RESUMO
Metformin is an antidiabetic drug used for the treatment of diabetes and metabolic diseases. Imbalance in the autonomic nervous system (ANS) is associated with metabolic diseases. This study aimed to test whether metformin could improve ANS function in obese rats. Obesity was induced by neonatal treatment with monosodium L-glutamate (MSG). During 21-100 days of age, MSG-rats were treated with metformin 250 mg/kg body weight/day or saline solution. Rats were euthanized to evaluate biometric and biochemical parameters. ANS electrical activity was recorded and analyzed. Metformin normalized the hypervagal response in MSG-rats. Glucose-stimulated insulin secretion in isolated pancreatic islets increased in MSG-rats, while the cholinergic response decreased. Metformin treatment normalized the cholinergic response, which involved mostly the M3 muscarinic acetylcholine receptor (M3 mAChR) in pancreatic beta-cells. Protein expression of M3 mAChRs increased in MSG-obesity rats, while metformin treatment decreased the protein expression by 25%. In conclusion, chronic metformin treatment was effective in normalizing ANS activity and alleviating obesity in MSG-rats.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , Acetilcolina/farmacologia , Animais , Glucose/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Neostigmina/farmacologia , Obesidade/induzido quimicamente , Obesidade/metabolismo , Obesidade/fisiopatologia , Ratos Wistar , Receptor Muscarínico M3/metabolismo , Glutamato de Sódio , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologiaRESUMO
Currently, metabolic disorders are one of the major health problems worldwide, which have been shown to be related to perinatal nutritional insults, and the autonomic nervous system and endocrine pancreas are pivotal targets of the malprogramming of metabolic function. We aimed to assess glucose-insulin homeostasis and the involvement of cholinergic responsiveness (vagus nerve activity and insulinotropic muscarinic response) in pancreatic islet capacity to secrete insulin in weaned rat offspring whose mothers were undernourished in the first 2 weeks of the suckling phase. At delivery, dams were fed a low-protein (4% protein, LP group) or a normal-protein diet (20.5% protein, NP group) during the first 2 weeks of the suckling period. Litter size was adjusted to six pups per mother, and rats were weaned at 21 days old. Weaned LP rats presented a lean phenotype (P < 0.01); hypoglycaemia, hypoinsulinaemia and hypoleptinaemia (P < 0.05); and normal corticosteronaemia (P > 0.05). In addition, milk insulin levels in mothers of the LP rats were twofold higher than those of mothers of the NP rats (P < 0.001). Regarding glucose-insulin homeostasis, weaned LP rats were glucose-intolerant (P < 0.01) and displayed impaired pancreatic islet insulinotropic function (P < 0.05). The M3 subtype of the muscarinic acetylcholine receptor (M3mAChR) from weaned LP rats was less responsive, and the superior vagus nerve electrical activity was reduced by 30% (P < 0.01). A low-protein diet in the suckling period malprogrammes the vagus nerve to low tonus and impairs muscarinic response in the pancreatic ß-cells of weaned rats, which are imprinted to secrete inadequate insulin amounts from an early age.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Ilhotas Pancreáticas/embriologia , Desnutrição/fisiopatologia , Fenômenos Fisiológicos da Nutrição Materna , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Glicemia/análise , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Dieta com Restrição de Proteínas/efeitos adversos , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Células Secretoras de Insulina , Ilhotas Pancreáticas/inervação , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/fisiopatologia , Lactação/fisiologia , Masculino , Desnutrição/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Cultura Primária de Células , Ratos , Ratos Wistar , Nervo Vago/fisiopatologia , DesmameRESUMO
We examined the long-term effects of protein restriction during puberty on the function of hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in male rats. Male Wistar rats from the age of 30 to 60 days were fed a low-protein diet (4%, LP). A normal-protein diet (20.5%) was reintroduced to rats from the age of 60 to 120 days. Control rats were fed a normal-protein diet throughout life (NP). Rats of 60 or 120 days old were killed. Food consumption, body weight, visceral fat deposits, lipid profile, glycemia, insulinemia, corticosteronemia, adrenocorticotropic hormone (ACTH), testosteronemia and leptinemia were evaluated. Glucose-insulin homeostasis, pancreatic-islet insulinotropic response, testosterone production and hypothalamic protein expression of the androgen receptor (AR), glucocorticoid receptor (GR) and leptin signaling pathway were also determined. LP rats were hypophagic, leaner, hypoglycemic, hypoinsulinemic and hypoleptinemic at the age of 60 days (P < 0.05). These rats exhibited hyperactivity of the HPA axis, hypoactivity of the HPG axis and a weak insulinotropic response (P < 0.01). LP rats at the age of 120 days were hyperphagic and exhibited higher visceral fat accumulation, hyperleptinemia and dyslipidemia; lower blood ACTH, testosterone and testosterone release; and reduced hypothalamic expression of AR, GR and SOCS3, with a higher pSTAT3/STAT3 ratio (P < 0.05). Glucose-insulin homeostasis was disrupted and associated with hyperglycemia, hyperinsulinemia and increased insulinotropic response of the pancreatic islets. The cholinergic and glucose pancreatic-islet responses were small in 60-day-old LP rats but increased in 120-day-old LP rats. The hyperactivity of the HPA axis and the suppression of the HPG axis caused by protein restriction at puberty contributed to energy and metabolic disorders as long-term consequences.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Metabolismo Energético , Maturidade Sexual , Testosterona/metabolismo , Animais , Células Cultivadas , Proteínas Alimentares/farmacologia , Metabolismo Energético/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacosRESUMO
PURPOSE: Environmental and nutritional disorders during perinatal period cause metabolic dysfunction in the progeny and impair human health. Advanced glycation end products (AGEs) are primarily produced during metabolism of excess blood glucose, which is observed in diabetes. Methylglyoxal (MG) is a precursor for the generation of endogenous AGEs, which disturbs the metabolism. This work aimed to investigate whether the maternal MG treatment during lactation programs the progeny to metabolic dysfunction later in life. METHODS: Female Wistar rats were divided into two groups: control group (C) treated with saline and MG group treated with MG (60 mg/kg/day) by gavage throughout the lactation period. Both mothers and offspring were fed a standard chow. At weaning, breast milk composition was analyzed and mothers euthanized for blood and tissue sample collections. At 90 days of age, offspring were submitted to glucose tolerance test (ivGTT) and euthanized for blood and tissue samples collection. RESULTS: MG mothers showed increase in glucose and fructosamine levels; however, they showed low insulin levels and failure in ß-cell function (p < 0.05). MG mothers also showed dyslipidemia (p < 0.05). Moreover, breast milk had elevated levels of glucose, triglycerides, cholesterol and fructosamine and low insulin (p < 0.05). Interestingly, MG offspring had increased body weight and adipose tissue at adulthood, and they also showed glucose intolerance and failure in ß-cell function (p < 0.05). Besides, MG offspring showed dyslipidemia (p < 0.05) increasing cardiovascular diseases risk. CONCLUSIONS: Maternal MG treatment negatively affects the male rat offspring, leading to type 2 diabetes and dyslipidemia in later life, possibly by changes in breast milk composition.
Assuntos
Diabetes Mellitus Tipo 2/induzido quimicamente , Dislipidemias/induzido quimicamente , Poluentes Ambientais/toxicidade , Lactação/efeitos dos fármacos , Exposição Materna/efeitos adversos , Obesidade/induzido quimicamente , Aldeído Pirúvico/toxicidade , Adiposidade/efeitos dos fármacos , Administração Oral , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/sangue , Dislipidemias/metabolismo , Dislipidemias/patologia , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/análise , Feminino , Insulina/análise , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Gordura Intra-Abdominal/efeitos dos fármacos , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/patologia , Lactação/metabolismo , Masculino , Leite/química , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Gravidez , Aldeído Pirúvico/administração & dosagem , Aldeído Pirúvico/análise , Distribuição Aleatória , Ratos Sprague-Dawley , Toxicocinética , Aumento de Peso/efeitos dos fármacosRESUMO
BACKGROUND/AIMS: The sulphonylurea glibenclamide (Gli) is widely used in the treatment of type 2 diabetes. In addition to its antidiabetic effects, low incidences of certain types of cancer have been observed in Gli-treated diabetic patients. However, the mechanisms underlying this observation remain unclear. The aim of the present work was to evaluate whether obese adult rats that were chronically treated with an antidiabetic drug, glibenclamide, exhibit resistance to rodent breast carcinoma growth. METHODS: Neonatal rats were treated with monosodium L-glutamate (MSG) to induce prediabetes. Control and MSG groups were treated with Gli (2 mg/kg body weight/day) from weaning to 100 days old. After Gli treatment, the control and MSG rats were grafted with Walker-256 tumour cells. After 14 days, grafted rats were euthanized, and tumour weight as well as glucose homeostasis were evaluated. RESULTS: Treatment with Gli normalized tissue insulin sensitivity and glucose tolerance, suppressed fasting hyperinsulinaemia, reduced fat tissue accretion in MSG rats, and attenuated tumour growth by 27% in control and MSG rats. CONCLUSIONS: Gli treatment also resulted in a large reduction in the number of PCNA-positive tumour cells. Although treatment did improve the metabolism of pre-diabetic MSG-rats, tumour growth inhibition may be a more direct effect of glibenclamide.
Assuntos
Proliferação de Células/efeitos dos fármacos , Glibureto/farmacologia , Estado Pré-Diabético/prevenção & controle , Animais , Caquexia/etiologia , Linhagem Celular Tumoral , Glucose/metabolismo , Glibureto/uso terapêutico , Hiperinsulinismo/prevenção & controle , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Imuno-Histoquímica , Masculino , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Estado Pré-Diabético/etiologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , 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
PURPOSE: The long-term effects of the development of chronic metabolic diseases such as type 2 diabetes and obesity have been associated with nutritional insults in critical life stages. In this study, we evaluated the effect of a low-protein diet on metabolism in mid-adulthood male rats. METHODS: At 90 days of age, Wistar male rats were fed a low-protein diet (4.0 %, LP group) for 30 days, whereas control rats were fed a normal-protein diet (20.5 %, NP group) throughout their lifetimes. To allow for dietary rehabilitation, from 120 to 180 days of age, the LP rats were fed a normal-protein diet. Then, we measured body composition, fat stores, glucose-insulin homeostasis and pancreatic islet function. RESULTS: At 120 days of age, just after low-protein diet treatment, the LP rats displayed a strong lean phenotype, hypoinsulinemia, as assessed under fasting and glucose tolerance test conditions, as well as weak pancreatic islet insulinotropic response to glucose and acetylcholine (p < 0.01). At 180 days of age, after poor-protein diet rehabilitation, the LP rats displayed a slight lean phenotype (p < 0.05), which was associated with a high body weight gain (p < 0.001). Additionally, fat pad accumulation, glycemia and insulinemia, as well as the pancreatic islet insulinotropic response, were not significantly different between the LP and NP rats (p > 0.05). CONCLUSIONS: Taken together, the present data suggest that the effects of dietary restriction as a stressor in adulthood are reversible with dietary rehabilitation, indicating that adulthood is not a sensitive or critical time window for metabolic programming.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Síndrome Metabólica/metabolismo , Desnutrição Proteico-Calórica/metabolismo , Acetilcolina/metabolismo , Animais , Glicemia/metabolismo , Composição Corporal , Peso Corporal , Proteínas Alimentares/administração & dosagem , Teste de Tolerância a Glucose , Homeostase , Insulina/sangue , Ilhotas Pancreáticas/metabolismo , Masculino , Fenótipo , Ratos , Ratos Wistar , Aumento de PesoRESUMO
Essential polyunsaturated fatty acids (PUFAs) prevent cardiometabolic diseases. We aimed to study whether a diet supplemented with a mixture of n-6/n-3 PUFAs, during perinatal life, attenuates outcomes of long-term metabolic dysfunction in prediabetic and obese mice. Seventy-day-old virgin female mice were mated. From the conception day, dams were fed a diet supplemented with sunflower oil and flaxseed powder (containing an n-6/n-3 PUFAs ratio of 1.2 : 1.0) throughout pregnancy and lactation, while control dams received a commercial diet. Newborn mice were treated with monosodium L-glutamate (MSG, 4 mg g-1 body weight per day) for the first 5 days of age. A batch of weaned pups was sacrificed to quantify the brain and pancreas total lipids; another batch were fed a commercial diet until 90 days of age, where glucose homeostasis and glucose-induced insulin secretion (GIIS) as well as retroperitoneal fat and Lee index were assessed. MSG-treated mice developed obesity, glucose intolerance, insulin resistance, pancreatic islet dysfunction, and higher fat stores. Maternal flaxseed diet-supplementation decreased n-6/n-3 PUFAs ratio in the brain and pancreas and blocked glucose intolerance, insulin resistance, GIIS impairment, and obesity development. The n-6/n-3 essential PUFAs in a ratio of 1.2 : 1.0 supplemented in maternal diet during pregnancy and lactation prevent metabolic dysfunction in MSG-obesity model.
RESUMO
INTRODUCTION: A sedentary lifestyle and high-fat feeding are risk factors for cardiometabolic disorders. This study determined whether moderate exercise training prevents the cardiometabolic changes induced by a high-fat diet (HFD). MATERIALS AND METHODS: Sixty-day-old rats were subjected to moderate exercise three times a week for 30 days. After that, trained rats received a HFD (EXE-HFD) or a commercial normal diet (EXE-NFD) for 30 more days. Sedentary animals also received the diets (SED-HFD and SED-NFD). Food intake and body weight were measured weekly. After 120 days of life, analyses were performed. Data were analysed with two-way ANOVA and the Tukey post-test. RESULTS: Body weight gain induced by HFD was attenuated in trained animals. HFD reduced food intake by approximately 30% and increased body fat stores by approximately 75%. Exercise attenuated 80% of the increase in fat pads and increased 24% of soleus muscle mass in NFD animals. HFD induced a hyper-response to glucose injection, and exercise attenuated this response by 50%. Blood pressure was increased by HFD, and the beneficial effect of exercise in reducing blood pressure was inhibited by HFD. HFD increased vagal activity by 65% in SED-HFD compared with SED-NFD rats, and exercise blocked this increase. HFD reduced sympathetic activity and inhibited the beneficial effect of exercise on ameliorating sympathetic activity. CONCLUSION: Four weeks of moderate exercise at low frequency was able to prevent the metabolic changes induced by a HFD but not the deleterious effects of diet on the cardiovascular system.