a promising agent for the amelioration of lipid metabolic disorders and diabetes associated with insulin resistance.
Assuntos
Adipogenia/efeitos dos fármacos , Complicações do Diabetes/tratamento farmacológico , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Oxazóis/farmacologia , PPAR alfa/antagonistas & inibidores , PPAR gama/antagonistas & inibidores , Tirosina/análogos & derivados , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Animais , Diferenciação Celular , Humanos , Resistência à Insulina/fisiologia , Masculino , Camundongos , Modelos Animais , Tirosina/farmacologia , Regulação para CimaRESUMO
AIM: To examine the effects of novel peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonist C333H on insulin resistance and lipid metabolism. METHODS: An established dual-luciferase reporter gene assay system was used in vitro to test the activity of C333H with respect to the transcription of human PPARalpha and PPARgamma. A preadipocyte differentiation assay and reverse transcription-polymerase chain reaction were used to detect the functional activities of C333H. In db/db mice, the effects of C333H were investigated with respect to lowering of blood glucose and lipid levels. RESULTS: C333H was determined to be a novel PPARalpha/gamma dual agonist because it strongly induced luciferase activity on human PPARalpha and PPARgamma, promoting the differentiation of preadipocytes to adipocytes, and functioning in upregulating the expression of some glucose and lipid metabolic target genes of the PPAR. In addition, C333H efficiently reduced blood lipid and glucose concentrations in db/db diabetic mice. CONCLUSION: C333H has dual action on both PPARalpha and PPARgamma, and might be of interest for the amelioration of lipid metabolic disorders and insulin resistance associated with type 2 diabetes.
