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1.
J Biol Chem ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32229584

RESUMO

G protein-coupled receptors (GPCRs) are important modulators of glucose-stimulated insulin secretion (GSIS), essential for maintaining energy homeostasis. Here, we investigated the role of Gß5-R7, a protein complex consisting of the atypical G protein ß subunit Gß5 and a regulator of G protein signaling (RGS) of the R7 family. Using the mouse insulinoma MIN6 cell line and pancreatic islets, we investigated the effects of G protein subunit ß 5 (Gnb5) knockout on insulin secretion. Consistent with previous work, the Gnb5 knockout diminished insulin secretion evoked by the muscarinic cholinergic agonist Oxo-M. We found that the Gnb5 knockout also attenuated activities of other GPCR agonists, including ADP, arginine vasopressin (AVP), glucagon-like peptide 1 (GLP-1), and forskolin, and surprisingly, the response to high glucose. Experiments with MIN6 cells cultured at different densities provided evidence that the Gnb5 knockout eliminated the stimulatory effect of cell adhesion on Oxo-M stimulated GSIS; this effect likely involved the adhesion GPCR GPR56. The Gnb5 knockout did not influence cortical actin depolymerization, but affected protein kinase C activity, and the 14-3-3ε substrate. Importantly, Gnb5 -/- islets or MIN6 cells had normal total insulin content and released normal insulin amounts in response to K+-evoked membrane depolarization. These results indicate that Gß5-R7 plays a role in the insulin secretory pathway downstream of signaling via all GPCRs and glucose. We propose that the Gß5-R7 complex regulates a phosphorylation event participating in the vesicular trafficking pathway, downstream of G protein signaling and actin depolymerization, but upstream of insulin granule release.

2.
Eur J Nutr ; 2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-30982179

RESUMO

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.

3.
J Cell Physiol ; 234(5): 6313-6323, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30317568

RESUMO

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high-fat diet (HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein-restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein-control diet) or a protein-restricted (6% protein-restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein-restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha protein content, and higher levels of malate and α-ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc-dependent kinase and acetyl coenzyme-A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl-CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.

4.
J Cell Physiol ; 234(5): 7019-7031, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30317580

RESUMO

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.

5.
Exp Physiol ; 103(11): 1481-1493, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30211444

RESUMO

NEW FINDINGS: What is the central question of this study? Early-life adversity is associated with increased risk for obesity and metabolic dysfunction. However, it is unclear whether obesity and metabolic dysfunction result from coping strategies to deal with adversity-related emotional dysregulation, a direct programming of systems regulating metabolic function, or a combination of both. What is the main finding and its importance? Early-life adversity increases vulnerability to later-life obesity and metabolic dysfunction, indicating that genetics and adult lifestyle are not the only determinants of obesity and related metabolic dysfunction. Moreover, consumption of cafeteria diet exacerbated metabolic dysfunction associated with early-life adversity, suggesting that poor dietary choices might have a bigger impact in the context of early-life adversity. ABSTRACT: Early-life adversity has become recognized as an important factor contributing to adult obesity and associated metabolic dysfunction. However, it is unclear whether obesity and metabolic dysfunction associated with early-life adversity result from coping strategies to deal with adversity-related emotional dysregulation, a direct programming of systems regulating metabolic function, or a combination. Interestingly, both early-life adversity and later-life dietary choices affect immune function, favouring pro-inflammatory mechanisms that are associated with obesity-related metabolic dysfunction. To investigate the unique and/or interactive effects of early-life adversity and later-life dietary choices for increased vulnerability to obesity and metabolic dysfunction, and specifically the role of the immune system in this vulnerability, we combined a naturalistic rat model of early-life scarcity-adversity with a rat model of obesity, the cafeteria diet. Our results indicate that early-life adversity alone induces insulin resistance, reduces pancreatic insulin secretion, plasma concentrations of triglycerides and cholesterol, and increases fasting glucose and tumour necrosis factor-α plasma concentrations. Importantly, animals exposed to adverse rearing were more vulnerable to metabolic dysregulation associated with the cafeteria diet, given that they consumed more energy, showed more severe hepatic steatosis and increased concentrations of the pro-inflammatory cytokine interleukin-1ß than normally reared animals fed the cafeteria diet. Together, our results suggest that early-life adversity negatively programmes physiological systems that regulate metabolic function and increases vulnerability to obesity and metabolic dysfunction in adulthood. These results highlight the intrinsic relationship between the quality of the early postnatal environment and later-life dietary choices on adult health outcomes.


Assuntos
Resistência à Insulina/fisiologia , Obesidade/metabolismo , Triglicerídeos/sangue , Animais , Dieta , Modelos Animais de Doenças , Feminino , Insulina/sangue , Interleucina-1beta/sangue , Masculino , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangue
6.
Metabolism ; 85: 250-258, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29751019

RESUMO

OBJECTIVE: The exposure to artificial light at night (ALAN) disrupts the biological rhythms and has been associated with the development of metabolic syndrome. MicroRNAs (miRNAs) display a critical role in fine-tuning the circadian system and energy metabolism. In this study, we aimed to assess whether altered miRNAs expression in the liver underlies metabolic disorders caused by disrupted biological rhythms. RESULTS: We found that C3H/HePas mice exposed to ALAN developed obesity, and hepatic steatosis, which was paralleled by decreased expression of Rev-erbα and up-regulation of its lipogenic targets ACL and FAS in liver. Furthermore, the expression of Rev-erbα-targeting miRNAs, miR-140-5p, 185-5p, 326-5p and 328-5p were increased in this group. Consistently, overexpression of these miRNAs in primary hepatocytes reduced Rev-erbα expression at the mRNA and protein levels. Importantly, overexpression of Rev-erbα-targeting miRNAs increased mRNA levels of Acly and Fasn. CONCLUSION: Thus, altered miRNAs profile is an important mechanism underlying the disruption of the peripheral clock caused by exposure to ALAN, which could lead to hepatic steatosis.


Assuntos
Ritmo Circadiano/fisiologia , Fígado Gorduroso/metabolismo , Luz , Fígado/metabolismo , MicroRNAs/metabolismo , Animais , Glicemia/metabolismo , Metabolismo Energético/fisiologia , Lipogênese/fisiologia , Masculino , Camundongos , MicroRNAs/genética , Atividade Motora/fisiologia
7.
Endocrine ; 60(3): 407-414, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29556948

RESUMO

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 Wistar
8.
Neural Plast ; 2017: 9652978, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28951790

RESUMO

The aim of this study was to investigate the effect of subdiaphragmatic vagotomy on insulin sensitivity, secretion, and degradation in metabolic programmed mice, induced by a low-protein diet early in life, followed by exposure to a high-fat diet in adulthood. Weaned 30-day-old C57Bl/6 mice were submitted to a low-protein diet (6% protein). After 4 weeks, the mice were distributed into three groups: LP group, which continued receiving a low-protein diet; LP + HF group, which started to receive a high-fat diet; and LP + HFvag group, which underwent vagotomy and also was kept at a high-fat diet. Glucose-stimulated insulin secretion (GSIS) in isolated islets, ipGTT, ipITT, in vivo insulin clearance, and liver expression of the insulin-degrading enzyme (IDE) was accessed. Vagotomy improved glucose tolerance and reduced insulin secretion but did not alter adiposity and insulin sensitivity in the LP + HFvag, compared with the LP + HF group. Improvement in glucose tolerance was accompanied by increased insulinemia, probably due to a diminished insulin clearance, as judged by the lower C-peptide : insulin ratio, during the ipGTT. Finally, vagotomy also reduced liver IDE expression in this group. In conclusion, when submitted to vagotomy, the metabolic programmed mice showed improved glucose tolerance, associated with an increase of plasma insulin concentration as a result of insulin clearance reduction, a phenomenon probably due to diminished liver IDE expression.


Assuntos
Resistência à Insulina/fisiologia , Insulina/metabolismo , Obesidade/cirurgia , Vagotomia/métodos , Animais , Dieta Hiperlipídica , Dieta com Restrição de Proteínas , Glucose/metabolismo , Insulisina/metabolismo , Fígado/metabolismo , Camundongos , Obesidade/metabolismo
9.
Pharmacol Res ; 122: 35-45, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28539257

RESUMO

Obesity-associated hypertension is accompanied by a number of cardiovascular risk factors including vascular insulin resistance (IR) and higher sympathetic nervous activity. Therefore, autonomic blockade was demonstrated to reverse hypertension, endothelial dysfunction and IR in obese individuals. We hypothesized that ß-AR blockade with propranolol would restore endothelial function and vascular insulin signaling in obesity, associated with an anti-inflammatory effect. Body weight, systolic blood pressure (SBP), plasma biochemical parameters and aortic endothelial function were analyzed in mice fed standard diet (control group) or a high fat diet (HFD) that were treated with vehicle (water) or propranolol (10mg/kg/day) for 8weeks. Propranolol treatment did not modify obesogenic effect of HFD feeding. However, propranolol was effective in preventing the rise in SBP, the hyperinsulinemia and the impaired endothelium-dependent relaxation to acetylcholine and to insulin in obese mice. Protective effect of propranolol administration in endothelial function was associated with increased nitric oxide (NO) production and phosphorylation of Akt (Ser473) and eNOS (Ser1177), but with reduced phospho-IRS-1(Ser307) and phospho-ERK1/2 (Thr202/Tyr204). In addition, ß-blocker propranolol prevented the NF-kB nuclear translocation and the increase in phospho-IκB-α (Ser32) and in interleukin(IL)-6 expression in aorta of obese mice, without significant changes in either aortic reactive oxygen species production or in circulating IL-6 and TNF-α levels. In ß2-AR knockout mice, despite increasing body weight and visceral fat, HFD did not increase SBP and showed a partial improvement of endothelial function, revealing a role of ß2-AR in cardiovascular effects of obesity. In conclusion, our results suggest that ß-AR blockade with propranolol is effective to prevent the endothelial dysfunction, vascular IR and pro-inflammatory state displayed in HFD-induced obesity, independent of changes in body weight.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Obesidade/complicações , Propranolol/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Óxido Nítrico/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Propranolol/farmacologia , Espécies Reativas de Oxigênio/metabolismo
10.
Eur J Nutr ; 56(2): 705-713, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26621632

RESUMO

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/metabolismo
11.
J. physiol. biochem ; 72(4): 625-633, dic. 2016. tab, graf
Artigo em Inglês | IBECS | ID: ibc-168370

RESUMO

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 β-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 (AU)


No disponible


Assuntos
Animais , Masculino , Ratos , Hiperglicemia/cirurgia , Hiperinsulinismo/cirurgia , Hipertrigliceridemia/cirurgia , Obesidade/cirurgia , Vagotomia , Modelos Animais de Doenças , Ratos Wistar , Resistência à Insulina , Peso Corporal , Técnicas de Cultura de Células , 1-Metil-3-Isobutilxantina/farmacologia , AMP Cíclico/metabolismo , Dieta Hiperlipídica
12.
BMC Cancer ; 16(1): 764, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27716121

RESUMO

BACKGROUND: Cachexia is one of the most important causes of cancer-related death. Supplementation with branched-chain amino acids, particularly leucine, has been used to minimise loss of muscle tissue, although few studies have examined the effect of this type of nutritional supplementation on the metabolism of the tumour-bearing host. Therefore, the present study evaluated whether a leucine-rich diet affects metabolomic derangements in serum and tumour tissues in tumour-bearing Walker-256 rats (providing an experimental model of cachexia). METHODS: After 21 days feeding Wistar female rats a leucine-rich diet, distributed in L-leucine and LW-leucine Walker-256 tumour-bearing groups, we examined the metabolomic profile of serum and tumour tissue samples and compared them with samples from tumour-bearing rats fed a normal protein diet (C - control; W - tumour-bearing groups). We utilised 1H-NMR as a means to study the serum and tumour metabolomic profile, tumour proliferation and tumour protein synthesis pathway. RESULTS: Among the 58 serum metabolites examined, we found that 12 were altered in the tumour-bearing group, reflecting an increase in activity of some metabolic pathways related to energy production, which diverted many nutrients toward tumour growth. Despite displaying increased tumour cell activity (i.e., higher Ki-67 and mTOR expression), there were no differences in tumour mass associated with changes in 23 metabolites (resulting from valine, leucine and isoleucine synthesis and degradation, and from the synthesis and degradation of ketone bodies) in the leucine-tumour group. This result suggests that the majority of nutrients were used for host maintenance. CONCLUSION: A leucine rich-diet, largely used to prevent skeletal muscle loss, did not affect Walker 256 tumour growth and led to metabolomic alterations that may partially explain the positive effects of leucine for the whole tumour-bearing host.


Assuntos
Caquexia/dietoterapia , Leucina/administração & dosagem , Neoplasias/sangue , Animais , Caquexia/sangue , Caquexia/etiologia , Linhagem Celular Tumoral , Dieta , Feminino , Metaboloma , Transplante de Neoplasias , Neoplasias/complicações , Neoplasias/patologia , Ratos Wistar , Carga Tumoral
13.
Sci Rep ; 6: 33464, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27633083

RESUMO

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/patologia
14.
J Physiol Biochem ; 72(4): 625-633, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27351887

RESUMO

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/metabolismo
15.
Obes Surg ; 25(4): 656-65, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25204409

RESUMO

BACKGROUND: Bariatric operations are frequently used to improve metabolic profile and comorbidities in obese subjects, but the effects of this procedure in hypothalamic-obese (HyO) patients are controversial. Here, using HyO rats, we investigate the effects of duodenal-jejunal bypass (DJB) upon obesity, serum lipid levels, glucose tolerance, and insulin action and secretion. METHODS: Hypothalamic obesity was induced in male rats by the administration of monosodium glutamate [4 g/kg body weight (BW), HyO group] during the first 5 days of life. Control (CTL) group received saline (1.25 g/kg BW). At 90 days of age, HyO rats were submitted to DJB (HyO DJB group) or sham surgery. After 2 months, lipid levels, glucose tolerance, obesity parameters, and insulin sensitivity and secretion were verified. RESULTS: HyO rats displayed obesity, hypertriglyceridemia, hypercholesterolemia, glucose intolerance, and hyperinsulinemia. A higher HOMA-IR and no alteration in the ratio of phospho (p)-Akt related to Akt protein content in the liver, after insulin stimulus, demonstrated that HyO rats were insulin resistant. Islets isolated from HyO rats hypersecreted insulin in response to glucose and carbachol (Cch). At 2 months after DJB, HyO rats still displayed higher fat stores, but showed normal serum lipids and insulin levels. The HyO DJB group displayed better glucose tolerance, associated with a normal hepatic insulin activation of Akt. Normal glucose and Cch-induced insulin secretion was observed in HyO DJB islets. CONCLUSIONS: DJB ameliorated glucose homeostasis, restored hepatic insulin action, and normalized islet function in HyO rats, indicating that this surgery may be useful for the treatment of hypothalamic obesity.


Assuntos
Cirurgia Bariátrica , Doenças Hipotalâmicas/cirurgia , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Obesidade/cirurgia , Animais , Animais Recém-Nascidos , Glicemia/metabolismo , Duodeno/cirurgia , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/patologia , Resistência à Insulina , Jejuno/cirurgia , Masculino , Obesidade/etiologia , Obesidade/patologia , Ratos , Ratos Wistar
16.
Acta Cir Bras ; 29(9): 609-14, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25252208

RESUMO

PURPOSE: To evaluate the effects of duodenal-jejunal bypass (DJB) on serum and hepatic profiles of obese rats fed on a western diet (WD). METHODS: Twenty eight male Wistar rats were fed a standard rodent chow diet (CTL group) or WD ad libitum. After 10 weeks, WD rats were submitted to sham (WD SHAM) or duodenal-jejunal bypass (WD DJB). Body weight, fat pad depots, glycemia, insulinemia, HOMA-IR, TyG, lipids profile and hepatic analyses were evaluated two months after surgery. RESULTS: The WD SHAM group presented greater obesity, hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia and hepatic steatosis than the CTL group. WD DJB rats presented decreased serum glucose and insulin resistance, when compared to WD SHAM animals, without changes in insulinemia. In addition, DJB surgery normalized serum TG and attenuated TG accumulation and steatosis in the liver of the WD DJB group. Hepatic ACC and FAS protein expressions were similar in all groups. CONCLUSION: Duodenal-jejunal bypass attenuates hepatic parameters of non-alcoholic fatty liver disease in obese rats fed on a western diet.


Assuntos
Dieta Ocidental , Duodeno/cirurgia , Derivação Gástrica/métodos , Jejuno/cirurgia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Obesidade/cirurgia , Acetil-CoA Carboxilase/análise , Tecido Adiposo , Animais , Glicemia/análise , Peso Corporal , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases/análise , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Triglicerídeos/sangue
17.
Acta cir. bras ; 29(9): 609-614, 09/2014. tab, graf
Artigo em Inglês | LILACS | ID: lil-722128

RESUMO

PURPOSE: To evaluate the effects of duodenal-jejunal bypass (DJB) on serum and hepatic profiles of obese rats fed on a western diet (WD). METHODS: Twenty eight male Wistar rats were fed a standard rodent chow diet (CTL group) or WD ad libitum. After 10 weeks, WD rats were submitted to sham (WD SHAM) or duodenal-jejunal bypass (WD DJB). Body weight, fat pad depots, glycemia, insulinemia, HOMA-IR, TyG, lipids profile and hepatic analyses were evaluated two months after surgery. RESULTS: The WD SHAM group presented greater obesity, hyperglycemia, hyperinsulinemia, insulin resistance, hypertriglyceridemia and hepatic steatosis than the CTL group. WD DJB rats presented decreased serum glucose and insulin resistance, when compared to WD SHAM animals, without changes in insulinemia. In addition, DJB surgery normalized serum TG and attenuated TG accumulation and steatosis in the liver of the WD DJB group. Hepatic ACC and FAS protein expressions were similar in all groups. CONCLUSION: Duodenal-jejunal bypass attenuates hepatic parameters of non-alcoholic fatty liver disease in obese rats fed on a western diet. .


Assuntos
Animais , Masculino , Dieta Ocidental , Duodeno/cirurgia , Derivação Gástrica/métodos , Jejuno/cirurgia , Hepatopatia Gordurosa não Alcoólica/cirurgia , Obesidade/cirurgia , Tecido Adiposo , Acetil-CoA Carboxilase/análise , Peso Corporal , Glicemia/análise , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Proteínas Serina-Treonina Quinases/análise , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Triglicerídeos/sangue
18.
Physiol Behav ; 105(5): 1104-11, 2012 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-22178647

RESUMO

The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. Taken together, our results suggest that the cafeteria diet administered from weaning age was able to induce obesity and reduce the reproductive capability in adult female rats, indicating that this obesity model can be used to better understand the mechanisms underlying reproductive dysfunction in obese subjects.


Assuntos
Hormônio Luteinizante/sangue , Obesidade/fisiopatologia , Ovário/fisiopatologia , Ovulação/fisiologia , Progesterona/sangue , Adiposidade , Fatores Etários , Ração Animal , Animais , Estradiol/sangue , Feminino , Ovário/anatomia & histologia , Prolactina/sangue , Ratos , Ratos Wistar , Comportamento Sexual Animal
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