RESUMEN
AIMS: The bile acid (BA), tauroursodeoxycholic acid (TUDCA) regulates glucose homeostasis; however, it is not clear whether its effects on insulin signaling are due to its direct interaction with the insulin receptor (IR) or through activation of the G-coupled BA receptor, TGR5. We, herein, investigated whether the actions of TUDCA on glucose homeostasis occur via IR or TGR5 activation. MAIN METHODS: Glucose homeostasis was evaluated in high-fat diet (HFD)-obese or control (CTL) mice, after 30 days or one intraperitoneal (ip) injection of 300 mg/kg TUDCA, respectively. Molecular docking was performed to investigate the potential binding of TUDCA on the IR and TGR5. KEY FINDINGS: After 30 days of TUDCA treatment, HFD mice exhibited improvements in glucose tolerance and insulin sensitivity, which were abolished when these rodents received the IR antagonist, S961. Molecular docking experiments showed that TUDCA demonstrates high binding affinity for TGR5 and IR and strongly interacts with the insulin binding sites 1 and 2 of the IR. Consistent with this potential agonist activity of TUDCA on IR, CTL mice displayed increased hepatic phosphorylation of AKT after an ip injection of TUDCA. This effect was not associated with altered glycemia in CTL mice and was dependent on IR activation, as S961 prevented hepatic AKT activation by TUDCA. Furthermore, TUDCA activated the hepatic protein kinase A (PKA) and cAMP response element-binding protein (CREB) pathway in CTL mice, even after the administration of S961. SIGNIFICANCE: We provide novel evidence that TUDCA may be an agonist of the IR, in turn activating AKT and contributing, at least in part, to its beneficial effects upon glucose homeostasis.
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Glucosa/metabolismo , Receptor de Insulina/agonistas , Ácido Tauroquenodesoxicólico/farmacología , Animales , Sitios de Unión , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis/efectos de los fármacos , Masculino , Ratones , Simulación del Acoplamiento Molecular , Obesidad/metabolismo , Unión Proteica , Receptor de Insulina/química , Receptores Acoplados a Proteínas G/metabolismo , Ácido Tauroquenodesoxicólico/administración & dosificaciónRESUMEN
To assess the effect of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) on the esophageal and intestinal morphology of western diet (WD)-obese rats and to characterize the stomach histopathology of WD rats submitted to VSG. Male Wistar rats received WD from 2-4 months of age, to induce obesity, before randomly submitting them to pseudo (WD-SHAM), VSG (WD-VSG) or RYGB (WD-RYGB) surgeries. Gastrointestinal histomorphometry was performed at 3-months post-surgery. The upper esophagus of VSG and RYGB rats increased luminal area, while reductions in the keratin layer of the mucosa and the tunica muscularis were observed only in the RYGB animals. In the lower esophagus, both surgeries increased keratin layer thickness, but reduced the mucosal mucus content, while RYGB increased the thickness of the tunica mucosa and muscularis. The glandular region of the stomach of WD-VSG rats exhibited hypotrophy, epithelial erosion, fibrosis and moderate inflammatory infiltration. VSG and RYGB increased the villi height in the ileum, and the thickness of the tunica muscularis in the jejunum and ileum of WD rats; furthermore, RYGB augmented the ileal villi height. Thus both approaches induced histomorphological alterations in the esophagus and intestine and VSG damaged the gastric mucosa, even over the long-term.
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Derivación Gástrica , Animales , Dieta Occidental , Gastrectomía , Masculino , Obesidad/cirugía , Ratas , Ratas WistarRESUMEN
Intermittent food restriction (IFR) is used mainly for weight loss; however, its effects on adipose tissue are not known when alternating with an obesogenic diet. To demonstrate its effects on morphological dynamics of fat deposits, female Wistar rats were distributed into groups: standard control (ST-C), with commercial diet; DIO control (DIO-C), with a diet that induces obesity (DIO) during the first and last 15 d, replaced by a standard diet for thirty intermediate days; standard restricted (ST-R), with standard diet during the first and last 15 d, with six cycles of IFR at 50 % of ST-C; and DIO restricted (DIO-R), in DIO during the first and last 15 d, with six cycles of IFR at 50 % of DIO-C. At 105 d of life, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were collected, weighed and histology performed. The DIO-R group showed higher total food intake (DIO-R 10 768·0 (SEM 357·52) kJ/g v. DIO-C 8868·6 (SEM 249·25) kJ/g, P < 0·0001), energy efficiency during RAI (DIO-R 2·26 (SEM 0·05) g/kJ v. DIO-C 0·70 (SEM 0·03) g/kJ, P < 0·0001) and WAT (DIO-R 5·65 (SEM 0·30) g/100 g v. DIO-C 4·56 (SEM 0·30) g/100 g) than their respective control. Furthermore, IFR groups presented hypertrophy of WAT and BAT, as well as fibrosis in BAT. Thus, IFR can establish prospective resistance to weight loss by favouring changes in adipose tissue morphology, increased energy intake and efficiency. Finally, the DIO diet before and after IFR aggravates the damages caused by the restriction.
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Tejido Adiposo Pardo , Tejido Adiposo Blanco/crecimiento & desarrollo , Ayuno , Conducta Alimentaria , Tejido Adiposo Pardo/crecimiento & desarrollo , Animales , Femenino , Estudios Prospectivos , Ratas , Ratas Wistar , Pérdida de PesoRESUMEN
D-pinitol is one of the major inositol found in plants and studies suggest its potential hypoglycemic and hypolipidemic actions in diabetic rodents. Here, we investigated the actions of D-pinitol on adiposity, and in lipid and glycemic homeostasis in monosodium glutamate (MSG)-obese mice. Swiss mice received daily subcutaneous injections of MSG [(4g/kg of body weight (BW)] or saline [1.25g/kg BW; control (CTL)] during their first five days of life. From 90-120 day-old, half of the MSG and CTL groups received 50 mg D-pinitol/kg BW/day (MPIN and CPIN groups) or vehicle (saline; MSG and CTL groups) by gavage. MSG mice displayed higher abdominal adiposity and hepatic triglycerides (TG) deposition, and increased hepatic expression of lipogenic genes (SREBP-1c, ACC-1 and FASN), but downregulation in AMPKα mRNA. MSG mice also exhibited hyperinsulinemia, islet hypersecretion and hypertrophy, glucose intolerance and insulin resistance. D-pinitol did not change adiposity, glucose intolerance, insulin resistance, but increased hepatic triglycerides (TG) content in MPIN mice, which was associated with increases in gene expressions of SREBP-1c and FASN, but reduction in AMPKα. Furthermore, D-pinitol enhanced insulin secretion in MPIN and CPIN groups. Therefore, D-pinitol enhanced glucose-induced insulin secretion, which may account to enhances hepatic lipogenesis and TG deposition in MPIN mice.
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Metabolismo de los Lípidos , Glutamato de Sodio , Animales , Glucemia , Inositol/análogos & derivados , Secreción de Insulina , Lípidos , Ratones , Ratones ObesosRESUMEN
AIMS: Bisphenol (BP)-A exposure can impair glucose and lipid metabolism. However, it is unclear whether this endocrine disruptor (ED) modulates these processes in postmenopause, a period with organic changes that increase the risk for metabolic diseases. Herein, we evaluated the effects of BPA exposure on adiposity, glucose homeostasis and hepatic steatosis in ovariectomized (OVX) mice fed on a high-fat diet (HFD). MAIN METHODS: Adult Swiss female mice were OVX and submitted to a normolipidic diet or HFD and drinking water without [control (OVX CTL) and OVX HFD groups, respectively] or with 1 µg/mL BPA (OVX CBPA and OVX HBPA groups, respectively), for 3 months. KEY FINDINGS: OVX HFD females displayed increased adiposity, glucose intolerance, insulin resistance and moderate hepatic steatosis. This effect was associated with a high hepatic expression of genes involved in lipogenesis (Srebf1 and Scd1), ß-oxidation (Cpt1a) and endoplasmic reticulum (ER) stress (Hspa5 and Hyou1). BPA did not alter adiposity or glucose homeostasis disruptions induced by HFD. However, this ED triggered severe steatosis, exacerbating hepatic fat and collagen depositions in OVX HBPA, in association with a reduction in Mttp mRNA, and up-regulation of genes involved in ß-oxidation (Acox1 and Acadvl), mitochondrial uncoupling (Ucp2), ER stress (Hyou1 and Atf6) and chronic liver injury (Tgfb1and Casp8). Furthermore, BPA caused mild steatosis in OVX CBPA females, increasing the hepatic total lipids and mRNAs for Srebf1, Scd1, Hspa5, Hyou1 and Atf6. SIGNIFICANCE: BPA aggravated hepatic steatosis in OVX mice. Especially when combined with a HFD, BPA caused NAFLD progression, which was partly mediated by chronic ER stress and the TGF-ß1 pathway.
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Compuestos de Bencidrilo/toxicidad , Disruptores Endocrinos/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Fenoles/toxicidad , Adiposidad/efectos de los fármacos , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Chaperón BiP del Retículo Endoplásmico , Femenino , Glucosa/metabolismo , Resistencia a la Insulina , Lipogénesis/efectos de los fármacos , Ratones , Enfermedad del Hígado Graso no Alcohólico/patología , OvariectomíaRESUMEN
Research on the deleterious actions of bisphenol (BP)-A have focused on its effects on insulin secretion during pre/perinatal periods or adulthood. Estrogens also modulate endocrine pancreas physiology in females during aging; however, the effects of BPA on islet morphophysiology after menopause have not been investigated. We evaluated the effects of BPA exposure on glucose homeostasis and islet morphofunction in ovariectomized (OVX) mice fed on a high-fat diet (HFD). Adult Swiss female mice were underwent to bilateral ovariectomy, and with the confirmation of the establishment of surgical menopause, the females were then submitted, or not,to a normolipidic diet or HFD [control (CTL) and HFD groups, respectively] without or with 1⯵g/mL BPA in their drinking water (CBPA and HBPA groups) for 90â¯days. HFD females displayed obesity, hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance. BPA did not modulate HFD-induced obesity or body glucose impairments in HBPA females, and islets isolated from both the HFD and HBPA groups exhibited insulin hypersecretion. The HBPA islets, however, displayed enlarged islet cells and reduced proliferation, in association with the downregulation of mRNAs encoding PDX-1, NGN3 and CCND2 and upregulation of mRNAs encoding ER-ß, GPR30, TNF-α and IL-1ß in HBPA islets. BPA consumption in OVX mice impaired the islet-cell hyperplasia response to the HFD, partly mediated by increased expression of ER-ß and GPR30, which impaired the expression of major genes involved in islet-cell survival and functionality. Together with higher pro-inflammatory cytokines expression in the islet milieu, these alterations may accelerate ß-cell failure in postmenopause.
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Compuestos de Bencidrilo/farmacología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/cirugía , Ovariectomía , Fenoles/farmacología , Animales , Compuestos de Bencidrilo/administración & dosificación , Proliferación Celular/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Femenino , Prueba de Tolerancia a la Glucosa , Islotes Pancreáticos/metabolismo , Ratones , Fenoles/administración & dosificaciónRESUMEN
PURPOSE: Obesity predisposes to cardiovascular and metabolic diseases. The amino acid, L-taurine (Tau), regulates glucose and lipid homeostasis and vascular function. Here we investigated whether Tau supplementation prevents endothelial dysfunction in the thoracic aortas of monosodium glutamate-induced obese (MSG) rats. METHODS: Male rats received subcutaneous injections of MSG (4 mg/kg body weight/day) or saline (control group, CTL) during the first five days of life. From 21 to 150 days of age, the rats were distributed into the groups: CTL, MSG, and CTL and MSG supplemented with 2.5% Tau in their drinking water (CTAU and MTAU). RESULTS: At 150-days old, MSG rats presented massive abdominal fat deposition, hypertriglyceridemia, hyperinsulinemia, glucose intolerance and high plasma levels of malondialdehyde (MDA), a lipid peroxidation marker. Tau supplementation attenuated fat accumulation in perigonadal adipose tissue and prevented the increase in triglycerides and MDA plasma levels. Aortic rings of MSG rats presented reduced vasodilation in response to acetylcholine (ACh). No modifications in insulin-induced vasodilatation, or Akt and eNOS phosphorylation, were observed in MSG aortas; thoracic aortas from MSG rats presented reduced tunica media thickness, with a lower aortic wall thickness/lumen diameter ratio and decreased total collagen content. Tau supplementation restored ACh-induced vasodilation and collagen content. CONCLUSIONS: Our study presents the first evidence that Tau prevents disruptions in vascular reactivity and in extracellular matrix composition in thoracic aortas of MSG-obese rats. The vascular protective actions of Tau may be linked to reduced lipid peroxidation and a reduction in cardiovascular risk factors, such as abdominal fat and hypertriglyceridemia.
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Aorta Torácica/efectos de los fármacos , Suplementos Dietéticos , Endotelio Vascular/efectos de los fármacos , Hipotálamo/metabolismo , Obesidad/fisiopatología , Taurina/farmacología , Animales , Aorta Torácica/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Taurina/administración & dosificaciónRESUMEN
The beneficial actions of L-taurine (Tau) against glucose intolerance, obesity, type 2 diabetes (T2D), and non-alcoholic fat liver disease (NAFLD) have been linked to its antioxidant and anti-inflammatory effects, which ameliorate tissue insulin sensitivity. Importantly, there are several lines of evidence that indicate a direct action of Tau on the endocrine pancreas to regulate the secretion and paracrine actions of insulin, glucagon, and somatostatin. Furthermore, Tau can also ameliorate glucose metabolism through the enhancement of insulin signaling. However, some of the benefits of Tau upon intermediary metabolism may manifest via considerable antagonism of the action of insulin. Therefore, this review discusses the mechanisms of action by which Tau may regulate endocrine pancreatic morphofunction, and glucose and lipid homeostasis.
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Glucosa/metabolismo , Metabolismo de los Lípidos/fisiología , Páncreas/metabolismo , Taurina/metabolismo , Animales , Humanos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Transducción de Señal/fisiologíaRESUMEN
PURPOSE: L-alanine (Ala) and L-arginine (Arg) have been reported to regulate pancreatic ß-cell physiology and to prevent body fat accumulation in diet-induced obesity. Here, we assessed growth and adiposity parameters, glucose tolerance, insulin secretion and the expression of insulin and nutrient-regulated proteins in monosodium glutamate (MSG)-obese mice supplemented with either Ala or Arg. METHODS: Male newborn C57Bl/6 mice received a daily subcutaneous injection of MSG or saline solution (CTL group), during the first 6 days of life. From 30 to 90 days of age, MSG and CTL mice received or not 2.55 % Ala (CAla or MArg groups) or 1.51 % Arg-HCl (CArg or MArg groups) in their drinking water. RESULTS: Adult MSG mice displayed higher adiposity associated with lower phosphorylation of the adipogenic enzyme, ACC, in adipose tissue. Glucose intolerance in MSG mice was linked to lower insulin secretion and to lower expression of IRß in adipose tissue, as well as AS160 phosphorylation in skeletal muscle. Perigonadal fat depots were smaller in Ala and Arg mice, while retroperitoneal fat pads were decreased by Ala supplementation only. Both Ala and Arg improved fed-state glycemia as well as IRß and pAS160 content, but only Ala led to improved glucose tolerance and insulin secretion. Adipostatic signals were increased in MAla mice, as indicated by enhanced AMPK phosphorylation and pACC content in fat depots. CONCLUSIONS: Ala supplementation led to more pronounced metabolic improvements compared to Arg, possibly due to suppression of lipogenesis through activation of the AMPK/ACC pathway.
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Adiposidad/efectos de los fármacos , Alanina/farmacología , Arginina/farmacología , Suplementos Dietéticos , Intolerancia a la Glucosa/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Glucemia/metabolismo , Colesterol/sangre , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Regulación de la Expresión Génica , Homeostasis/efectos de los fármacos , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/inducido químicamente , Fosforilación , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Albúmina Sérica/metabolismo , Glutamato de Sodio , Triglicéridos/sangreRESUMEN
In a state of caloric restriction (CR), improved insulin action was associated with the activation of AMP-activated kinase (AMPK). Here, we verified whether AMPK was involved in impaired ß-cell function in islets from rats subjected to CR for 21 days. Eight-week-old male rats were distributed into a control (CTL) group that was fed an isocaloric diet ad libitum or a CR group that received 60% of the food consumed by the CTL group. From days 18-21, CTL and CR rats were treated with sense (CTLS and CRS) or antisense (CTLAS and CRAS) AMPKα2 oligonucleotides. Caloric restriction was associated with decreased body weight, perigonadal fat pads and insulinaemia, while higher glucose tolerance was observed in CRS rats. Antisense treatment normalized insulinaemia and glucose tolerance in CRAS rats and increased cholesterolaemia in CRAS and CTLAS groups. These effects were associated with reduced pAMPK/AMPK protein expression in the liver of rats treated with antisense oligonucleotides. Additionally, CRS islets showed higher pAMPK/AMPK content and lower glucose-induced insulin release. As expected, antisense oligonucleotides against AMPKα2 efficiently reduced pAMPK/AMPK protein in CRAS and CTLAS islets. The lower AMPK content in CRAS islets normalized the insulin secretion in islets exposed to 16.7 mM glucose. In addition, CTLAS islets presented higher insulin secretion at 2.8 and 16.7 mM glucose. These findings support the hypothesis that higher AMPK protein expression is involved in impaired ß-cell function in islets from rats subjected to CR for 21 days.
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Proteínas Quinasas Activadas por AMP/metabolismo , Restricción Calórica , Glucosa/metabolismo , Insulina/metabolismo , Procesamiento Proteico-Postraduccional/fisiología , Animales , Glucemia/metabolismo , Restricción Calórica/métodos , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Masculino , Ratas WistarRESUMEN
Malnutrition programs the neuroendocrine axis by disruption of food-intake control, leading to obesity. Taurine (Tau) is neuroprotective and improves anorexigenic actions in the hypothalamus. We evaluated the hypothalamic gene-expression profile and food-intake control in protein-restricted mice submitted to a high-fat diet (HFD) and Tau supplementation. Mice were fed on a control (14 % protein-C) or a protein-restricted diet (6 % protein-R) for 6 weeks. Thereafter, mice received, or not, HFD for 8 weeks (CH and RH) with or without 5 % Tau supplementation (CHT and RHT). Protein restriction led to higher food intake, but calories were matched to controls. Excessive calorie intake occurred in HFD mice and this was prevented by Tau supplementation only in the CH group. Additionally, RH and CH mice developed hypothalamic leptin resistance, which was prevented by Tau. Global alterations in the expressions of genes involved in hypothalamic metabolism, cellular defense, apoptosis and endoplasmic reticulum stress pathways were induced by dietary manipulations and Tau treatment. The orexigenic peptides NPY and AgRP were increased by protein restriction and lowered by the HFD. The anorexigenic peptide Pomc was increased by HFD, and this was prevented by Tau only in CH mice. Thus, food intake was disrupted by dietary protein restriction and obesity. HFD-induced alterations were not enhanced by previous protein deficiency, but the some beneficial effects of Tau supplementation upon food intake were blunted by protein restriction. Tau effects upon feeding behavior control are complex and involve interactions with a vast gene network, preventing hypothalamic leptin resistance.
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Grasas de la Dieta/farmacología , Suplementos Dietéticos , Hipotálamo/metabolismo , Leptina/metabolismo , Deficiencia de Proteína/mortalidad , Taurina/farmacología , Animales , Apoptosis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Hipotálamo/patología , Masculino , Ratones , Deficiencia de Proteína/patología , Transducción de Señal/efectos de los fármacosRESUMEN
The occurrence of metabolic disorders, such as diabetes, obesity, atherosclerosis, and hypertension, increases with age. Inappropriate food intake, when combined with genetic and hormonal factors, can trigger the occurrence of these diseases in aged organisms. This study investigated whether short-term calorie restriction (CR; 40% of the intake of control animals (CTL) for 21 days) benefits 1-year-old (CR1yr) and 2-year-old (CR2yr) Wistar rats, with regard to insulin secretion and action. Plasma insulin and the insulin secreted by isolated islets were measured with radioimmunoassay, and the insulin sensitivity of peripheral tissues was assessed with the intraperitoneal glucose tolerance test (IPGTT), intraperitoneal insulin tolerance test, and hepatic and muscle adenosine monophosphate-activated protein kinase (AMPK) phosphorylation measurements. Body weight, epididymal fat pad, epididymal fat pad/body weight index, plasma glucose, and insulin were lower in the CR1yr than in the control (CTL1yr) rats. Serum cholesterol, triglycerides, and protein, as well as hepatic and muscle glycogen content, were similar between the CR and CTL groups. The IPGTT was higher in CR2yr and CTL2yr rats than in CR1yr and CTL1yr rats, and insulin sensitivity was higher in CR1yr and CR2yr rats than in their respective CTLs. This was associated with an increase in hepatic and muscle AMPK phosphorylation. No differences in glucose-induced insulin secretion in the isolated islets were observed between CRs and their respective CTL rats. In conclusion, short-term calorie restriction provoked more severe alterations in CR1yr than CR2yr rats. The normoglycemia observed in both CR groups seems to be due to an increase in insulin sensitivity, with the involvement of liver and muscle AMPK.
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Proteínas Quinasas Activadas por AMP/fisiología , Glucemia/fisiología , Restricción Calórica/métodos , Homeostasis , Factores de Edad , Animales , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Pancreatic ß-cells are highly sensitive to suboptimal or excess nutrients, as occurs in protein-malnutrition and obesity. Taurine (Tau) improves insulin secretion in response to nutrients and depolarizing agents. Here, we assessed the expression and function of Cav and KATP channels in islets from malnourished mice fed on a high-fat diet (HFD) and supplemented with Tau. Weaned mice received a normal (C) or a low-protein diet (R) for 6 weeks. Half of each group were fed a HFD for 8 weeks without (CH, RH) or with 5% Tau since weaning (CHT, RHT). Isolated islets from R mice showed lower insulin release with glucose and depolarizing stimuli. In CH islets, insulin secretion was increased and this was associated with enhanced KATP inhibition and Cav activity. RH islets secreted less insulin at high K(+) concentration and showed enhanced KATP activity. Tau supplementation normalized K(+)-induced secretion and enhanced glucose-induced Ca(2+) influx in RHT islets. R islets presented lower Ca(2+) influx in response to tolbutamide, and higher protein content and activity of the Kir6.2 subunit of the KATP. Tau increased the protein content of the α1.2 subunit of the Cav channels and the SNARE proteins SNAP-25 and Synt-1 in CHT islets, whereas in RHT, Kir6.2 and Synt-1 proteins were increased. In conclusion, impaired islet function in R islets is related to higher content and activity of the KATP channels. Tau treatment enhanced RHT islet secretory capacity by improving the protein expression and inhibition of the KATP channels and enhancing Synt-1 islet content.
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Calcio/metabolismo , Grasas de la Dieta/farmacología , Suplementos Dietéticos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Desnutrición/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Taurina/farmacología , Animales , Humanos , Secreción de Insulina , Masculino , Ratones , Proteína 25 Asociada a Sinaptosomas/metabolismoRESUMEN
Feeding behavior is a major determinant of body composition, adiposity, and glucose homeostasis. Both obesity and malnutrition are risk factors for the metabolic syndrome and are associated with altered food intake. Here we assessed the effects of taurine (TAU) supplementation upon adiposity, food intake, and central insulin signaling in malnourished mice fed on a high-fat diet (HFD). Weaned male C57BL/6 mice were fed a control (14% protein-C) or a protein-restricted (6% protein-R) diet. After 6 weeks, both groups received or not HFD for 8 weeks (CH and RH). Half of the HFD groups were supplemented with 5% TAU (CHT and RHT). Both HFD groups were overweight and showed increased perigonadal and retroperitoneal fat pads. TAU supplementation attenuated obesity in CHT but not in RHT mice. HFD induced hypercholesterolemia and glucose intolerance, although only CH group presented fasting hyperglycemia. TAU supplementation also improved glucose homeostasis only in CHT mice. Western blot analysis showed a reduction of 55% in CH hypothalamic content of phosphorylated IRS-1 (pIRS-1) at basal condition compared with C. TAU treatment increased 35% Akt phosphorylation levels in CHT without modification in RHT hypothalamus. However, TAU supplementation did not alter hypothalamic pIRS-1 amount. CH and RH mice presented increased calorie intake that was normalized in CHT but not in RHT. In conclusion, mice fed on an HFD developed obesity, hypercholesterolemia, glucose intolerance, and increased calorie intake. TAU promoted increased hypothalamic insulin action only in CH mice which was linked to prevention of overfeeding, obesity, and glucose intolerance. Protein-restriction promoted metabolic damages that were not prevented by TAU supplementation.
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Dieta Alta en Grasa , Conducta Alimentaria/efectos de los fármacos , Hipotálamo/metabolismo , Insulina/metabolismo , Desnutrición/metabolismo , Transducción de Señal/efectos de los fármacos , Taurina/farmacología , Adiposidad/efectos de los fármacos , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Suplementos Dietéticos , Prueba de Tolerancia a la Glucosa , Hipotálamo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Taurina/administración & dosificaciónRESUMEN
BACKGROUND: Hypertension is a major public health epidemic that is highly associated with sexual dysfunction in both men and women. Despite its high prevalence, clinical and animal literature on the underlying mechanisms of sexual dysfunction in hypertensive women is remarkably limited. METHODS: Using a well-established rodent model of renovascular hypertension-the 2-kidney, 1-clip (2K1C) Goldblatt model-we investigated possible reproductive deficits in female rats. We evaluated several aspects of reproductive function in hypertensive female rats: estrous cycle, sexual behavior, ovulation, and plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol at proestrus afternoon. RESULTS: Clipping of the left renal artery resulted in dramatic elevations in systolic blood pressure and heart rate. Renovascular hypertension was associated with a delay for reestablishing estrous cyclicity (50% of 2K1C rats failed to resume cycling by 15 days after surgery). In rats that resumed cycling, 2K1C female rats showed a decrease in sexual behavior, evidenced by a decreased lordosis quotient and a reduction in ovulation, as demonstrated by a decreased number of oocytes. Moreover, plasma levels of LH on the proestrus afternoon were reduced in hypertensive female rats, but no changes in estradiol or FSH were observed. CONCLUSIONS: Our results demonstrate that renovascular hypertension induces an overall decrease in reproductive function in female rats. Most important, our results indicate that the animal model of renovascular hypertension could be used as a relevant tool to understand better the pathophysiological mechanisms involved in the reproductive deficits in women with renovascular hypertension.
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Hipertensión Renovascular/fisiopatología , Reproducción/fisiología , Animales , Estradiol/sangre , Ciclo Estral/fisiología , Femenino , Hormona Folículo Estimulante/sangre , Ligadura , Hormona Luteinizante/sangre , Ovulación , Proestro/sangre , Ratas , Ratas Wistar , Conducta Sexual Animal/fisiologíaRESUMEN
SCOPE: Poor nutrition during the perinatal period is associated with an increased risk for metabolic syndrome in adulthood. Taurine (TAU) regulates ß-cell function and glucose homeo-stasis. Here, we assessed the effects of TAU supplementation upon adiposity and glucose control in malnourished mice fed a high-fat diet (HFD). METHODS AND RESULTS: Weaned male C57BL/6J mice were fed a control (14% protein - C) or a protein-restricted (6% protein - R) diet for 6 weeks. Afterwards, mice received or not an HFD for 8 weeks (CH and RH). Half of the HFDmice were supplemented with 5% TAU after weaning (CHT and RHT). Protein restriction led to typical malnutrition features. HFD increased body weight, adiposity, and led to hyperleptinemia, hyperphagia, glucose intolerance, and higher liver glucose output in RH and CH groups. Fasted R mice showed higher plasma adiponectin levels and increased phosphorylation of the AMP-activated protein kinase (p-AMPK) in the liver. These parameters were reduced in RH mice and increased p-AMPK persisted in RHT. TAU prevented obesity and improved glucose tolerance only in CHT, but liver glucose control was ameliorated in both supplemented groups. Better CHT liver glucose control was linked to increased Akt (thymoma viral proto-oncogene/protein kinase B) phosphorylation. CONCLUSION: Malnourished mice fed an HFD developed obesity, glucose intolerance, and increased liver glucose output. TAU preserved only normal liver glucose control in RHT mice, an effect associated with increased liver p-AMPK content.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Hígado/metabolismo , Desnutrición/metabolismo , Taurina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/sangre , Adiposidad/efectos de los fármacos , Aminoácidos/sangre , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Suplementos Dietéticos , Intolerancia a la Glucosa , Leptina/metabolismo , Hígado/efectos de los fármacos , Masculino , Desnutrición/dietoterapia , Ratones , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM.
Asunto(s)
Glucosa/metabolismo , Homeostasis/fisiología , Hígado/metabolismo , Receptor de Bradiquinina B1/deficiencia , Receptor de Bradiquinina B1/metabolismo , Receptor de Bradiquinina B2/deficiencia , Receptor de Bradiquinina B2/metabolismo , Animales , Glucemia/metabolismo , Composición Corporal/genética , Composición Corporal/fisiología , Homeostasis/genética , Hiperglucemia/sangre , Hiperglucemia/genética , Hiperglucemia/metabolismo , Resistencia a la Insulina/genética , Resistencia a la Insulina/fisiología , Sistema Calicreína-Quinina/genética , Sistema Calicreína-Quinina/fisiología , Ratones , Ratones Noqueados , Ratones Obesos , Fosforilación , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B2/genéticaRESUMEN
Isolated islets from low-protein (LP) diet rats showed decreased insulin secretion in response to glucose and carbachol (Cch). Taurine (TAU) increases insulin secretion in rodent islets with a positive effect upon the cholinergic pathway. Here, we investigated the effect of TAU administration upon glucose tolerance and insulin release in rats fed on a normal protein diet (17%) without (NP) or with 2.5% of TAU in their drinking water (NPT), and LP diet fed rats (6%) without (LP) or with TAU (LPT). Glucose tolerance was found to be higher in LP, compared to NP rats. However, plasma glucose levels, during ipGTT, in LPT rats were similar to those of controls. Isolated islets from LP rats secreted less insulin in response to increasing glucose concentrations (2.8-22.2 mmol/L) and to 100 µmol/L Cch. This lower secretion was accompanied by a reduction in Cch-induced internal Ca(2+) mobilization. TAU supplementation prevents these alterations, as judged by the higher secretion induced by glucose or Cch in LPT islets. In addition, Ach-M3R, syntaxin 1 and synaptosomal associated protein of 25 kDa protein expressions in LP were lower than in NP islets. The expressions of these proteins in LPT were normalized. Finally, the sarcoendoplasmatic reticulum Ca(2+)-ATPase 3 protein expression was higher in LPT and NPT, compared with controls. In conclusion, TAU supplementation to LP rats prevented alterations in glucose tolerance as well as in insulin secretion from isolated islets. The latter effect involves the normalization of the cholinergic pathway, associated with the preservation of exocytotic proteins.
Asunto(s)
Dieta con Restricción de Proteínas , Suplementos Dietéticos , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Taurina/farmacología , Animales , Western Blotting , Carbacol/administración & dosificación , Regulación de la Expresión Génica , Glucosa/administración & dosificación , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo , Sintaxina 1/genética , Sintaxina 1/metabolismo , Taurina/sangreRESUMEN
Congenitally analbuminaemic individuals and rats (NARs) exhibit several metabolic abnormalities, including hypertriglyceridaemia and plasma free fatty acid deficiency. Our aim was to study glucose homeostasis and insulin secretion in NARs. Plasma concentrations of lipids, glucose and insulin and secretion of insulin from the pancreatic islets were measured in female NARs and control animals (Sprague-Dawley rats; SDRs). Glucose homeostasis tests were also performed. Plasma glucose levels were similar between NARs and SDRs, irrespective of feeding status. However, fed insulinaemia was â¼37% higher (P 0.05) in NARs than in SDRs. The NARs displayed a markedly increased glucose tolerance, i.e. the integrated glycaemic response was one-third that of the control animals. Enhanced glucose tolerance was associated with threefold higher insulinaemia at peak glycaemia after a glucose load than in the control animals. Similar peripheral insulin sensitivity was observed between groups. Isolated pancreatic islets from NARs secreted significantly more insulin than islets from SDRs in response to a wide range of glucose concentrations (2.8-33.3 mm). Despite having similar liver glycogen contents in the fully fed state, NARs had â¼40% (P 0.05) lower glycogen contents than SDRs after 6 h fasting. The injection of a gluconeogenic substrate, pyruvate, elicited a faster rise in glycaemia in NARs compared with SDRs. Overall, NARs displayed enhanced glucose tolerance, insulin secretion and gluconeogenic flux. The higher glucose tolerance in NARs compared with SDRs is attributed to enhanced islet responsiveness to secretagogues, while peripheral insulin sensitivity seems not to be involved in this alteration. We propose that the enhanced glucose metabolism is a chronic compensatory adaptation to decreased free fatty acid availability in NARs.
Asunto(s)
Glucemia/metabolismo , Ácidos Grasos no Esterificados/sangre , Hipertrigliceridemia/sangre , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Albúmina Sérica/deficiencia , Animales , Enfermedades Carenciales/sangre , Enfermedades Carenciales/complicaciones , Enfermedades Carenciales/diagnóstico , Femenino , Prueba de Tolerancia a la Glucosa/métodos , Hipertrigliceridemia/etiología , Secreción de Insulina , Ratas , Ratas Sprague-DawleyRESUMEN
Alterations in food intake such as caloric restriction modulate the expression of SIRT1 and SIRT4 proteins that are involved in pancreatic ß-cell function. Here, we search for a possible relationship between insulin secretion and the expression of SIRT1, SIRT4, PKC and PKA in islets from adult rats submitted to CR for 21 days. Rats were fed with an isocaloric diet (CTL) or received 60% (CR) of the food ingested by CTL. The dose-response curve of insulin secretion to glucose was shifted to the right in the CR compared with CTL islets (EC(50) of 15.1±0.17 and 10.5±0.11 mmol/L glucose). Insulin release by the depolarizing agents arginine and KCl was reduced in CR compared with CTL islets. Total islet insulin content and glucose oxidation were also reduced in CR islets. Leucine-stimulated secretion was similar in both groups, slightly reduced in CR islets stimulated by leucine plus glutamine but higher in CR islets stimulated by ketoisocaproate (KIC). Insulin secretion was also higher in CR islets stimulated by carbachol, compared with CTL islets. No differences in the rise of cytosolic Ca(2+) concentrations stimulated by either glucose or KCl were observed between groups of islets. Finally, SIRT1, but not SIRT4, protein expression was lower in CR compared with CTL islets, whereas no differences in the expression of PKC and PKA proteins were observed. In conclusion, the lower insulin secretion in islets from CR rats was, at least in part, due to an imbalance between the expression of SIRT1 and SIRT4.