RESUMEN
Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-ß (TGF-ß1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-ß1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-ß1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-ß1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-ß1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.
Asunto(s)
Terapia por Ejercicio , Hipotálamo/metabolismo , Obesidad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Edad , Animales , Regulación de la Temperatura Corporal , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Regulación hacia Abajo , Ingestión de Alimentos , Metabolismo Energético , Conducta Alimentaria , Hipotálamo/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa/metabolismo , Obesidad/genética , Obesidad/fisiopatología , Obesidad/terapia , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/genética , Pérdida de PesoRESUMEN
Uncoupling protein 2 (UCP2) is a member of the uncoupling protein family. It is expressed in the inner mitochondrial membrane and plays a role in the control of free radical production, oxidative damage, insulin secretion, and fatty-acid peroxide exportation. Although UCP2 expression occurs in several tissues, some of its most remarkable functions are exerted in organs of difficult experimental access, such as the central nervous system, particularly the hypothalamus and the pancreatic islets. In addition, due to its low levels of expression in the mitochondrial membrane, studying UCP2 expression and function depends on specific- and well-established methods. This chapter describes methods for directly assessing UCP2 expression and function in different tissues. Purified mitochondria preparations are used for enhancing the capacity of detection of UCP2 protein or for evaluating the role of UCP2 in mitochondria respiration. Exposure of experimental animals to cold environment leads to increased UCP2 expression, while reduction of its expression can be achieved directly by targeting its mRNA with antisense oligonucleotides, or indirectly by targeting PGC-1alpha expression with antisense oligonucleotides.
Asunto(s)
Regulación de la Expresión Génica , Canales Iónicos/genética , Canales Iónicos/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Animales , Elementos sin Sentido (Genética) , Frío , Hipotálamo/metabolismo , Immunoblotting , Canales Iónicos/aislamiento & purificación , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Mitocondrias/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/aislamiento & purificación , Oxígeno/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Reacción en Cadena de la Polimerasa , Proteínas de Unión al ARN/genética , Ratas , Ratas Wistar , Factores de Transcripción/genética , Proteína Desacopladora 2RESUMEN
Insulin signalling in the hypothalamus plays a role in maintaining body weight. The forkhead transcription factor Foxo1 is an important mediator of insulin signalling in the hypothalamus. Foxo1 stimulates the transcription of the orexigenic neuropeptide Y and Agouti-related protein through the phosphatidylinositol-3-kinase/Akt signalling pathway, but the role of hypothalamic Foxo1 in insulin resistance and obesity remains unclear. Here, we identify that a high-fat diet impaired insulin-induced hypothalamic Foxo1 phosphorylation and degradation, increasing the nuclear Foxo1 activity and hyperphagic response in rats. Thus, we investigated the effects of the intracerebroventricular (i.c.v.) microinfusion of Foxo1-antisense oligonucleotide (Foxo1-ASO) and evaluated the food consumption and weight gain in normal and diet-induced obese (DIO) rats. Three days of Foxo1-ASO microinfusion reduced the hypothalamic Foxo1 expression by about 85%. i.c.v. infusion of Foxo1-ASO reduced the cumulative food intake (21%), body weight change (28%), epididymal fat pad weight (22%) and fasting serum insulin levels (19%) and increased the insulin sensitivity (34%) in DIO but not in control animals. Collectively, these data showed that the Foxo1-ASO treatment blocked the orexigenic effects of Foxo1 and prevented the hyperphagic response in obese rats. Thus, pharmacological manipulation of Foxo1 may be used to prevent or treat obesity.