RESUMEN
Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
Asunto(s)
Acetiltransferasas/metabolismo , Dieta Aterogénica , Grasas de la Dieta/farmacología , Resistencia a la Insulina , Obesidad/metabolismo , Acetiltransferasas/deficiencia , Acetiltransferasas/genética , Animales , Peso Corporal/efectos de los fármacos , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Grasas de la Dieta/administración & dosificación , Elongasas de Ácidos Grasos , Eliminación de Gen , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina , Péptidos y Proteínas de Señalización Intracelular/fisiología , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Noqueados , Obesidad/inducido químicamente , Obesidad/genética , Fosfoproteínas/fisiología , Fosforilación , Proteína Quinasa C-epsilon/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
Diabetic retinopathy is known to be worsened when hypoglycemia occurs, however the pathogenic mechanisms are not defined. Vascular endothelial growth factor (VEGF) is increased in ocular fluid with diabetic retinopathy and linked with development of retinopathy. In this study, we examined whether glucose deficiency could up-regulate VEGF levels in retinal pigmented cells. Exposure to glucose deprived medium induced 30% up-regulation of VEGF mRNA. In hypoxia, as one of the most well-known inducer of VEGF, its up-regulation mechanism is mainly due to increase of transcription of VEGF gene via hypoxia response element in 5'-untranslated region (5'-UTR). We examined the role of 5'-UTR and 3'-UTR of VEGF gene in glucose deprived conditions using luciferase assay system. 5'-UTR containing reporter vector did not show increase of activity in glucose deprived conditions in contrast to the result in oxygen deprived condition. Both 5'-UTR and 3'-UTR containing vector demonstrated significant increase of activity in glucose deficient conditions compared with 5'-UTR containing vector. These findings suggest 3'-UTR of VEGF gene is important for increasing mRNA level in glucose deprived condition.