RESUMEN
Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats.
Asunto(s)
Resistencia a Medicamentos/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Insulina/farmacología , Leptina/farmacología , Obesidad/patología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Adiposidad/efectos de los fármacos , Adiposidad/genética , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Dieta Aterogénica , Resistencia a Medicamentos/genética , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/genética , Glucosa/metabolismo , Hipotálamo/enzimología , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Masculino , Obesidad/etiología , Obesidad/metabolismo , Oligonucleótidos Antisentido/farmacología , Proteínas Tirosina Fosfatasas/genética , Ratas , Ratas Wistar , Saciedad/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: In this prospective study, we assessed nutritional and immunologic risk factors for infectious complications and deaths related to infection in elderly patients undergoing major elective surgery. METHODS: Seventy patients 60 y or older were enrolled in this study. The preoperative variables analyzed were body mass index, body mass index knee height, triceps skinfold, subscapular skinfold, mid-arm muscle circumference, mid-arm muscle area, albumin, transferrin, prealbumin, and retinol-binding protein levels, immunoglobulins G, A, and M, C3, and C4 levels, total lymphocyte counts, and the occurrence of delayed hypersensitivity reactions (multitest). RESULTS: Abnormally low levels of prealbumin (P = 0.004), retinol-binding protein (P = 0.05), and transferrin (P = 0.04) were related to infectious complications. Prealbumin levels (P = 0.02) and lymphocyte counts below 1500 cells/mm(3) (P = 0.04) were associated with mortality secondary to infection. Univariate regression analysis showed that levels of prealbumin (P = 0.02, odds ratio = 13.3, 95% confidence limits = 1.6, 110.9), retinol-binding protein (P = 0.03, odds ratio = 4.8, 95% confidence limits = 1.2, 19.3), and transferrin (P = 0.03; odds ratio = 4.2, 95% confidence limit = 1.2, 15.6) were associated with infectious complications. Multivariate analysis associated only prealbumin levels with infectious complications (P = 0.02, odds ratio = 13.3, 95% confidence limit = 1.6, 110.9). Regression analysis provided no conclusion regarding mortality because of the small number of deaths recorded. CONCLUSIONS: In patients with a good cardiac index (Goldman I and II) who underwent major elective surgery, prealbumin protein, retinol-binding protein, and transferrin levels below normal values represented a significant risk for postoperative infectious complications. Lymphocyte counts lower than 1500/m(3) and abnormal prealbumin values were associated with postoperative mortality secondary to infection. The anthropometric variables evaluated did not predict postoperative infectious complications and mortality.
Asunto(s)
Procedimientos Quirúrgicos Electivos , Estado de Salud , Infecciones/epidemiología , Estado Nutricional , Complicaciones Posoperatorias/epidemiología , Anciano , Anciano de 80 o más Años , Proteínas Sanguíneas/análisis , Brasil , Femenino , Humanos , Infecciones/sangre , Infecciones/mortalidad , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/inmunología , Prealbúmina/análisis , Estudios Prospectivos , Análisis de Regresión , Proteínas de Unión al Retinol/análisis , Factores de Riesgo , Transferrina/análisisRESUMEN
Short-term muscle denervation is a reproducible model of tissue-specific insulin resistance. To investigate the molecular basis of insulin resistance in denervated muscle, the downstream signaling molecules of the insulin-signaling pathway were examined in intact and denervated soleus muscle of rats. Short-term denervation induced a significant fall in glucose clearance rates (62% of control, P < 0.05) as detected by euglycemic hyperinsulinemic clamp and was associated with a significant decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR; 73% of control, P < 0.05), IR substrate 1 (IRS1; 69% of control, P < 0.05), and IRS2 (82% of control, P < 0.05) and serine phosphorylation of Akt (39% of control, P < 0.05). Moreover, denervation reduced insulin-induced association between IRS1/IRS2 and p85/phosphatidylinositol (PI) 3-kinase. Nevertheless, denervation caused an increase in PI 3-kinase activity associated with IRS1 (275%, P < 0.05) and IRS2 (180%, P < 0.05), but the contents of phosphorylated PI detected by HPLC were significantly reduced in lipid fractions. In the face of the apparent discrepancy, we evaluated the expression and activity of the 5-inositol, lipid phosphatase SH2 domain-containing inositol phosphatase (SHIP2), and the serine phosphorylation of p85/PI 3-kinase. No major differences in SHIP2 expression were detected between intact and denervated muscle. However, serine phosphorylation of p85/PI 3-kinase was reduced in denervated muscle, whereas the blockade of SHIP2 expression by antisense oligonucleotide treatment led to partial restoration of phosphorylated PI contents and to improved glucose uptake. Thus modulation of the functional status of SHIP2 may be a major mechanism of insulin resistance induced by denervation.