RESUMEN
Resistin promotes hypothalamic neuroinflammation and insulin resistance through Toll like receptor 4 (TLR4), this hormone is thought to be a link between obesity and insulin-resistance. Indeed, resistin plasma levels are higher in obese and insulin resistant subjects. However, the impact of maternal resistin on the predisposition of offspring to hypothalamic neuroinflammation is unknown. Here, female mice were treated with resistin during gestation/lactation periods, then hypothalamic neuroinflammation was investigated in male offspring at p28 and p90. At p28, resistin increased the expression of inflammation markers (IL6, TNFα and NFκB) and TLR4 in the hypothalamus and decreased both hypothalamic insulin and leptin receptors' expression. The hypothalamic up-regulation IL6, TNFα and TLR4 was sustained until p90 promoting most likely hypothalamic inflammation. Maternal resistin also increased IL6 and TNFα in the adipose tissue of offspring at p90 associated with a higher body weight gain. In contrast, liver and muscle were not affected. These findings reveal that the augmentation of maternal resistin during gestation and lactation promotes hypothalamic and adipose tissue inflammation of offspring as evidenced by sustained increase of inflammation markers from weaning to adulthood. Thus, maternal resistin programs offspring hypothalamic and adipose tissue inflammation predisposing then offspring to body weight gain.
Asunto(s)
Intolerancia a la Glucosa/etiología , Hipotálamo/inmunología , Inflamación/etiología , Resistencia a la Insulina , Insulinoma/etiología , Resistina/efectos adversos , Aumento de Peso/efectos de los fármacos , Animales , Animales Recién Nacidos , Peso Corporal , Femenino , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hipotálamo/patología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Insulinoma/metabolismo , Insulinoma/patología , Lactancia , Leptina/metabolismo , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Ratones , Embarazo , Resistina/administración & dosificación , DesteteRESUMEN
To explore the relationship between the serum resistin level and different types of coronary heart diseases (CHD). Literature was retrieved by formal searching of PubMed, Web of Science, Google Scholar, the Cochrane Library, Wanfang Data, China Biological Medicine Database (SinoMed) and China National Knowledge Infrastructure (CNKI) and by hand searching of reference lists of related articles. RevMan5.3 statistical software was utilized for processing and analysis. A total of 22 literatures involving 2070 subjects were included. Meta-analysis showed that the level of serum resistin in the patients with stable angina (SA), unstable angina(UA) or acute myocardial infarction (AMI) were significantly higher than those of normal controls, respectively [SMD(95% CI)were 1.97(1.15, 2.79), 2.54(1.76, 3.31), and 3.62(2.62, 4.62), all P<0.00001]. Serum resistin level in patients with UA or AMI was higher than those in patients with SA, respectively [SMD=0.90, 95CI(0.28,1.52), P=0.005], [SMD=2.28, 95%CI(0.74, 3.82), P=0.004].The level of serum resistin in patients with AMI was also higher than those in patients with UA [SMD=1.22, 95%CI(0.58, 1.85), P=0.0002]. The study demonstrated that increased serum resistin level is significantly associated with the severity of CHD.
Asunto(s)
Enfermedad Coronaria/sangre , Resistina/efectos adversos , Enfermedad Coronaria/patología , Femenino , Humanos , Masculino , Resistina/sangreRESUMEN
UNLABELLED: Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1α. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1α-signaling pathway. CONCLUSION: Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases.
Asunto(s)
Proteínas Quinasas Dependientes de GMP Cíclico/fisiología , Hígado Graso/inducido químicamente , Mitocondrias Hepáticas/efectos de los fármacos , Proteína Quinasa C/fisiología , Resistina/efectos adversos , Resistina/farmacología , Transactivadores/fisiología , eIF-2 Quinasa/fisiología , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hígado Graso/fisiopatología , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/fisiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transducción de Señal/fisiología , Factores de TranscripciónRESUMEN
The serum levels of resistin, a 12-kDa protein primarily expressed in inflammatory cells in humans, are increased in patients with chronic kidney disease and in those with diabetes mellitus. Both groups of patients have an increased risk of infections mainly as a result of disturbed polymorphonuclear leukocyte (PMNL) functions. Therefore, we investigated the influence of resistin on human PMNLs. Serum resistin concentrations were determined with a sandwich enzyme immunoassay. Using PMNLs from healthy subjects, chemotaxis was tested by the under-agarose method. Flow cytometric assays to measure oxidative burst and phagocytosis were conducted in whole blood. The uptake of deoxyglucose was determined as measure of the PMNL activation state. The activity of intracellular kinases was assessed by Western blotting and by in vitro kinase assays. Resistin inhibited PMNL chemotaxis and decreased the oxidative burst stimulated by Escherichia coli and by PMA, but did not influence PMNL phagocytosis of opsonized E. coli and PMNL glucose uptake. The inhibition of PMNLs by resistin was observed at concentrations found in serum samples of uremic patients, but not in concentrations measured in healthy subjects. Experiments with specific signal transduction inhibitors and measurements of intracellular kinases suggest that PI3K is a major target of resistin. In conclusion, resistin interferes with the chemotactic movement and the stimulation of the oxidative burst of PMNL, and therefore may contribute to the disturbed immune response in patients with increased resistin serum levels such as uremic and diabetic subjects.
Asunto(s)
Inhibición de Migración Celular/inmunología , Quimiotaxis de Leucocito/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Resistina/fisiología , Adulto , Cromonas/farmacología , Diabetes Mellitus/enzimología , Diabetes Mellitus/inmunología , Diabetes Mellitus/patología , Escherichia coli/crecimiento & desarrollo , Escherichia coli/inmunología , Femenino , Glucosa/metabolismo , Hexosas/metabolismo , Humanos , Masculino , Morfolinas/farmacología , Activación Neutrófila/efectos de los fármacos , Neutrófilos/enzimología , Neutrófilos/microbiología , Neutrófilos/patología , Oxidación-Reducción/efectos de los fármacos , Fagocitosis/inmunología , Inhibidores de Proteínas Quinasas/farmacología , Resistina/efectos adversos , Resistina/sangre , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Uremia/enzimología , Uremia/inmunología , Uremia/patologíaRESUMEN
Second generation antipsychotics (SGA) are obesitogenic and diabetogenic. Role of ghrelin (RIA), resistin and TNF-alpha (ELISA) in weight gain and insulin resistance (fasting plasma insulin, HOMA, ELISA) was studied in Hungarian psychiatryic patients (n=60) treated with SGA (clozapine, olanzapine, risperidone, quetiapine, 15 each). After 1 year, 80% of patients became overweight/obese (BMI > 27/30) and 35% (n= 21/60) presented impaired glucose tolerance (13/60) or diabetes (8/60). Ghrelin (1.3 +/- 0.6 ng/ml), resistin (9.8 +/- 3.7 ng/ml), TNF-alpha (5.8 +/- 1.7 pg/ml), insulin (10.4 +/- 7.6 U/ml, HOMA A: 2.5 +/- 1.8, HOMA B: 133 +/- 62.5) were significantly higher in patients than in healthy matched controls. Resistin and TNF-alpha positively correlated with each other, insulin, HOMA, and negatively with ghrelin. Ghrelin contributes to weight gain, resistin and TNF-alpha to insulin resistance. A negative feedback regulation may exist between adipocytokines and ghrelin production. SGA drugs enhance ghrelin production despite the suppressive effect of adipocytokines. All four SGA drugs are equally obesitogenic and diabetogenic.