RESUMEN
We used parabiosis to determine whether the central nervous system (CNS)-mediated antidiabetic effects of leptin are mediated by release of brain-derived circulating factors. Parabiosis was surgically induced at 4 weeks of age, and an intracerebroventricular (ICV) cannula was placed in the lateral cerebral ventricle at 12 weeks of age for ICV infusion of leptin or saline vehicle. Ten days after surgery, food intake, body weight, and blood glucose were measured for 5 consecutive days, and insulin-deficiency diabetes was induced in all rats by a single streptozotocin (STZ) injection (40 mg/kg). Five days after STZ injection, leptin or vehicle was infused ICV for 7 days, followed by 5-day recovery period. STZ increased blood glucose and food intake. Chronic ICV leptin infusion restored normoglycemia in leptin-infused rats while reducing blood glucose by â¼27% in conjoined vehicle-infused rats. This glucose reduction was caused mainly by decreased hepatic gluconeogenesis. Chronic ICV leptin infusion also reduced net cumulative food intake and increased GLUT4 expression in skeletal muscle in leptin/vehicle compared with vehicle/vehicle conjoined rats. These results indicate that leptin's CNS-mediated antidiabetic effects are mediated, in part, by release into the systemic circulation of leptin-stimulated factors that enhance glucose utilization and reduce liver gluconeogenesis.
Asunto(s)
Sistema Nervioso Central/metabolismo , Leptina/metabolismo , Leptina/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Hipoglucemiantes/sangre , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Infusiones Intraventriculares , Insulina/sangre , Leptina/administración & dosificación , Leptina/sangre , Masculino , Parabiosis , Ratas , Ratas Endogámicas Lew , EstreptozocinaRESUMEN
Heart failure has a high mortality rate, and current therapies offer limited benefits. The authors demonstrate that activation of the central nervous system leptin-melanocortin pathway confers remarkable protection against progressive heart failure following severe myocardial infarction. The beneficial cardiac-protective actions of leptin require activation of brain melanocortin-4 receptors and elicit improvements in cardiac substrate oxidation, cardiomyocyte contractility, Ca2+ coupling, and mitochondrial efficiency. These findings highlight a potentially novel therapeutic approach for myocardial infarction and heart failure.
