RESUMO
Glyphosate-based herbicides (GBH) are the most widely used pesticides globally. Studies have indicated that they may increase the risk of various organic dysfunctions. Herein, we verified whether exposure to GBH during puberty increases the susceptibility of male and female mice to obesity when they are fed a high-fat diet (HFD) in adulthood. From the 4th-7th weeks of age, male and female C57Bl/6 mice received water (CTL group) or 50 mg GBH /kg body weight (BW; GBH group). From the 8th-21st weeks of age, the mice were fed a standard diet or a HFD. It was found that pubertal GBH exposure exacerbated BW gains and hyperphagia induced by HFD, but only in female GBH-HFD mice. These female mice also exhibited high accumulation of perigonadal and subcutaneous fat, as well as reduced lean body mass. Both male and female GBH-HFD displayed hypertrophic white adipocytes. However, only in females, pubertal GBH exposure aggravated HFD-induced fat accumulation in brown adipocytes. Furthermore, GBH increased plasma cortisol levels by 80% in GBH-HFD males, and 180% in GBH-HFD females. In conclusion, pubertal GBH exposure aggravated HFD-induced obesity, particularly in adult female mice. This study provides novel evidence that GBH misprograms lipid metabolism, accelerating the development of obesity when individuals are challenged by a second metabolic stressor, such as an obesogenic diet.
Assuntos
Dieta Hiperlipídica , Herbicidas , Camundongos , Masculino , Feminino , Animais , Dieta Hiperlipídica/efeitos adversos , Glifosato , Herbicidas/toxicidade , Obesidade/induzido quimicamente , Metabolismo dos LipídeosRESUMO
Taurine has been reported to improve the action of insulin in normal, pre-, and diabetic conditions. However, the mechanism by which this amino acid ameliorates insulin sensitivity is not yet completely understood. Insulin acts on target tissues by interacting with the extracellular portion of a tyrosine kinase receptor, whose structure is known as the ectodomain (ECD) of the insulin receptor (IR). Some studies indicate that taurine can bind to the IR, which would contribute to its beneficial actions on glucose homeostasis. However, the binding mode of the amino acid on the IR ECD is unknown. Herein, using in silico experiments, we aimed to verify whether taurine may be an agonist of the IR and also to demonstrate the potential binding sites of taurine on the IR ECD. Molecular modeling predicted that taurine might interact with the three largest pocket sites for ligands present in the IR ECD. Taurine demonstrated high-energy interactions with these pockets, showing the highest affinity and highest molecular interaction with pocket 1, followed by decreasing energies and binding to pockets 2 and 3 of the IR ECD. The taurine interaction sites on the IR were not the same as the insulin interaction sites. Thus, these data indicate that taurine may be an agonist of the IR ECD, acting with high affinity at pocket 1 of the ECD. The predicted binding sites observed in this study probably constitute the regions of interaction of taurine on the IR and contribute to the mechanism by which taurine ameliorates insulin signaling pathway activation, thereby improving glucose homeostasis and the other cellular functions that are regulated by this intracellular signaling cascade.
Assuntos
Receptor de Insulina , Taurina , Aminoácidos , Sítios de Ligação , Glucose/metabolismo , Insulina/metabolismo , Simulação de Acoplamento Molecular , Receptor de Insulina/metabolismo , Taurina/farmacologiaRESUMO
Adaptation of islet ß-cell mass and function under limiting or excess nutrient availability is critical for maintenance of glucose homeostasis. Taurine regulates islet function of obese mice in normal and low dietary protein conditions, but whether this involves remodeling of the endocrine pancreas architecture is not well understood. Here, we carried functional and morphometric evaluation of the endocrine pancreas of normal and protein-restricted mice fed a high-fat diet (HFD) and investigated the role of taurine supplementation. Weaned mice were placed in a normal (C) or a low-protein diet (R) for 6 weeks, followed by HFD for 8 weeks (CH and RH). Half of HFD groups received 5% taurine supplementation since weaning (CHT and RHT) until the end of the experiment. Isolated islets from both CH and RH groups showed increased insulin release in association with increased pancreas weight and independently of changes in islet or ß-cell area. In normal protein CHT mice, taurine supplementation prevented obesity-induced insulin hypersecretion and promoted increased islet and ß-cell areas in association with increased protein expression of the proliferation marker, PCNA. On a low-protein background, taurine effects on islet function and morphology were blunted, but it prevented obesity-induced DNA fragmentation. In summary, taurine regulates islet function and morphology to improve the adaptive response to diet-induced obesity, but these effects are dependent on adequate dietary protein levels.
Assuntos
Ilhotas Pancreáticas , Taurina , Animais , Dieta Hiperlipídica/efeitos adversos , Proteínas Alimentares/metabolismo , Suplementos Nutricionais , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Taurina/metabolismo , Taurina/farmacologiaRESUMO
Physical inactivity, associated with the ingestion of hypercaloric foods, contributes to obesity development. In contrast, physical exercise training (ET) can slow obesity progression. Vitamin (Vit) D, a hormone that regulates adipocyte metabolism, may represent a strategy to reduce obesity; however, it is currently not known whether Vit D enhances the anti-obesity benefits of physical exercise. We hypothesized that swimming ET may prevent Western diet (WD)-induced obesity, and that Vit D supplementation could enhance the anti-obesity actions of ET. Male Wistar rats were fed, from 21 to 90 days of age, on a standard diet, or a WD, in association or not (sedentary control [CTL-SED] and WD [WD-SED] groups) with swimming ET for 15 min/day, 3 days a week (exercised CTL [CTL-EXE] and WD [WD-EXE] groups). Additionally, at 60 days of age, half of the CTL-EXE and WD-EXE groups were submitted, or not, to oral Vit D supplementation (CTL-EXE-VD and WD-EXE-VD groups, respectively). At 91 days old, WD-SED rats displayed increased body weight, abdominal adiposity, hypercholesterolemia, hyperleptinaemia and high circulating levels of tumour necrosis factor (TNF)-α. Swimming ET attenuated the increase in abdominal adiposity induced by WD. Furthermore, the WD-EXE group exhibited reductions in glycaemia, triglyceridaemia, cholesterolaemia, leptinaemia and in plasma TNF-α concentrations. Vitamin D supplementation, combined with ET, did not provide any additive benefit against adiposity, only potentiating the effects of ET action on the reduction in triglyceridaemia. Exercise training, independently of Vit D, provides a strategy to attenuate the adiposity expansion that is induced by WD, mediated in part by reductions in leptinaemia and TNF-α levels.
Assuntos
Dieta Ocidental , Condicionamento Físico Animal , Animais , Suplementos Nutricionais , Masculino , Obesidade/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa , Vitamina D/farmacologia , Vitamina D/uso terapêutico , VitaminasRESUMO
Maternal obesity increases the risk of nonalcoholic fatty liver disease (NAFLD) in offspring. The Roux-en-Y gastric bypass (RYBG) is effective for achieving weight loss and ameliorates NAFLD. To determine whether these benefits are maintained after pregnancy and/or lactation, and whether they modulate hepatic morphofunction in the next generation, we evaluated hepatic lipid metabolism in Western diet (WD)-obese female rats that underwent RYGB and in their F1 offspring at adulthood. Female Wistar rats consumed a WD from 21 to 130 days of age, before being submitted to RYGB (WD-RYGB-F0) or SHAM (WD-SHAM-F0) operations. After 5 weeks, these females were mated with control male breeders, and the male and female F1 offspring were identified as WD-RYGB-F1 and WD-SHAM-F1. WD-RYGB-F0 dams exhibited lower serum lipids levels, but severe hepatic steatosis and pathological features of advanced liver injury. The hepatic proteins involved in lipogenesis were reduced in WD-RYGB-F0, as were the genes related to ß-oxidation and bile acids (BAs). Although the female and male WD-RYGB-F1 groups did not exhibit hepatic steatosis, the livers of female WD-RYGB-F1 demonstrated higher amounts of lipogenic genes and proteins, while male WD-RYGB-F1 presented a similar downregulation of lipogenic factors to that seen in WD-RYGB-F0 dams. In contrast, maternal and offspring groups of both sexes displayed reductions in the expressions of genes involved in BAs physiology and gluconeogenesis. As such, RYGB aggravates NAFLD after pregnancy and lactation and induces a gender-dependent differential expression of the hepatic lipogenesis pathway in offspring, indicating that female WD-RYGB-F1 may be an increased risk of developing NAFLD.
Assuntos
Derivação Gástrica , Hepatopatia Gordurosa não Alcoólica , Adulto , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Derivação Gástrica/efeitos adversos , Humanos , Lactação , Lipogênese , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/complicações , Obesidade/cirurgia , Gravidez , Ratos , Ratos WistarRESUMO
AIMS: Vitamin (Vit) D regulates various organic processes, including adipose tissue morphofunction and lipid metabolism. Studies indicate that Vit D bioavailability is reduced in obesity, which could contribute to obesity development; however, the effects of Vit D supplementation on increased adiposity in western diet (WD)-obese rats (an experimental model that better resembles the obesogenic human obesity condition) have not been studied, to date. Thus, we hypothesized that Vit D supplementation following the induction of obesity in WD rats might reduce their body weight (BW) and adiposity. MAIN METHODS: Male Wistar rats were fed on a standard chow [control (CTL) group] or a WD to induce obesity (WD group), from 21 to 59 days of age. Subsequently, from 60 to 90-days, half of the CTL and of the WD rats were randomly submitted, or not, to oral Vit D supplementation (CTL-VD and WD-VD groups, respectively). KEY FINDINGS: At 91 days of age, WD rats were obese, displaying higher abdominal circumference and white fat stores, dyslipidemia, hyperleptinemia and greater plasma levels of tumor necrosis factor (TNF)-α. Vit D supplementation decreased BW gain, abdominal fat deposition and ameliorated the plasma lipid profile in WD-VD rats. These effects were accompanied by reductions in leptinemia and in circulating TNF-α levels in these rodents. SIGNIFICANCE: Vit D supplementation, following the induction of obesity, may represent a good strategy to attenuate BW gain and abdominal adiposity, and ameliorate the plasma lipid profile in WD rats. These effects may be mediated, at least in part, by reductions in circulating levels of leptin and TNF-α.
Assuntos
Adiposidade/efeitos dos fármacos , Dieta Ocidental/efeitos adversos , Obesidade/tratamento farmacológico , Fator de Necrose Tumoral alfa/sangue , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Lipídeos/sangue , Masculino , Obesidade/sangue , Obesidade/etiologia , Obesidade/fisiopatologia , Ratos WistarRESUMO
One of the most consumed pesticides in the world is glyphosate, the active ingredient in the herbicide ROUNDUP®. Studies demonstrate that glyphosate can act as an endocrine disruptor and that exposure to this substance at critical periods in the developmental period may program the fetus to induce reproductive damage in adulthood. Our hypothesis is that maternal exposure to glyphosate during pregnancy and lactation in mice will affect the development of male reproductive organs, impairing male fertility during adult life. Female mice consumed 0.5% glyphosate-ROUNDUP® in their drinking water [glyphosate-based herbicide (GBH) group] or filtered water [control (CTRL) group] from the fourth day of pregnancy until the end of the lactation period. Male F1 offspring were designated, according to their mother's treatment, as CTRL-F1 and GBH-F1. Female mice that drank glyphosate displayed reduced body weight (BW) gain during gestation, but no alterations in litter size. Although GBH male F1 offspring did not exhibit modifications in BW, they demonstrated delayed testicular descent. Furthermore, at PND150, GBH-F1 mice presented a lower number of spermatozoa in the cauda epididymis and reduced epithelial height of the seminiferous epithelium. Notably, intratesticular testosterone concentrations were enhanced in GBH-F1 mice; we show that it is an effect associated with increased plasma and pituitary concentrations of luteinizing hormone. Therefore, data indicate that maternal exposure to glyphosate-ROUNDUP® during pregnancy and lactation may lead to decreased spermatogenesis and disruptions in hypothalamus-pituitary-testicular axis regulation in F1 offspring.
Assuntos
Glicina/análogos & derivados , Herbicidas/toxicidade , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Espermatogênese/efeitos dos fármacos , Animais , Animais Lactentes , Modelos Animais de Doenças , Feminino , Ganho de Peso na Gestação/efeitos dos fármacos , Glicina/toxicidade , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Lactação , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Epitélio Seminífero/efeitos dos fármacos , Epitélio Seminífero/patologia , Contagem de Espermatozoides , Espermatozoides/efeitos dos fármacos , Espermatozoides/crescimento & desenvolvimento , Testosterona/análise , Testosterona/metabolismo , GlifosatoRESUMO
PURPOSE: Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. METHODS: Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. RESULTS: The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased ß-cell area and mass. CONCLUSIONS: RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and ß-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.
Assuntos
Glicemia , Peso Corporal , Derivação Gástrica/efeitos adversos , Insulina/sangue , Pâncreas/metabolismo , Pâncreas/fisiopatologia , Animais , Feminino , Masculino , Mães , Obesidade/cirurgia , Ratos , Ratos WistarRESUMO
Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 µg EE and 60 µg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the ß subunit of the insulin receptor (IRß) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRß. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.
Assuntos
Androstenos/efeitos adversos , Anticoncepcionais Orais Combinados/efeitos adversos , Etinilestradiol/efeitos adversos , Hiperinsulinismo/induzido quimicamente , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Animais , Feminino , Glucose/metabolismo , Hiperinsulinismo/metabolismo , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , CamundongosRESUMO
Obesity in fathers leads to DNA damage and epigenetic changes in sperm that may carry potential risk factors for metabolic diseases to the next generation. Taurine (TAU) supplementation has demonstrated benefits against testicular dysfunction and pancreatic islet impairments induced by obesity, but it is not known if these protective actions prevent the propagation of metabolic disruptions to the next generation; as such, we hypothesized that paternal obesity may increase the probability of endocrine pancreatic dysfunction in offspring, and that this could be prevented by TAU supplementation in male progenitors. To test this, male C57Bl/6 mice were fed on a control diet (CTL) or a high-fat diet (HFD) without or with 5% TAU in their drinking water (CTAU and HTAU) for 4 months. Subsequently, all groups of mice were mated with CTL females, and the F1 offspring were identified as: CTL-F1, CTAU-F1, HFD-F1, and HTAU-F1. HFD-fed mice were normoglycemic, but glucose intolerant and their islets hypersecreted insulin. However, at 90 days of age, HFD-F1 offspring displayed normal glucose homeostasis and adiposity, but reduced glucose-induced insulin release. HFD-F1 islets also exhibited ß- and α-cell hypotrophy, and lower δ-cell number per islet. Paternal TAU supplementation prevented the decrease in glucose-induced insulin secretion and normalized ß-cell size and δ-cell number, and increased α-cell size/islet in HTAU-F1 mice. In conclusion, HFD consumption by male founders decreases ß-cell secretion and islet-cell distribution in their offspring. TAU attenuates the deleterious effects of paternal obesity on insulin secretion and islet-cell morphology in F1 offspring.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Sistema Endócrino/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Ilhotas Pancreáticas/efeitos dos fármacos , Pancreatopatias/tratamento farmacológico , Taurina/administração & dosagem , Animais , Sistema Endócrino/fisiopatologia , Intolerância à Glucose/etiologia , Intolerância à Glucose/patologia , Homeostase , Secreção de Insulina , Ilhotas Pancreáticas/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/fisiopatologia , Pancreatopatias/etiologia , Pancreatopatias/patologiaRESUMO
Obesity predisposes to glucose intolerance and type 2 diabetes (T2D). This disease is often characterized by insulin resistance, changes in insulin clearance, and ß-cell dysfunction. However, studies indicate that, for T2D development, disruptions in glucagon physiology also occur. Herein, we investigated the involvement of glucagon in impaired glycemia control in monosodium glutamate (MSG)-obese mice. Male Swiss mice were subcutaneously injected daily, during the first 5 days after birth, with MSG (4 mg/g body weight [BW]) or saline (1.25 mg/g BW). At 90 days of age, MSG-obese mice were hyperglycemic, hyperinsulinemic, and hyperglucagonemic and had lost the capacity to increase their insulin/glucagon ratio when transitioning from the fasting to fed state, exacerbating hepatic glucose output. Furthermore, hepatic protein expressions of phosphorylated (p)-protein kinase A (PKA) and cAMP response element-binding protein (pCREB), and of phosphoenolpyruvate carboxykinase (PEPCK) enzyme were higher in fed MSG, before and after glucagon stimulation. Increased pPKA and phosphorylated hormone-sensitive lipase content were also observed in white fat of MSG. MSG islets hypersecreted glucagon in response to 11.1 and 0.5 mmol/L glucose, a phenomenon that persisted in the presence of insulin. Additionally, MSG α cells were hypertrophic displaying increased α-cell mass and immunoreactivity to phosphorylated mammalian target of rapamycin (pmTOR) protein. Therefore, severe glucose intolerance in MSG-obese mice was associated with increased hepatic glucose output, in association with hyperglucagonemia, caused by the refractory actions of glucose and insulin in α cells and via an effect that may be due to enhanced mTOR activation.
Assuntos
Glicemia/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucagon/sangue , Intolerância à Glucose/sangue , Resistência à Insulina , Insulina/sangue , Obesidade/sangue , Glutamato de Sódio , Tecido Adiposo Branco/metabolismo , Animais , Biomarcadores/sangue , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Intolerância à Glucose/induzido quimicamente , Intolerância à Glucose/fisiopatologia , Fígado/metabolismo , Masculino , Camundongos , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Fosforilação , Serina-Treonina Quinases TOR/metabolismoRESUMO
We investigated the insulin release induced by glucose, the Ca2+ oscillatory pattern, and the cyclic AMP (cAMP)/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC) pathways in islets from adult rats that were reared under diets with 17% protein (C) or 6% protein (LP) during gestation, suckling, and after weaning and in rats receiving diets with 6% protein during gestation and 17% protein after birth (R). First-phase glucose-induced insulin secretion was reduced in LP and R islets, and the second phase was partially restored in the R group. Glucose stimulation did not modify intracellular Ca2+ concentration, but it reduced the Ca2+ oscillatory frequency in the R group compared with the C group. Intracellular cAMP concentration was higher and PKA-Cα expression was lower in the R and LP groups compared with the C group. The PKCα content in islets from R rats was lower than that in C and LP rats. Thus, nutritional recovery from a low-protein diet during fetal life did not repair the kinetics of insulin release, impaired Ca2+ handling, and altered the cAMP/PKA and PLC/PKC pathways.
Assuntos
Cálcio/metabolismo , Dieta com Restrição de Proteínas , Secreção de Insulina/fisiologia , Transdução de Sinais/fisiologia , Animais , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Masculino , Estado Nutricional/fisiologia , Gravidez , Ratos , Ratos Wistar , Fosfolipases Tipo C/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
PURPOSE: Duodeno-jejunal bypass (DJB) operation improves glucose homeostasis in morbid obesity, independently of weight loss or reductions in adiposity, through mechanisms not yet fully elucidated. Herein, we evaluated the effects of DJB upon glucose homeostasis, endocrine pancreatic morphology, and ß-cell responsiveness to potentiating agents of cholinergic and cAMP pathways, in western diet (WD) obese rats, at 2 months after operation. METHODS: From 8 to 18 weeks of age male Wistar rats fed on a WD. After this period, a sham (WD Sham group) or DJB (WD DJB) operations were performed. At 2 months after operation glucose homeostasis was verified. RESULTS: Body weight was similar between WD DJB and WD Sham rats, but WD DJB rats showed a decrease in Lee index, retroperitoneal and perigonadal fat pads. Also, WD DJB rats displayed reduced fasting glycemia and insulinemia, and increased insulin-induced Akt activation in the gastrocnemius. Islets from WD DJB rats secreted less amounts of insulin, in response to activators of the cholinergic (carbachol and phorbol 12-myristate 13-acetate) and cAMP (forskolin and 3-isobutyl-1-methyl-xantine) pathways. Islets of WD DJB rats had higher sintaxin-1 protein content than WD Sham, but without modification in muscarinic-3 receptor, protein kinase (PK)-Cα, and (PK)-Aα protein amounts. In addition, islets of WD DJB animals showed reduction in islets and ß-cell masses. CONCLUSION: DJB surgery improves fasting glycemia and insulin action in skeletal muscle. Better endocrine pancreatic morphofunction was associated, at least in part, with the regulation of the cholinergic and cAMP pathways, and improvements in syntaxin-1 islet protein content induced by DJB.
Assuntos
Derivação Gástrica/métodos , Células Secretoras de Insulina/metabolismo , Obesidade/cirurgia , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Dieta Ocidental , Teste de Tolerância a Glucose , Resistência à Insulina , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/metabolismo , Ratos , Ratos WistarRESUMO
AIMS: Hypothalamic obesity is a severe condition without any effective therapy. Bariatric operations appear as an alternative treatment, but the effects of this procedure are controversial. We, herein, investigated the effects of duodeno-jejunal bypass (DJB) surgery upon the lipid profile and expression of genes and proteins, involved in the regulation of hepatic lipid metabolism, in hypothalamic obese (HyO) rats. METHODS: During the first 5days of life, male newborn Wistar rats received subcutaneous injections of monosodium glutamate [4g/kg body weight, HyO group] or saline (control, CTL group). At 90days of life, HyO rats were randomly submitted to DJB (HyO DJB) or Sham-operations (HyO Sham group). Six months after DJB, adiposity, hepatic steatosis and lipid metabolism were verified. KEY FINDINGS: HyO Sham rats were obese, hyperinsulinemic, insulin resistant and dyslipidemic. These rats had higher liver contents of trygliceride (TG) and presented disorganization of the hepatocyte structures, in association with higher hepatic contents of acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 mRNAs and protein. DJB surgery normalized insulinemia, insulin resistance, and dyslipidemia in HyO rats. TG content in the liver and the hepatic microscopic structures were also normalized in HyO DJB rats, while the expressions of ACC and FASN proteins were decreased in the liver of these rodents. SIGNIFICANCE: The DJB-induced amelioration in hepatic steatosis manifested as a late effect in HyO rats, and was partly associated with a downregulation in hepatic de novo lipogenesis processes, indicating that DJB protects against liver steatosis in hypothalamic obesity.
Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/cirurgia , Derivação Gástrica , Metabolismo dos Lipídeos , Obesidade/metabolismo , Obesidade/cirurgia , Acetil-CoA Carboxilase/metabolismo , Animais , Ácido Graxo Sintases/metabolismo , Fígado Gorduroso/patologia , Masculino , Obesidade/induzido quimicamente , Obesidade/patologia , Ratos , Glutamato de Sódio , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismoRESUMO
PURPOSE: Obesity is usually associated with low-grade inflammation, which impairs insulin action. The amino acid, taurine (TAU), regulates glucose homeostasis and lipid metabolism and presents anti-inflammatory actions. Here, we evaluated whether inflammatory markers are altered in the serum and retroperitoneal adipose tissue of monosodium glutamate (MSG) obese rats, supplemented or not with TAU. METHODS: Male Wistar rats received subcutaneous injections of MSG (4 mg/kg body weight/day, MSG group) or hypertonic saline (CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5 % TAU in their drinking water (CTAU and MTAU). RESULTS: At 120 days of age, MSG rats were obese and hyperinsulinemic. TAU supplementation reduced fat deposition without affecting insulinemia in MTAU rats. MSG rats presented increased pIκ-Bα/Iκ-Bα protein expression in the retroperitoneal adipose tissue. TAU supplementation decreased the ratio of pIκ-Bα/Iκ-Bα protein, possibly contributing to the increased Iκ-Bα content in MTAU adipose tissue. Furthermore, MSG obesity or supplementation did not alter TNF-α, IL-1ß or IL-6 content in adipose tissue. In contrast, MSG rats presented lower serum TNF-α, IL-4 and IL-10 concentrations, and these alterations were prevented by TAU treatment. CONCLUSION: MSG obesity in rats was not associated with alterations in pro-inflammatory markers in retroperitoneal fat stores; however, reductions in the serum concentrations of anti-inflammatory cytokines and of TNF-α were observed. TAU treatment decreased adiposity, and this effect was associated with the normalization of circulating TNF-α and IL-4 concentrations in MTAU rats.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Suplementos Nutricionais , Regulação da Expressão Gênica , Gordura Intra-Abdominal/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , Obesidade/dietoterapia , Taurina/uso terapêutico , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Hiperinsulinismo/dietoterapia , Hiperinsulinismo/etiologia , Hiperinsulinismo/imunologia , Hiperinsulinismo/metabolismo , Proteínas I-kappa B/agonistas , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Injeções Subcutâneas , Interleucina-4/antagonistas & inibidores , Interleucina-4/sangue , Interleucina-4/metabolismo , Gordura Intra-Abdominal/imunologia , Masculino , Inibidor de NF-kappaB alfa/agonistas , Inibidor de NF-kappaB alfa/genética , Obesidade/etiologia , Obesidade/imunologia , Obesidade/metabolismo , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos Wistar , Glutamato de Sódio/administração & dosagem , Glutamato de Sódio/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Herein, we investigated whether subdiaphragmatic vagotomy has benefits on obesity, body glucose homeostasis, and insulin secretion in cafeteria (CAF)-obese rats. Wistar rats were fed a standard or CAF diet for 12 weeks. Subsequently, CAF rats were randomly submitted to truncal vagotomy (CAF Vag) or sham operation (CAF Sham). CAF Sham rats were hyperphagic, obese, and presented metabolic disturbances, including hyperinsulinemia, glucose intolerance, insulin resistance, hyperglycemia, and hypertriglyceridemia. Twelve weeks after vagotomy, CAF Vag rats presented reductions in body weight and perigonadal fat stores. Vagotomy did not modify glucose tolerance but normalized fed glycemia, insulinemia, and insulin sensitivity. Isolated islets from CAF Sham rats secreted more insulin in response to the cholinergic agent, carbachol, and when intracellular cyclic adenine monophosphate (cAMP) is enhanced by forskolin or 3-isobutyl-1-methylxanthine. Vagotomy decreased glucose-induced insulin release due to a reduction in the cholinergic action on ß-cells. This effect also normalized islet secretion in response to cAMP. Therefore, vagotomy in rats fed on a CAF-style diet effectively decreases adiposity and restores insulin sensitivity. These effects were mainly associated with the lack of cholinergic action on the endocrine pancreas, which decreases insulinemia and may gradually reduce fat storage and improve insulin sensitivity.
Assuntos
Hiperglicemia/cirurgia , Hiperinsulinismo/cirurgia , Hipertrigliceridemia/cirurgia , Obesidade/cirurgia , Vagotomia , Nervo Vago/cirurgia , 1-Metil-3-Isobutilxantina/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Carbacol/farmacologia , Colforsina/farmacologia , AMP Cíclico/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Glucose/metabolismo , Glucose/farmacologia , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Wistar , Técnicas de Cultura de Tecidos , Nervo Vago/metabolismoRESUMO
OBJECTIVE: While bile acids are important for the digestion process, they also act as signaling molecules in many tissues, including the endocrine pancreas, which expresses specific bile acid receptors that regulate several cell functions. In this study, we investigated the effects of the conjugated bile acid TUDCA on glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. METHODS: Pancreatic islets were isolated from 90-day-old male mice. Insulin secretion was measured by radioimmunoassay, protein phosphorylation by western blot, Ca(2+) signals by fluorescence microscopy and ATP-dependent K(+) (KATP) channels by electrophysiology. RESULTS: TUDCA dose-dependently increased GSIS in fresh islets at stimulatory glucose concentrations but remained without effect at low glucose levels. This effect was not associated with changes in glucose metabolism, Ca(2+) signals or KATP channel activity; however, it was lost in the presence of a cAMP competitor or a PKA inhibitor. Additionally, PKA and CREB phosphorylation were observed after 1-hour incubation with TUDCA. The potentiation of GSIS was blunted by the Gα stimulatory, G protein subunit-specific inhibitor NF449 and mimicked by the specific TGR5 agonist INT-777, pointing to the involvement of the bile acid G protein-coupled receptor TGR5. CONCLUSION: Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , AMP Cíclico/fisiologia , Glucose/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Ácido Tauroquenodesoxicólico/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Relação Dose-Resposta a Droga , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Canais KATP/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
AIMS: Fat deposition in the liver, which leads to nonalcoholic fatty liver disease is associated with obesity. Taurine (Tau) regulates lipid metabolism, representing a possible nutraceutical agent against obesity and its comorbidities. Here, we investigated whether Tau supplementation prevents hepatic lipid accumulation by regulation of the main hepatic genes involved in de novo lipogenesis and ß-oxidation. MAIN METHODS: Male rats received subcutaneous injections of monosodium glutamate (MSG; 4 mg/kg body weight/day) or saline (control group, CTL) during the first 5 days of life. From 21 to 120 days of age, half of each of the MSG and CTL groups received 2.5% Tau in drinking water (CTau and MTau). KEY FINDINGS: MSG-treated rats were normoglycemic, hypertriglyceridemic and insulin resistant (IR). MSG rats also exhibited massive obesity and higher hepatic triglyceride (TG) content. This effect was associated with enhanced gene expression of fatty acid synthase (FASN), but reduced carbohydrate response element-binding protein (ChREBP), microsomal TG transfer protein (MTP) and carnitine palmitoyltransferase (CPT)-1a mRNAs in MSG livers. Tau supplementation decreased whole body fat accumulation and serum TG levels, without altering IR. Tau also normalized hepatic TG content by enhancing ChREBP, MTP, peroxisome proliferator-activated receptor (PPAR)-α, ACO (acyl-CoA oxidase) and CPT-1a gene expressions. SIGNIFICANCE: Therefore, increased hepatic TG deposition in MSG-obese rats is associated with an enhanced FASN, and reduced MTP and CPT-1a genes. Tau supplementation prevented obesity and hepatic TG deposition by upregulating MTP mRNA, ameliorating hepatic lipid efflux, and consequently enhancing PPAR-α which increases lipid oxidation through ACO and CPT-1a gene expressions.
Assuntos
Suplementos Nutricionais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Obesidade/prevenção & controle , Taurina/farmacologia , Animais , Fígado/patologia , Masculino , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos WistarRESUMO
Taurine (Tau) regulates ß-cell function and glucose homeostasis under normal and diabetic conditions. Here, we assessed the effects of Tau supplementation upon glucose homeostasis and the morphophysiology of endocrine pancreas, in leptin-deficient obese (ob) mice. From weaning until 90-day-old, C57Bl/6 and ob mice received, or not, 5% Tau in drinking water (C, CT, ob and obT). Obese mice were hyperglycemic, glucose intolerant, insulin resistant, and exhibited higher hepatic glucose output. Tau supplementation did not prevent obesity, but ameliorated glucose homeostasis in obT. Islets from ob mice presented a higher glucose-induced intracellular Ca(2+) influx, NAD(P)H production and insulin release. Furthermore, α-cells from ob islets displayed a higher oscillatory Ca(2+) profile at low glucose concentrations, in association with glucagon hypersecretion. In Tau-supplemented ob mice, insulin and glucagon secretion was attenuated, while Ca(2+) influx tended to be normalized in ß-cells and Ca(2+) oscillations were increased in α-cells. Tau normalized the inhibitory action of somatostatin (SST) upon insulin release in the obT group. In these islets, expression of the glucagon, GLUT-2 and TRPM5 genes was also restored. Tau also enhanced MafA, Ngn3 and NeuroD mRNA levels in obT islets. Morphometric analysis demonstrated that the hypertrophy of ob islets tends to be normalized by Tau with reductions in islet and ß-cell masses, but enhanced δ-cell mass in obT. Our results indicate that Tau improves glucose homeostasis, regulating ß-, α-, and δ-cell morphophysiology in ob mice, indicating that Tau may be a potential therapeutic tool for the preservation of endocrine pancreatic function in obesity and diabetes.