RESUMEN
OBJECTIVE: Hypertrophic obesity is associated with impaired insulin sensitivity and lipid-mobilizing activity of zinc-α2-glycoprotein. Adipose tissue (AT) of growth hormone (GH) -deficient patients is characterized by extreme adipocyte hypertrophy due to defects in AT lipid metabolism. It was hypothesized that zinc-α2-glycoprotein is regulated by GH and mediates some of its beneficial effects in AT. METHODS: AT from patients with GH deficiency and individuals with obesity-related GH deficit was obtained before and after 5-year and 24-month GH supplementation therapy. GH action was tested in primary human adipocytes. Relationships of GH and zinc-α2-glycoprotein with adipocyte size and insulin sensitivity were evaluated in nondiabetic patients with noncancerous cachexia and hypertrophic obesity. RESULTS: AT in GH-deficient adults displayed a substantial reduction of zinc-α2-glycoprotein. GH therapy normalized AT zinc-α2-glycoprotein. Obesity-related relative GH deficit was associated with almost 80% reduction of zinc-α2-glycoprotein mRNA in AT. GH increased zinc-α2-glycoprotein mRNA in both AT of obese men and primary human adipocytes. Interdependence of GH and zinc-α2-glycoprotein in regulating AT morphology and metabolic phenotype was evident from their relationship with adipocyte size and AT-specific and whole-body insulin sensitivity. CONCLUSIONS: The results demonstrate that GH is involved in regulation of AT zinc-α2-glycoprotein; however, the molecular mechanism linking GH and zinc-α2-glycoprotein in AT is yet unknown.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Hormona de Crecimiento Humana/administración & dosificación , Obesidad/metabolismo , Proteínas de Plasma Seminal/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Administración Oral , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Suplementos Dietéticos , Femenino , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/farmacología , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Zn-alfa-2-GlicoproteínaRESUMEN
BACKGROUND: Insulin signaling and Tau protein phosphorylation in the hippocampi of young and old obese Zucker fa/fa rats and their lean controls were assessed to determine whether obesity-induced peripheral insulin resistance and aging are risk factors for central insulin resistance and whether central insulin resistance is related to the pathologic phosphorylation of the Tau protein. RESULTS: Aging and obesity significantly attenuated the phosphorylation of the insulin cascade kinases Akt (protein kinase B, PKB) and GSK-3ß (glycogen synthase kinase 3ß) in the hippocampi of the fa/fa rats. Furthermore, the hyperphosphorylation of Tau Ser396 alone and both Tau Ser396 and Thr231 was significantly augmented by aging and obesity, respectively, in the hippocampi of these rats. CONCLUSIONS: Both age-induced and obesity-induced peripheral insulin resistance are associated with central insulin resistance that is linked to hyperTau phosphorylation. Peripheral hyperinsulinemia, rather than hyperglycemia, appears to promote central insulin resistance and the Tau pathology in fa/fa rats.
Asunto(s)
Envejecimiento/fisiología , Hipocampo/fisiopatología , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Obesidad/fisiopatología , Proteínas tau/metabolismo , Animales , Western Blotting , Prueba de Tolerancia a la Glucosa , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Masculino , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Zucker , Transducción de Señal , Proteínas tau/genéticaRESUMEN
Melatonin was previously shown to reduce blood pressure and left ventricular (LV) remodeling in several models of experimental heart damage. This study investigated whether melatonin prevents LV remodeling and improves survival in isoproterenol-induced heart failure. In the first experiment, four groups of 3-month-old male Wistar rats (12 per group) were treated for 2 wk as follows: controls, rats treated with melatonin (10 mg/kg/day) (M), rats treated with isoproterenol (5 mg/kg/day intraperitoneally the second week) (Iso), and rats treated with melatonin (2 wk) and isoproterenol (the second week) in corresponding doses (IsoM). In the second experiment, 30 rats were treated with isoproterenol and 30 rats with isoproterenol plus melatonin for a period of 28 days and their mortality was investigated. Isoproterenol-induced heart failure with hypertrophy of the left and right ventricles (LV, RV), lowered systolic blood pressure (SBP) and elevated pulmonary congestion. Fibrotic rebuilding was accompanied by alterations of tubulin level in the LV and oxidative stress development. Melatonin failed to reduce the weight of the LV or RV; however, it curtailed the weight of the lungs and attenuated the decline in SBP. Moreover, melatonin decreased the level of oxidative stress and of insoluble and total collagen and partly prevented the beta-tubulin alteration in the LV. Most importantly, melatonin reduced mortality and prolonged the average survival time. In conclusion, melatonin exerts cardioprotective effects and improves outcome in a model of isoproterenol-induced heart damage. The antiremodeling effect of melatonin may be of potential benefit in patients with heart failure.
Asunto(s)
Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Isoproterenol/toxicidad , Melatonina/uso terapéutico , Animales , Cardiomegalia/inducido químicamente , Cardiomegalia/tratamiento farmacológico , Masculino , Ratas , Ratas WistarRESUMEN
The metabolic action of oxytocin has recently been intensively studied to assess the ability of the peptide to regulate energy homeostasis. Despite the obvious weight-reducing effect of oxytocin observed in experimental studies, plasma oxytocin levels were found to be unchanged or even elevated in human obesity. The aim of our study was to evaluate the changes in the oxytocin system in Zucker rats, an animal model closely mirroring morbid obesity in humans. Plasma oxytocin levels were measured in obese Zucker rats and lean controls by enzyme immunoassay after plasma extraction. The expression of oxytocin and oxytocin receptor (OXTR) was assessed at the mRNA and protein levels by quantitative real-time PCR and immunoblotting respectively. Plasma and tissue activity of oxytocinase, the main enzyme involved in oxytocin degradation, were measured by fluorometric assay using an arylamide derivate as the substrate. Obese Zucker rats displayed a marked reduction in plasma oxytocin levels. Elevated liver and adipose tissue oxytocinase activity was noticed in obese Zucker rats. Hypothalamic oxytocin gene expression was not altered by the obese phenotype. OXTR mRNA and protein levels were upregulated in the adipose tissue of obese animals in contrast to the reduced OXTR protein levels in skeletal muscle. Our results show that obesity is associated with reduced plasma oxytocin due to increased peptide degradation by liver and adipose tissue rather than changes in hormone synthesis. This study highlights the importance of the oxytocin system in the pathogenesis of obesity and suggests oxytocinase inhibition as a candidate approach in the therapy of obesity.
Asunto(s)
Tejido Adiposo/metabolismo , Hígado/metabolismo , Obesidad Mórbida/metabolismo , Oxitocina/sangre , Animales , Cistinil Aminopeptidasa/sangre , Humanos , Masculino , Músculo Esquelético/metabolismo , Obesidad Mórbida/genética , Proteolisis , Ratas , Ratas Zucker , Receptores de Oxitocina/genética , Receptores de Oxitocina/metabolismoRESUMEN
PPAR γ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPAR γ agonist pioglitazone (PIO) on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS) and peripheral (left ventricle, LV) levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10 mg/kg/day, 2 weeks) or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPAR γ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while ß -catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that ß -catenin and SOD levels are important agents mediating PIO effects in the BS and LV.