RESUMEN
Alzheimer's disease (AD) is characterized by the deposition in the brain of senile plaques composed of amyloid-ß peptides (Aßs) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE), has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aß levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aß25-35 for 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aß-degrading enzymes associated with these GPE-related effects. GPE prevented the Aß-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1, and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme, was also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aß insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aß levels through modulation of levels and/or activity of Aß proteases.
Asunto(s)
Péptidos beta-Amiloides , Hipocampo , Factor I del Crecimiento Similar a la Insulina , Oligopéptidos , Transducción de Señal , Animales , Péptidos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas , Factor I del Crecimiento Similar a la Insulina/metabolismo , Transducción de Señal/efectos de los fármacos , Femenino , Oligopéptidos/farmacología , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Fragmentos de Péptidos/metabolismo , Ratas Wistar , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Péptidos Similares a la InsulinaRESUMEN
Diets rich in saturated fats are more detrimental to health than those containing mono- or unsaturated fats. Fatty acids are an important source of energy, but they also relay information regarding nutritional status to hypothalamic metabolic circuits and when in excess can be detrimental to these circuits. Astrocytes are the main site of central fatty acid ß-oxidation, and hypothalamic astrocytes participate in energy homeostasis, in part by modulating hormonal and nutritional signals reaching metabolic neurons, as well as in the inflammatory response to high-fat diets. Thus, we hypothesized that how hypothalamic astrocytes process-specific fatty acids participates in determining the differential metabolic response and that this is sex dependent as males and females respond differently to high-fat diets. Male and female primary hypothalamic astrocyte cultures were treated with oleic acid (OA) or palmitic acid (PA) for 24 h, and an untargeted metabolomics study was performed. A clear predictive model for PA exposure was obtained, while the metabolome after OA exposure was not different from controls. The observed modifications in metabolites, as well as the expression levels of key metabolic enzymes, indicate a reduction in the activity of the Krebs and glutamate/glutamine cycles in response to PA. In addition, there were specific differences between the response of astrocytes from male and female mice, as well as between hypothalamic and cerebral cortical astrocytes. Thus, the response of hypothalamic astrocytes to specific fatty acids could result in differential impacts on surrounding metabolic neurons and resulting in varied systemic metabolic outcomes.
Asunto(s)
Astrocitos , Hipotálamo , Ácido Oléico , Ácido Palmítico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ácido Oléico/farmacología , Femenino , Ácido Palmítico/farmacología , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Caracteres Sexuales , Células CultivadasRESUMEN
Context: Anomalies in the growth hormone (GH)/insulin-like growth factor (IGF) axis, are common in children with type 1 diabetes mellitus (T1DM), even in those reaching a normal or near-normal final height. However, concentrations of the IGF bioavailability regulatory factors (pappalysins [PAPP-As] and stanniocalcins [STCs]) have not been reported in children with T1DM. Objective: To determine serum concentrations of PAPP-As and STCs in children at diagnosis of T1DM and after insulin treatment and the correlation of these factors with other members of the GH/IGF axis, beta-cell insulin reserve, auxology, and nutritional status. Methods: A single-center prospective observational study including 47 patients (59.5% male), with T1DM onset at median age of 9.2 years (interquartile range: 6.3, 11.9) was performed. Blood and anthropometric data were collected at diagnosis and after 6 and 12 months of treatment. Results: At 6 and 12 months after T1DM diagnosis, there was improvement in the metabolic control (decrease in glycated hemoglobin [HbA1c] at 12 months -3.66 [95% CI: -4.81, -2.05], P = .001), as well as in body mass index SD and height SD (not statistically significant). STC2 increased (P < .001) and PAPP-A2 decreased (P < .001) at 6 and 12 months of treatment onset (P < .001), which was concurrent with increased total IGF-I and IGF-binding protein concentrations, with no significant modification in free IGF-I concentrations. HbA1c correlated with PAPP-A2 (r = +0.41; P < .05) and STC2 (r = -0.32; P < .05). Conclusion: Implementation of insulin treatment after T1DM onset modifies various components of the circulating IGF system, including PAPP-A2 and STC2. How these modifications modulate linear growth remains unknown.
RESUMEN
CONTEXT: Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. OBJECTIVE: We determined serum levels of PAPP-As and STCs in association with IGF axis components in prepubertal and pubertal patients with PWS, also analyzing the effect of GH treatment. METHODS: Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at 6 months of treatment in 11 children. RESULTS: Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and they had higher concentrations of free IGF-I, IGFBP-5, and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and had increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs, and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. CONCLUSION: The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.
Asunto(s)
Glicoproteínas , Hormona de Crecimiento Humana , Factor I del Crecimiento Similar a la Insulina , Síndrome de Prader-Willi , Proteína Plasmática A Asociada al Embarazo , Proteolisis , Humanos , Niño , Masculino , Femenino , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/análisis , Síndrome de Prader-Willi/metabolismo , Síndrome de Prader-Willi/sangre , Síndrome de Prader-Willi/tratamiento farmacológico , Proteína Plasmática A Asociada al Embarazo/metabolismo , Proteína Plasmática A Asociada al Embarazo/análisis , Adolescente , Glicoproteínas/sangre , Glicoproteínas/metabolismo , Hormona de Crecimiento Humana/sangre , Preescolar , Disponibilidad Biológica , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/sangre , Estudios de Casos y ControlesRESUMEN
Dietary restriction is a frequent strategy for weight loss, but adherence is difficult and returning to poor dietary habits can result in more weight gain than that previously lost. How weight loss due to unrestricted intake of a healthy diet affects the response to resumption of poor dietary habits is less studied. Moreover, whether this response differs between the sexes and if the insulin-like growth factor (IGF) system, sex dependent and involved in metabolic control, participates is unknown. Mice received rodent chow (6% Kcal from fat) or a high-fat diet (HFD, 62% Kcal from fat) for 4 months, chow for 3 months plus 1 month of HFD, or HFD for 2 months, chow for 1 month then HFD for 1 month. Males and females gained weight on HFD and lost weight when returned to chow at different rates (p < 0.001), but weight gain after resumption of HFD intake was not affected by previous weight loss in either sex. Glucose metabolism was more affected by HFD, as well as the re-exposure to HFD after weight loss, in males. This was associated with increases in hypothalamic mRNA levels of IGF2 (p < 0.01) and IGF binding protein (IGFBP) 2 (p < 0.05), factors involved in glucose metabolism, again only in males. Likewise, IGF2 increased IGFBP2 mRNA levels only in hypothalamic astrocytes from males (p < 0.05). In conclusion, the metabolic responses to dietary changes were less severe and more delayed in females and the IGF system might be involved in some of the sex specific observations.
Asunto(s)
Dieta Alta en Grasa , Aumento de Peso , Masculino , Femenino , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Pérdida de Peso , ARN Mensajero , Glucosa , Ratones Endogámicos C57BLRESUMEN
Leptin inhibits food intake and reduces the size of body fat depots, changing adipocyte sensitivity to insulin to restrain lipid accrual. This adipokine may modulate the production of cytokines that could diminish insulin sensitivity, particularly in visceral adipose tissue. To explore this possibility, we examined the effects of chronic central administration of leptin on the expression of key markers of lipid metabolism and its possible relationship with changes in inflammatory- and insulin-signaling pathways in epididymal adipose tissue. Circulating non-esterified fatty acids and pro- and anti-inflammatory cytokines were also measured. Fifteen male rats were divided into control (C), leptin (L, icv, 12 µg/day for 14 days), and pair-fed (PF) groups. We found a decrease in the activity of glucose-6-phosphate dehydrogenase and malic enzyme in the L group, with no changes in the expression of lipogenic enzymes. A reduction in the expression of lipoprotein lipase and carnitine palmitoyl-transferase-1A, together with a decrease in the phosphorylation of insulin-signaling targets and a low-grade inflammatory pattern, were detected in the epididymal fat of L rats. In conclusion, the decrease in insulin sensitivity and increased pro-inflammatory environment could regulate lipid metabolism, reducing epididymal fat stores in response to central leptin infusion.
Asunto(s)
Resistencia a la Insulina , Leptina , Ratas , Masculino , Animales , Leptina/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos , Tejido Adiposo/metabolismo , Citocinas/metabolismo , Inflamación/metabolismoRESUMEN
Leptin is involved in the modulation of insulin signaling in peripheral tissues, being closely associated with changes in lipid metabolism. This adipokine modifies inflammatory pathways that can interact with insulin targets in peripheral organs; however, the mechanisms remain unclear. Inflammatory and insulin signaling targets, cytokines, adiponectin, irisin and non-esterified fatty acid (NEFA) levels and enzymes of fatty acid anabolism were studied in the gastrocnemius of chronic centrally infused leptin (L), pair-fed and control rats. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) and c-Jun N-terminal kinase (JNK) was reduced in L rats (59% and 58%, respectively). The phosphorylation of the insulin receptor and Akt and adiponectin and irisin content was increased in L rats (154%, 157%, 308% and 329%, respectively). The levels of glucose-6-phosphate dehydrogenase, the mRNA content of acetyl Co-A carboxylase and NEFA concentrations were diminished in the muscles of L rats (59%, 50% and 61%, respectively). The activation of JNK correlated positively with STAT3 phosphorylation, tumoral necrosis factor-α and NEFA and negatively with irisin and Akt phosphorylation. These data suggest that the activation of insulin signaling targets and a decrease in NEFA content are associated with a reduction in muscle inflammation parameters, suggesting that leptin may integrate these pathways.
RESUMEN
Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro- and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling.
Asunto(s)
Insulina , Leptina , Tejido Adiposo , Animales , Ratas , Factor de Transcripción STAT3 , Transducción de SeñalRESUMEN
Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2-/-) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2-/- mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2-/- mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2-/- mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2-/- mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2-/- mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2-/- mice. Conversely, D IRS2-/- mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.
Asunto(s)
Citocinas/metabolismo , Hipotálamo/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Animales , Glucemia/metabolismo , Quimiocina CX3CL1/sangre , Citocinas/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Metabolismo Energético/genética , Ácidos Grasos Insaturados/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Sustrato del Receptor de Insulina/deficiencia , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Leptina/metabolismo , Metabolismo de los Lípidos/genética , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.
Asunto(s)
Hipotálamo/efectos de los fármacos , Insulina/farmacología , Leptina/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hipófisis/efectos de los fármacos , Animales , Ácidos Grasos no Esterificados/sangre , Regulación de la Expresión Génica , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Hipotálamo/metabolismo , Inyecciones Intravenosas , Inyecciones Intraventriculares , Insulina/metabolismo , Leptina/metabolismo , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Masculino , Hipófisis/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Transducción de Señal , Triglicéridos/sangreRESUMEN
The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.
Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Hormona del Crecimiento/genética , Factor I del Crecimiento Similar a la Insulina/genética , Leptina/farmacología , Termogénesis/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Metabolismo Energético/genética , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Hormona del Crecimiento/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fosforilación/efectos de los fármacos , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Somatostatina/genética , Somatostatina/metabolismo , Proteína 3 Supresora de la Señalización de Citocinas/genética , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Termogénesis/genética , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMEN
Alzheimer's disease (AD) is the most common form of dementia and has a higher incidence in women. The main component of the senile plaques characteristic of AD is amyloid-beta (Aß), with surrounding astrocytes contributing to the degenerative process. We hypothesized that the sex difference in the incidence of AD could be partially due to differential astrocytic responses to Aß. Thus, the effect of Aß1-40 on cell viability, the inflammatory response, and oxidative status was studied in cultures of hippocampal astrocytes from male and female rats. Aß1-40 increased astrocyte viability in both female and male cultures by activating proliferation and survival pathways. Pro-inflammatory and anti-inflammatory responses were induced in astrocytes from both sexes. Aß1-40 did not affect endoplasmic reticulum stress although it induced oxidative stress in male and female astrocytes. Interestingly, male astrocytes had an increase in cell number and significantly lower cell death in response to Aß1-40. Conversely, astrocytes from females displayed a greater inflammatory response after the Aß1-40 challenge. These results suggest that the inflammatory and oxidative environment induced by Aß1-40 in female astrocytes may contribute to enhance the vulnerability to AD and warrants further studies to unveil the mechanisms underlying sex differences in astrocytic responses.
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Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Astrocitos , Neuroinmunomodulación/fisiología , Fragmentos de Péptidos/metabolismo , Animales , Astrocitos/inmunología , Astrocitos/metabolismo , Proliferación Celular , Supervivencia Celular/inmunología , Células Cultivadas , Femenino , Hipocampo/inmunología , Hipocampo/metabolismo , Masculino , Estrés Oxidativo , Ratas , Caracteres Sexuales , Factores SexualesRESUMEN
Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.
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Dieta Alta en Grasa , Obesidad/dietoterapia , Obesidad/metabolismo , Pérdida de Peso/fisiología , Animales , Glucemia/análisis , Glucemia/metabolismo , Ingestión de Energía , Femenino , Hipotálamo/metabolismo , Resistencia a la Insulina , Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Factor II del Crecimiento Similar a la Insulina/análisis , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Caracteres SexualesRESUMEN
Glycine-proline-glutamate (GPE) is a cleaved tripeptide of IGF-I that can be processed to cycloprolylglycine (cPG) in the brain. IGF-I protects the hippocampal somatostatinergic system from ß-amyloid (Aß) insult and although neither IGF-I-derived peptides bind to IGF-I receptors, they exert protective actions in several neurological disorders. As their effects on the hippocampal somatostatinergic system remain unknown, the objective of this study was to evaluate if cPG and/or GPE prevent the deleterious effects of Aß25-35 infusion on this system and whether changes in intracellular-related signaling and interleukin (IL) content are involved in their protective effect. We also determined the effect of cPG or GPE co-administration with Aß25-35 on IL secretion in glial cultures and the influence of these ILs on signaling activation and somatostatin synthesis in neuronal cultures. cPG or GPE co-administration reduced Aß-induced cell death and pro-inflammatory ILs, increased IL-4 and partially avoided the reduction of components of the somatostatinergic system affected by Aß25-35. GPE increased activation of Akt and CREB and reduced GSK3ß activation and astrogliosis, whereas cPG increased phosphorylation of extracellular signal-regulated kinases. Both peptides converged in the activation of mTOR and S6 kinase. Co-administration of these peptides with Aß25-35 to glial cultures increased IL-4 and reduced IL-1ß; this release of IL-4 could be responsible for activation of Akt and increased somatostatin in neuronal cultures. Our findings suggest that cPG and GPE exert protective effects against Aß on the somatostatinergic system by a reduction of the inflammatory environment that may activate different pro-survival pathways in these neurons.
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Péptidos beta-Amiloides/farmacología , Hipocampo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Oligopéptidos/uso terapéutico , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/uso terapéutico , Somatostatina/metabolismo , Animales , Muerte Celular/efectos de los fármacos , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Inflamación/metabolismo , Inflamación/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Oligopéptidos/farmacología , Péptidos Cíclicos/farmacología , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Somatostatina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Somatostatin (SRIF), a neuropeptide highly distributed in the hippocampus and involved in learning and memory, is markedly reduced in the brain of Alzheimer's disease patients. The effects of insulin-like growth factor-I (IGF-I) against ß amyloid (Aß)-induced neuronal death and associated cognitive disorders have been extensively reported in experimental models of this disease. Here, we examined the effect of IGF-I on the hippocampal somatostatinergic system in Aß-treated rats and the molecular mechanisms associated with changes in this peptidergic system. Intracerebroventricular Aß25-35 administration during 14â¯days (300â¯pmol/day) to male rats increased Aß25-35 levels and cell death and markedly reduced SRIF and SRIF receptor 2 levels in the hippocampus. These deleterious effects were associated with reduced Akt and cAMP response element-binding protein (CREB) phosphorylation and activation of c-Jun N-terminal kinase (JNK). Subcutaneous IGF-I co-administration (50⯵g/kg/day) reduced hippocampal Aß25-35 levels, cell death and JNK activation. In addition, IGF-I prevented the reduction in the components of the somatostatinergic system affected by Aß infusion. Its co-administration also augmented protein kinase A (PKA) activity, as well as Akt and CREB phosphorylation. These results suggest that IGF-I co-administration may have protective effects on the hippocampal somatostatinergic system against Aß insult through up-regulation of PKA activity and Akt and CREB phosphorylation.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/farmacología , Fármacos Neuroprotectores/farmacología , Somatostatina/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Fragmentos de Péptidos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Receptores de Somatostatina/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Insulin potentiates leptin effects on muscle accrual and glucose homeostasis. However, the relationship between leptin's central effects on peripheral insulin sensitivity and the associated structural changes remain unclear. We hypothesized that central leptin infusion modifies muscle size through activation of insulin signaling. Muscle insulin signaling, enzymes of fatty acid metabolism, mitochondrial respiratory chain complexes, proliferating cell nuclear antigen (PCNA) and fiber area were analyzed in the gastrocnemius of chronic central infused (L), pair-fed (PF) and control rats. PCNA-positive nuclei, fiber area, GLUT4 and glycogen levels and activation of Akt and mechanistic target of rapamycin were increased in L, with no changes in PF. Acetyl-CoA carboxylase-ß mRNA levels and non-esterified fatty acid and triglyceride content were reduced and carnitine palmitoyltransferase-1b expression and mitochondrial complexes augmented in L. These results suggest that leptin promotes an increase in muscle size associated with improved insulin signaling favored by lipid profile.
Asunto(s)
Insulina/metabolismo , Leptina/administración & dosificación , Fibras Musculares Esqueléticas/patología , Transducción de Señal , Animales , Núcleo Celular/metabolismo , Transporte de Electrón , Ácidos Grasos/biosíntesis , Regulación de la Expresión Génica , Glucosa/metabolismo , Glucógeno/metabolismo , Inyecciones Intraventriculares , Leptina/farmacología , Metabolismo de los Lípidos , Masculino , Mitocondrias/metabolismo , Tamaño de los Órganos , Oxidación-Reducción , Antígeno Nuclear de Célula en Proliferación/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Ratas Wistar , Ribosomas/metabolismoRESUMEN
An excess of saturated fatty acids can be toxic for tissues, including the brain, and this has been associated with the progression of neurodegenerative diseases. Since palmitic acid (PA) is a free fatty acid that is abundant in the diet and circulation and can be harmful, we have investigated the effects of this fatty acid on lipotoxicity in hippocampal astrocytes and the mechanism involved. Moreover, as males and females have different susceptibilities to some neurodegenerative diseases, we accessed the responses of astrocytes from both sexes, as well as the possible involvement of estrogens in the protection against fatty acid toxicity. PA increased endoplasmic reticulum stress leading to cell death in astrocytes from both males and females. Estradiol (E2) increased the levels of protective factors, such as Hsp70 and the anti-inflammatory cytokine interleukin-10, in astrocytes from both sexes. In male astrocytes, E2 decreased pJNK, TNFα, and caspase-3 activation. In contrast, in female astrocytes E2 did not affect the activation of JNK or TNFα levels, but decreased apoptotic cell death. Hence, although E2 exerted protective effects against the detrimental effects of PA, the mechanisms involved appear to be different between male and female astrocytes. This sexually dimorphic difference in the protective mechanisms induced by E2 could be involved in the different susceptibilities of males and females to some neurodegenerative processes.
RESUMEN
BACKGROUND: Insulin regulates glucose homeostasis through direct effects on the liver, among other organs, with leptin modulating insulin's hepatic actions. Since central leptin may modify insulin signaling in the liver, we hypothesized that leptin infusion activates hepatic glycogen synthesis following peripheral administration of a bolus of glucose or insulin, thus regulating glycemia. FINDINGS: Oral glucose and intraperitoneal insulin tolerance tests were performed in control, intracerebroventricular leptin-treated and pair-fed rats during 14 days. An improvement in glycemia and an increase in hepatic free glucose and glycogen concentrations after glucose or insulin overload were observed in leptin-treated rats. In order to analyze whether the liver was involved in these changes, we studied activation of insulin signaling by Western blotting and multiplex bead immunoassay after leptin infusion. Our studies revealed an increase in phosphorylation of insulin receptor substrate-1 and Akt in leptin-treated rats. Examination of parameters related to glucose uptake and metabolism in the liver revealed an augment in glucose transporter 2 and a decrease in phosphoenolpyruvate carboxylase protein levels in this group. CONCLUSIONS: These results indicate that central leptin increases hepatic insulin signaling, associated with increased glycogen concentrations after glucose or insulin overload, leading to an improvement in glycemia.
RESUMEN
Insulin receptor substrate-2-deficient (IRS2(-/-)) mice are considered a good model to study the development of diabetes because IRS proteins mediate the pleiotropic effects of insulin-like growth factor-I (IGF-I) and insulin on metabolism, mitogenesis and cell survival. The hypothalamus might play a key role in the early onset of diabetes, owing to its involvement in the control of glucose homeostasis and energy balance. Because some inflammatory markers are elevated in the hypothalamus of diabetic IRS2(-/-) mice, our aim was to analyze whether the diabetes associated with the absence of IRS2 results in hypothalamic injury and to analyze the intracellular mechanisms involved. Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IκB and c-FLIPL were decreased. This was accompanied by increased levels of Nox-4 and catalase, enzymes involved in oxidative stress. In summary, the hypothalamus of diabetic IRS2(-/-) mice showed an increase in oxidative stress and inflammatory markers that finally resulted in cell death via substantial activation of the extrinsic apoptotic pathway. Conversely, non-diabetic IRS2(-/-) mice did not show cell death in the hypothalamus, possibly owing to an increase in the levels of circulating IGF-I and in the enhanced hypothalamic IGF-IR phosphorylation that would lead to the stimulation of survival pathways. In conclusion, diabetes in IRS2-deficient male mice is associated with increased oxidative stress and apoptosis in the hypothalamus.
Asunto(s)
Apoptosis , Diabetes Mellitus Experimental/patología , Hipotálamo/patología , Proteínas Sustrato del Receptor de Insulina/deficiencia , Estrés Oxidativo , Animales , Biomarcadores/metabolismo , Caspasas/metabolismo , Citocinas/metabolismo , Inflamación/patología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptor IGF Tipo 1/metabolismoRESUMEN
Several studies indicate that 17ß-estradiol (E2) protects against amyloid ß-peptide (Aß)-induced cell death and activates factors associated with learning and memory, a function involving the hippocampal somatostatinergic system. As alterations in somatostatin have been demonstrated in Alzheimer's disease, we examined whether E2 prevents changes in the hippocampal somatostatinergic system induced by Aß25-35 and cell death, as well as the possible involvement of leptin and insulin-like growth factor (IGF)-I signaling. We also measured the levels of Aß proteases neprilysin and insulin-degrading-enzyme. Co-administration of E2 with Aß25-35 reduced both its levels and cell death, in addition to preventing the Aß-induced depletion of some somatostatinergic parameters. Activation of leptin and IGF-I pathways increased after E2 co-administration, and this correlated with changes in the somatostatinergic system. Changes in some components of this system were inversely related with Aß levels and cell death. Moreover, neprilysin levels were increased only in Aß plus E2-treated rats and E2 prevented the Aß-induced insulin-degrading-enzyme reduction. Our results suggest that the E2-induced reduction in cell death is related to lower Aß levels, probably because of IGF-I and somatostatin modulation of Aß proteases. We asked how 17ß-estradiol (E2) protects against ß-amyloid (Aß)-induced cell death. E2 co-administration prevents Aß-produced depletion of hippocampal somatostatin (SRIF) by an IGF-I-mediated mechanism, being related this protective effect with an increase in Aß proteases. Our results suggest that the E2-induced reduction in cell death is related to lower Aß levels, probably because of SRIF modulation of Aß proteases. CREB, cAMP response element-binding protein; IGF-I, insulin-like growth factor-I; STAT3, signal transducer and activator of transcription-3.