RESUMO
The hypothalamic-pituitary-adrenal axis (HPA) exerts important catabolic peripheral effects and influences autonomic nervous system (ANS)-mediated processes. Impaired negative-feedback control or reduced HPA axis sensitivity and altered ANS activity appear to be associated with the development and maintenance of obesity. In the present study, we examined the hypothesis that the central HPA axis is dysregulated favouring ANS disbalance in monosodium l-glutamate (MSG)-induced rat obesity. Glucose homeostasis, corticosterone, leptin and ANS electrical activity were evaluated. Adult MSG-induced obese rats exhibited fasting hyperinsulinaemia, insulin resistance, glucose intolerance, hypercorticosteronaemia, hyperleptinaemia and altered ANS activity. A decrease in food intake was observed during corticotrophin-releasing hormone (CRH) treatment in both control and MSG-treated rats. By contrast, food intake was significantly elevated in control rats treated with dexamethasone (DEXA), whereas no alterations were observed following DEXA treatment in MSG-induced obese rats. After DEXA injection, an increase in fasting insulin and glucose levels, associated with insulin resistance, was seen in both groups. As expected, there was a decrease of parasympathetic activity and an increase of sympathetic nervous activity in CRH-treated control animals and the opposite effect was seen after DEXA treatment. By contrast, there was no effect on ANS activity in MSG-rats treated with CRH or DEXA. In conclusion, impairment of the HPA axis can lead to disbalance of ANS activity in MSG-treated rats, contributing to the establishment and maintenance of obesity.
Assuntos
Sistema Nervoso Autônomo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Obesidade/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Corticosterona/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Insulina/metabolismo , Masculino , Obesidade/induzido quimicamente , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiopatologia , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Glutamato de Sódio/análogos & derivadosRESUMO
PURPOSE: The incidences of obesity and related diseases have reached epidemic proportions, and new therapeutic approaches are needed. Soy isoflavones have been identified as an important dietary factor for preventing and treating metabolic dysfunction. This study examined the effects of high doses of isoflavone on glucose and fat metabolism in a model of programmed obesity and evaluated its effects on the autonomic nervous system. METHODS: Litters of Wistar rats were standardized at nine pups per dam in normal litters (NL) or reduced to three pups per dam at the third day of life (P3) in small litters (SL) to induce postnatal overfeeding. Gavage with a soy bean isoflavone mixture (1â g/day) diluted in water was started at P60 and continued for 30 days. The control animals received vehicle gavage. At P90, biometric and metabolic parameters as well as direct autonomic nerve activity were measured. RESULTS: Increases in glycaemia and insulinaemia observed in SL rats were reduced by isoflavone treatment, which also caused lower glucose-induced insulin secretion by pancreatic islets. Sympathetic activity in the major splanchnic nerve was increased, while vagus nerve activity was reduced by isoflavone treatment. The dyslipidaemia induced by overfeeding in SL rats was restored by isoflavone treatment. CONCLUSION: The present study shows that treatment with isoflavone reduces adiposity and improves glucose and lipid metabolism. Collectively, these effects may depend on autonomic changes.
Assuntos
Isoflavonas/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hipernutrição/metabolismo , Adiposidade/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Teste de Tolerância a Glucose , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Obesidade/sangue , Ratos , Ratos Wistar , Glycine max/química , Triglicerídeos/sangueRESUMO
OBJECTIVES: Obesity is a metabolic and hormonal disorder with serious social and psychological impacts. There is a close relationship among obesity, neuroendocrine homeostasis and behavioral patterns. However, few data are available in the literature regarding this subject. This study assessed behavior and memory of adult obese rats by monosodium l-glutamate (MSG) neonatal treatment or highly palatable dietary treatment. METHODS: MSG obesity was induced by subcutaneous injections of MSG (4 mg/g) during the first 5 days of life (Ob-MSG); control group (C-MSG), received saline solution equimolar. Both groups were fed with commercial chow. To induce dietary obesity, 21-day-old rats were assigned to two experimental diets: highly palatable diet (Ob-Diet) and control diet (C-Diet) composed of commercial chow. Ninety-day-old animals were submitted to behavioral assessment by the open-field test and short- and long-term memory by the object recognition test. Biometric variables were obtained, the Lee index was calculated and mass of retroperitoneal and perigonadal fat pads was measured. Furthermore, an altered behavioral profile was investigated by quantification of plasmatic corticosterone, expression, and activity of hypothalamic extracellular signal-regulated kinase protein (ERK) 1 and 2. RESULTS: Increased Lee index and fat pads were observed in Ob-MSG and Ob-Diet groups. Ob-MSG presented a higher level of anxiety and impaired long-term memory compared to C-MSG, while there was no difference between Ob-Diet and C-Diet. The Ob-MSG group presented a higher level of plasmatic corticosterone and increased phosphorylation of hypothalamic ERK1 and 2. DISCUSSION: Both treatments induced obesity but only Ob-MSG showed altered behavioral parameters, which is related to increased concentration of corticosterone and hypothalamic ERK1 and 2 activation.
Assuntos
Corticosterona/sangue , Modelos Animais de Doenças , Hipotálamo/metabolismo , Sistema de Sinalização das MAP Quinases , Consolidação da Memória , Neurônios/metabolismo , Obesidade/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Corticosterona/agonistas , Ativação Enzimática/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/enzimologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Consolidação da Memória/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/química , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Obesidade/sangue , Obesidade/induzido quimicamente , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Glutamato de Sódio/toxicidadeRESUMO
Maternal obesity programmes a range of metabolic disturbances for the offspring later in life. Moreover, environmental changes during the suckling period can influence offspring development. Because both periods significantly affect long-term metabolism, we aimed to study whether cross-fostering during the lactation period was sufficient to rescue a programmed obese phenotype in offspring induced by maternal obesity following monosodium L-glutamate (MSG) treatment. Obesity was induced in female Wistar rats by administering subcutaneous MSG (4 mg/g body weight) for the first 5 days of postnatal life. Control and obese female rats were mated in adulthood. The resultant pups were divided into control second generation (F2) (CTLF2), MSG-treated second generation (F2) (MSGF2), which suckled from their CTL and MSG biological dams, respectively, or CTLF2-CR, control offspring suckled by MSG dams and MSGF2-CR, MSG offspring suckled by CTL dams. At 120 days of age, fat tissue accumulation, lipid profile, hypothalamic leptin signalling, glucose tolerance, glucose-induced, and adrenergic inhibition of insulin secretion in isolated pancreatic islets were analysed. Maternal MSG-induced obesity led to an obese phenotype in male offspring, characterized by hyperinsulinaemia, hyperglycaemia, hyperleptinaemia, dyslipidaemia, and impaired leptin signalling, suggesting central leptin resistance, glucose intolerance, impaired glucose-stimulated, and adrenergic inhibition of insulin secretion. Cross-fostering normalized body weight, food intake, leptin signalling, lipid profiles, and insulinaemia, but not glucose homeostasis or insulin secretion from isolated pancreatic islets. Our findings suggest that alterations during the lactation period can mitigate the development of obesity and prevent the programming of adult diseases.
Assuntos
Modelos Animais de Doenças , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal , Adiposidade , Animais , Animais Recém-Nascidos , Feminino , Desenvolvimento Fetal , Aromatizantes/administração & dosagem , Aromatizantes/efeitos adversos , Aditivos Alimentares/administração & dosagem , Aditivos Alimentares/efeitos adversos , Injeções Subcutâneas , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Gravidez , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Glutamato de Sódio/efeitos adversos , Técnicas de Cultura de Tecidos , Aumento de PesoRESUMO
Neuroendocrine dysfunctions such as the hyperactivity of the vagus nerve and hypothalamus-pituitary-adrenal (HPA) axis greatly contribute to obesity and hyperinsulinemia; however, little is known about these dysfunctions in the pancreatic ß-cells of obese individuals. We used a hypothalamic-obesity model obtained by neonatal treatment with monosodium l-glutamate (MSG) to induce obesity. To assess the role of the HPA axis and vagal tonus in the genesis of hypercorticosteronemia and hyperinsulinemia in an adult MSG-obese rat model, bilateral adrenalectomy (ADX) and subdiaphragmatic vagotomy (VAG) alone or combined surgeries (ADX-VAG) were performed. To study glucose-induced insulin secretion (GIIS) and the cholinergic insulinotropic process, pancreatic islets were incubated with different glucose concentrations with or without oxotremorine-M, a selective agonist of the M3 muscarinic acetylcholine receptor (M3AChR) subtype. Protein expression of M3AChR in pancreatic islets, corticosteronemia, and vagus nerve activity was also evaluated. Surgeries reduced 80% of the body weight gain. Fasting glucose and insulin were reduced both by ADX and ADX-VAG, whereas VAG was only associated with hyperglycemia. The serum insulin post-glucose stimulation was lower in all animals that underwent an operation. Vagal activity was decreased by 50% in ADX rats. In the highest glucose concentration, both surgeries reduced GIIS by 50%, whereas ADX-VAG decreased by 70%. Additionally, M3AChR activity was recovered by the individual surgeries. M3AChR protein expression was reduced by ADX. Both the adrenal gland and vagus nerve contribute to the hyperinsulinemia in the MSG model, although adrenal is more crucial as it appears to modulate parasympathetic activity and M3AChR expression in obesity.
Assuntos
Sistema Hipotálamo-Hipofisário/fisiopatologia , Insulina/metabolismo , Obesidade/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Nervo Vago/fisiopatologia , Animais , Glucose/farmacologia , Sistema Hipotálamo-Hipofisário/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/induzido quimicamente , Obesidade/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Wistar , Glutamato de Sódio , Nervo Vago/metabolismoRESUMO
BACKGROUND/AIMS: The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. METHODS: We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. RESULTS: Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. CONCLUSION: Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma.
Assuntos
Carcinoma 256 de Walker/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Metformina/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Glicemia , Carcinoma 256 de Walker/metabolismo , Carcinoma 256 de Walker/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Intolerância à Glucose/tratamento farmacológico , Intolerância à Glucose/patologia , Hipoglicemiantes/administração & dosagem , Insulina/metabolismo , Resistência à Insulina/genética , Ilhotas Pancreáticas/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Ratos , Glutamato de Sódio/toxicidadeRESUMO
BACKGROUND/AIMS: Impaired pancreatic beta cell function and insulin secretion/action are a link between obesity and type 2 diabetes, which are worldwide public health burdens. We aimed to characterize the muscarinic acetylcholine receptor (mAChR) M1-M4 subtypes in isolated pancreatic islets from pre-diabetic obese rats that had been treated neonatally with monosodium L-glutamate (MSG). METHODS: At 90 days of age, both the MSG and the control groups underwent biometric and biochemical evaluation. Anti-muscarinic drugs were used to study mAChR function either in vivo or in vitro. RESULTS: The results demonstrated that atropine treatment reduced insulin secretion in the MSG-treated and control groups, whereas treatment with an M2mAChR-selective antagonist increased secretion. Moreover, the insulinostatic effect of an M3mAChR-selective antagonist was significantly higher in the MSG-treated group. M1mAChR and M3mAChR expression was increased in the MSG-obese group by 55% and 73%, respectively. In contrast, M2mAChR expression decreased by 25% in the MSG group, whereas M4mAChR expression was unchanged. CONCLUSIONS: Functional changes in and altered content of the mAChR (M1-M4) subtypes are pivotal to the demand for high pancreatic beta cell insulin secretion in MSG-obese rats, which is directly associated with vagal hyperactivity and peripheral insulin resistance.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Obesidade/metabolismo , Receptores Muscarínicos/metabolismo , Glutamato de Sódio/farmacologia , Animais , Glicemia/análise , Teste de Tolerância a Glucose , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Obesidade/patologia , Ratos , Ratos Wistar , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M3/metabolismo , Receptor Muscarínico M4/metabolismo , Receptores Muscarínicos/químicaRESUMO
Impaired pancreatic ß-cell function, as observed in the cases of early nutrition disturbance, is a major hallmark of metabolic diseases arising in adulthood. In the present study, we aimed to investigate the function/composition of the muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3, in the pancreatic islets of adult offspring of rats that were protein malnourished during lactation. Neonates were nursed by mothers that were fed either a low-protein (4 %, LP) or a normal-protein (23 %, NP) diet. Adult rats were pre-treated with anti-muscarinic drugs and subjected to the glucose tolerance test; the function and protein expression levels of M2mAChR and M3mAChR were determined. The LP rats were lean and hypoinsulinaemic. The selective M2mAChR antagonist methoctramine increased insulinaemia by 31 % in the NP rats and 155 % in the LP rats, and insulin secretion was increased by 32 % in the islets of the NP rats and 88 % in those of the LP rats. The selective M3mAChR antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide decreased insulinaemia by 63 % in the NP rats and 40 % in the LP rats and reduced insulin release by 41 % in the islets of the NP rats and 28 % in those of the LP rats. The protein expression levels of M2mAChR and M3mAChR were 57 % higher and 53 % lower, respectively, in the islets of the LP rats than in those of the NP rats. The expression and functional compositions of M2mAChR and M3mAChR were altered in the islets of the LP rats, as a result of metabolic programming caused by the protein-restricted diet, which might be another possible effect involved in the weak insulin secretion ability of the islets of the programmed adult rats.
Assuntos
Ração Animal/análise , Proteínas Alimentares/administração & dosagem , Células Secretoras de Insulina/fisiologia , Lactação/fisiologia , Receptores Muscarínicos/classificação , Receptores Muscarínicos/metabolismo , Fenômenos Fisiológicos da Nutrição Animal , Animais , Glicemia , Dieta/veterinária , Feminino , Glucose/metabolismo , Intolerância à Glucose , Teste de Tolerância a Glucose , Homeostase , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Antagonistas Muscarínicos/farmacologia , Gravidez , Ratos , Ratos WistarRESUMO
Similar to gestation/lactation, puberty is also a critical phase in which neuronal connections are still being produced and during which metabolic changes may occur if nutrition is disturbed. In the present study we aimed to determine whether peripubertal protein restriction induces metabolic programming. Thirty-day-old male rats were fed either a low protein (LP group) diet (4% w/w protein) or a normal protein (NP group) diet (23%) until 60 days of age, when they received the NP diet until they were 120 days old. Body weight (BW), food intake, fat tissue accumulation, glucose tolerance, and insulin secretion were evaluated. The nerve electrical activity was recorded to evaluate autonomous nervous system (ANS) function. Adolescent LP rats presented hypophagia and lower BW gain during the LP diet treatment (P<0.001). However, the food intake and BW gain by the LP rats were increased (P<0.001) after the NP diet was resumed. The LP rats presented mild hyperglycemia, hyperinsulinemia, severe hyperleptinemia upon fasting, peripheral insulin resistance and increased fat tissue accumulation and vagus nerve activity (P<0.05). Glucose-induced insulin secretion was greater in the LP islets than in the NP islets; however, the cholinergic response was decreased (P<0.05). Compared with the islets from the NP rats, the LP islets showed changes in the activity of muscarinic receptors (P<0.05); in addition, the inhibition of glucose-induced insulin secretion by epinephrine was attenuated (P<0.001). Protein restriction during adolescence caused high-fat tissue accumulation in adult rats. Islet dysfunction could be related to an ANS imbalance.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Ilhotas Pancreáticas/metabolismo , Puberdade/metabolismo , Animais , Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Glucose/farmacologia , Hiperglicemia/metabolismo , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Masculino , RatosRESUMO
Pancreatic islets from adult rats whose mothers were protein restricted during lactation undersecrete insulin. The current work analyzes whether this secretory dysfunction can be improved when the pancreatic islets are grafted into hyperglycemic diabetic rats. Two groups of rats were used: the adult offspring from dams that received a low protein diet (4%) during the initial 2/3 of lactation (LP) and, as a control, the adult offspring from dams that consumed a normal protein diet (23%) during the entire period of lactation (NP). Islets from NP- and LP-rats were transplanted into diabetic recipient rats, which were generated by streptozotocin treatment. The islets were transplanted via the portal vein under anesthesia. The fed blood glucose levels were monitored during the 4 days post-transplantation. Transplanted islets from LP-rats (T LP) decreased the fed glucose levels of diabetic rats 34% (21.37 ± 0.24 mM, p<0.05); however, the levels still remained 2-fold higher than those of the sham-operated controls (6.88 ± 0.39 mM, p<0.05). Grafts with NP-islets (T NP) produced the same effect as the LP-islets in diabetic rats. The high fasting blood glucose levels of diabetic rats were improved by the transplantations. Islet grafts from both rat groups recovered 50% of the retroperitoneal fat mass of the diabetic rats (0.55 ± 0.08 g/100 g of body weight for T NP and 0.56 ± 0.07 g/100 g of body weight for T LP, p<0.05). Because pancreatic islets from both the NP- and LP-rats were able to regulate fasting blood glucose concentrations in hyperglycemic rats, we propose that the altered function of pancreatic islets from LP-rats is not permanent.