RESUMO
4-(5 H -2,3-(2,5-Dimethyl-2,5-hexano)-5-methyl-8-nitrodibenzo[b,e][1,4]diazepin-11-yl)benzoic acid (HX531) is a novel retinoid X receptor antagonist. This study provides evidence that HX531 improves leptin resistance without increasing plasma leptin levels in KK-A y mice, an animal model with high plasma leptin levels and leptin resistance. Under normal dietary conditions, 3 weeks of treatment with HX531 (0.03% and 0.06% food admixture) in KK-A y mice decreased plasma leptin levels in a dose- and time-dependent manner, in addition to decreasing body weight and mesenteric fatty tissue weight. To evaluate the effect of HX531 on leptin resistance, leptin was injected intraperitoneally in the KK-A y mice for 4 days after 1 week of treatment with HX531 (0.06% food admixture). This pretreatment with HX531 resulted in exogenously administered leptin causing a significant decrease in food intake. These results suggested that HX531 decreased plasma leptin levels accompanied by a decrease in fatty tissue content in the KK-A y mice and a simultaneous improvement in leptin resistance. This is the first report that HX531 improves leptin resistance without increasing plasma leptin level in KK-A y mice, under normal dietary conditions.
Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta , Leptina/metabolismo , Receptores X de Retinoides/antagonistas & inibidores , Ácido 3-Hidroxibutírico/sangue , Tecido Adiposo/patologia , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Resistência a Medicamentos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Privação de Alimentos , Leptina/sangue , Leptina/farmacologia , Masculino , Mesentério , Camundongos , Camundongos Endogâmicos , Reto/fisiopatologiaRESUMO
NIP-222 is a novel peroxisome proliferator-activated receptor (PPAR)gamma agonist. This study provides evidence that NIP-222 decreases urinary albumin excretion (UAE) in diabetic mice independent of its PPARgamma activation. We compared the effect of NIP-222 and another PPARgamma agonist, troglitazone, on UAE, plasma glucose level, blood pressure, and creatinine clearance (C(cr)) in streptozotocin (STZ)-induced diabetic mice. Treatment for 3 weeks with NIP-222 (30 mg/kg) was associated with a significant decrease in UAE without any change in blood pressure, creatinine clearance, or plasma glucose level. In contrast, UAE did not decrease in mice treated with troglitazone (300 mg/kg). These results indicate that NIP-222 has PPARgamma independent effects on UAE in diabetic mice and suggest that this agent may have potential to minimize the development and progression of diabetic nephropathy.