RESUMO
Disruption of biological rhythms due to exposure to artificial light at night (ALAN) has emerged as a new risk factor for metabolic diseases. However, the effects of ALAN exposure on energy metabolism with concomitant misalignment in the circadian system caused by nutritional imbalance remain largely unexplored. Here, we evaluate whether a low-protein (LP) diet could enhance the effects induced by exposure to ALAN on the energy metabolism and consequently predispose to metabolic disorders. Male C57BL6/J mice were weaned on a normal protein (NP) or a LP diet and housed on 12 h light:12 h darkness (LD) cycle. After 6 weeks, mice maintained on their respective diets were subdivided into normal light/darkness cycle (NP/LD; LP/LD) or exposed to ALAN (NP/LL; LP/LL) for 8 weeks. We observed that exposure to ALAN concomitant to LP diet disrupts the behavioral rhythms, without shifting the timing of food intake. Furthermore, exposure to ALAN leads to increased body and fat pad weights, higher levels of fast and fed glycemia and glucose intolerance independent of the diet consumed. Importantly, the effects of ALAN on circadian regulation of insulin sensitivity were diet-dependent with LP/LL mice showing insulin resistance in an opposite time of day than NP/LL. At the molecular level, exposure to ALAN concurrent with LP diet increased the expression of phosphoenolpyruvate carboxykinase 1 in both periods analyzed and inverted the pattern of fibroblast growth factor 21 (Fgf21) expression in the liver. Our data suggest that dietary protein restriction modulates the effects induced by nighttime light exposure on glucose metabolism, which could be partially related with the dysregulation of hepatic Fgf21 expression.
Assuntos
Ritmo Circadiano , Dieta com Restrição de Proteínas/efeitos adversos , Ingestão de Energia , Intolerância à Glucose/etiologia , Poluição Luminosa/efeitos adversos , Animais , Glicemia , Fatores de Crescimento de Fibroblastos/metabolismo , Glucose/metabolismo , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora , Obesidade/etiologia , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismoRESUMO
The sulfur-containing amino acid, taurine (Tau), regulates glucose and lipid homeostasis under normal, pre- and diabetic conditions. Here, we aimed to verify whether Tau supplementation exerts its beneficial effects against obesity, hyperglycemia and alterations in islet functions, in leptin-deficient obese (ob/ob), over a long period of treatment. From weaning until 12 months of age, female ob/ob mice received, or not, 5% Tau in drinking water (obTau group). After this period, a reduction in hypertriglyceridemia and an improvement in glucose tolerance and insulin sensitivity were observed in obTau mice. In addition, the daily metabolic flexibility was restored in obTau mice. In the gastrocnemius muscle of obTau mice, the activation of AMP-activated protein kinase (AMPK) was increased, while total AMPK protein content was reduced. Finally, isolated islets from obTau mice expressed high amounts of pyruvate carboxylase (PC) protein and lower glucose-induced insulin secretion. Taking these evidences together Tau supplementation had long-term positive actions on glucose tolerance and insulin sensitivity, associated with a reduction in glucose-stimulated insulin secretion, in ob/ob mice. The improvement in insulin actions in obTau mice was due, at least in part, to increased activation of AMPK in skeletal muscle, while the increased content of the PC enzyme in pancreatic islets may help to preserve glucose responsiveness in obTau islets, possibly contributing to islet cell survive.
Assuntos
Glicemia/metabolismo , Homeostase/efeitos dos fármacos , Hipertrigliceridemia , Taurina/farmacologia , Animais , Teste de Tolerância a Glucose , Hipertrigliceridemia/sangue , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/patologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Obesos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologiaRESUMO
Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described. However, the possible role of TUDCA in insulin clearance had not yet been explored. Here, we demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. TUDCA also increased IDE expression in human hepatic cell line HepG2. This effect was not observed in the presence of an inhibitor of the hepatic membrane bile acid receptor, S1PR2, nor when its downstream proteins were inhibited, including IR, PI3K and Akt. These results indicate that treatment with TUDCA may be helpful to counteract obesity-induced hyperinsulinemia through increasing insulin clearance, likely through enhanced liver IDE expression in a mechanism dependent on S1PR2-Insulin pathway activation.
Assuntos
Insulina/farmacocinética , Insulisina/efeitos dos fármacos , Fígado/enzimologia , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Dieta Hiperlipídica , Células Hep G2 , Humanos , Hiperinsulinismo/tratamento farmacológico , Insulisina/metabolismo , Fígado/metabolismo , Camundongos , Camundongos ObesosRESUMO
Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock.
Assuntos
Relógios Biológicos , Regulação da Expressão Gênica no Desenvolvimento , Hipotálamo/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Deficiência de Proteína/fisiopatologia , Tecido Adiposo Branco/metabolismo , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Dieta com Restrição de Proteínas/efeitos adversos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Insulina/genética , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Isoquinolinas/farmacologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Especificidade de Órgãos , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Deficiência de Proteína/etiologia , Distribuição Aleatória , Tiofenos/farmacologia , DesmameRESUMO
Taurine (Tau) restores ß-cell function in obesity; however, its action is lost in malnourished obese rodents. Here, we investigated the mechanisms involved in the lack of effects of Tau in this model. C57BL/6 mice were fed a control diet (CD) (14% protein) or a protein-restricted diet (RD) (6% protein) for 6 wk. Afterward, mice received a high-fat diet (HFD) for 8 wk [CD + HFD (CH) and RD + HFD (RH)] with or without 5% Tau supplementation after weaning on their drinking water [CH + Tau (CHT) and RH + Tau (RHT)]. The HFD increased insulin secretion through mitochondrial metabolism in CH and RH. Tau prevented all those alterations in CHT only. The expression of the taurine transporter (Tau-T), as well as Tau content in pancreatic islets, was increased in CH but had no effect on RH. Protein malnutrition programs ß cells and impairs Tau-induced restoration of mitochondrial metabolism and biogenesis. This may be associated with modulation of the expression of Tau-T in pancreatic islets, which may be responsible for the absence of effect of Tau in protein-malnourished obese mice.-Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., dos Santos-Silva, J. C. R., Boschero, A. C., Zoppi, C. C., Carneiro, E. M. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteínas Alimentares/administração & dosagem , Insulina/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Deficiência de Proteína/metabolismo , Taurina/farmacologia , Animais , Linhagem Celular , Suplementos Nutricionais , Regulação da Expressão Gênica/fisiologia , Ilhotas Pancreáticas , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Endogâmicos C57BL , Taurina/administração & dosagemRESUMO
Pancreatic beta cell (ß) dysfunction is an outcome of malnutrition. We assessed the role of the amplifying pathway (AMP PATH) in ß cells in malnourished obese mice. C57Bl-6 mice were fed a control (C) or a low-protein diet (R). The groups were then fed a high-fat diet (CH and RH). AMP PATH contribution to insulin secretion was assessed upon incubating islets with diazoxide and KCl. CH and RH displayed increased glucose intolerance, insulin resistance and glucose-stimulated insulin secretion. Only RH showed a higher contribution of the AMP PATH. The mitochondrial membrane potential of RH was decreased, and ATP flux was unaltered. In RH islets, glutamate dehydrogenase (GDH) protein content and activity increased, and the AMP PATH contribution was reestablished when GDH was blunted. Thus, protein malnutrition induces mitochondrial dysfunction in ß cells, leading to an increased contribution of the AMP PATH to insulin secretion through the enhancement of GDH content and activity.
Assuntos
Envelhecimento/patologia , Insulina/metabolismo , Desnutrição Proteico-Calórica/metabolismo , Animais , Intolerância à Glucose/complicações , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Glutamato Desidrogenase/metabolismo , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Mitocôndrias/metabolismo , Desnutrição Proteico-Calórica/complicações , Desnutrição Proteico-Calórica/patologiaRESUMO
BACKGROUNDS/AIMS: Obese rats obtained by neonatal monosodium glutamate (MSG) administration present insulin hypersecretion. The metabolic mechanism by which glucose catabolism is coupled to insulin secretion in the pancreatic ß-cells from MSG-treated rats is understood. The purpose of this study was to evaluate glucose metabolism in pancreatic islets from MSG-treated rats subjected to swimming training. METHODS: MSG-treated and control (CON) rats swam for 30 minutes (3 times/week) over a period of 10 weeks. Pancreatic islets were isolated and incubated with glucose in the presence of glycolytic or mitochondrial inhibitors. RESULTS: Swimming training attenuated fat pad accumulation, avoiding changes in the plasma levels of lipids, glucose and insulin in MSG-treated rats. Adipocyte and islet hypertrophy observed in MSG-treated rats were attenuated by exercise. Pancreatic islets from MSG-treated obese rats also showed insulin hypersecretion, greater glucose transporter 2 (GLUT2) expression, increased glycolytic flux and reduced mitochondrial complex III activity. CONCLUSION: Swimming training attenuated islet hypertrophy and normalised GLUT2 expression, contributing to a reduction in the glucose responsiveness of pancreatic islets from MSG-treated rats without altering glycolytic flux. However, physical training increased the activity of mitochondrial complex III in pancreatic islets from MSG-treated rats without a subsequent increase in glucose-induced insulin secretion.