Dietary Protein Modulates the Efficacy of Taurine Supplementation on Adaptive Islet Function and Morphology in Obesity.

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.

Physical exercise attenuates obesity development in Western-diet fed obese rats independently of vitamin D supplementation.

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.

Vitamin D supplementation decreases visceral adiposity and normalizes leptinemia and circulating TNF-α levels in western diet-fed obese rats.

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.

Taurine supplementation in high-fat diet fed male mice attenuates endocrine pancreatic dysfunction in their male offspring.

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.

Taurine supplementation induces long-term beneficial effects on glucose homeostasis in ob/ob mice.

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.

Taurine supplementation regulates Iκ-Bα protein expression in adipose tissue and serum IL-4 and TNF-α concentrations in MSG obesity.

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.

Improvement in the expression of hepatic genes involved in fatty acid metabolism in obese rats supplemented with taurine.

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.

Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucagon hypersecretion, and controls ß, α, and δ-cell masses in genetic obese mice.

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.

Taurine supplementation restores insulin secretion and reduces ER stress markers in protein-malnourished mice.

Endoplasmic reticulum (ER) stress is a cellular response to increased intra-reticular protein accumulation or poor ER function. Chronic activation of this pathway may lead to beta cell death and metabolic syndrome (MS). Poor nutrition during perinatal period, especially protein malnutrition, is associated with increased risk for MS in later life. Here, we analyzed the effects of taurine (TAU) supplementation upon insulin secretion and ER stress marker expression in pancreatic islets and in the liver from mice fed a low-protein diet. Malnourished mice had lower body weight and plasma insulin. Their islets secreted less insulin in response to stimulatory concentrations of glucose. TAU supplementation increased insulin secretion in both normal protein and malnourished mice. Western blot analysis revealed lower expression of the ER stress markers CHOP and ATF4 and increased phosphorylation of the survival protein Akt in pancreatic islets of TAU-supplemented mice. The phosphorylation of the mitogenic protein extracellular signal-regulated kinase (ERK1/2) was increased after acute incubation with TAU. Finally, the ER stress markers p-PERK and BIP were increased in the liver of malnourished mice and TAU supplementation normalized these parameters.In conclusion, malnutrition leads to impaired islet function which is restored with TAU supplementation possibly by increasing survival signals and lowering ER stress proteins. Lower ER stress markers in the liver may also contribute to the improvement of insulin action on peripheral organs.

Effects of taurine supplementation and swimming, associated or not, on obesity and glucose homeostasis in mice / Efeito da suplementação com taurina e da natação, associadas ou não, sobre a obesidade e homeostase glicêmica em camundongos

Studies show that physical exercise (PE) is associated with a reduced fat accumulation and increased insulin sensitivity, and taurine (TAU) improves glucose homeostasis in lean rodents. The aim in this work was evaluate the effects of supplementing TAU and practice of PE, associated or not, on obesity and glucose homeostasis on obese MSG-mice. Neonate male Swiss mice received injections of monosodium glutamate (MSG group) or saline (CON group). From the 30th to the 90th day of life, one group of animals received TAU in drinking water (MSG TAU group), another was subjected to PE (MSG PE group) and a third group underwent both procedures (MSG PE TAU group). Mice treated with MSG become obese, hypertriglyceridemic, glucose intolerant and insulin resistant. The supplementation with TAU and the PE, isolated or associated, reduced the triglycerides (38%), glucose intolerance (around 30%) and KITT (79%) in MSG-obese animals, but did not influence the accumulation of fat. Interestingly, the combination of both strategies significantly reduced the insulin resistance, compared to animals subjected to isolated strategies. In conclusion, the supplementation with TAU and PE, isolated or associated, did not influence the accumulation of fat in MSG-obese mice, however, reduce the triglycerides and insulin resistance.

O exercício físico (EF) está associado à redução do acúmulo de gordura e aumento na sensibilidade à insulina e a taurina (TAU) melhora a homeostase glicêmica em roedores magros. Objetivou-se avaliar os efeitos da suplementação com TAU e do EF, associados ou não, sobre a obesidade e a homeostase glicêmica em camundongos obesos-MSG. Camundongos Swiss machos neonatos receberam injeções de glutamato monossódico (grupo MSG) ou salina (grupo CON). Do 30º ao 90º dia de vida, um grupo de animais MSG recebeu TAU na água de beber (MSG TAU); outro foi submetido ao EF (MSG EX) e um terceiro grupo foi submetido aos dois procedimentos (MSG EX TAU). Camundongos -MSG tornaram-se obesos, hipertrigliceridêmicos, intolerantes à glicose e resistentes à insulina. A suplementação com TAU e o EF, associados ou isolados, reduziram a trigliceridemia (38%), a intolerância à glicose (30%) e o KITT (79%) nos animais obesos-MSG, porém, não influenciaram o acúmulo de gordura. A associação das duas estratégias diminui significativamente a resistência à insulina, comparado aos animais submetidos às estratégias isoladas. Conclui-se que a suplementação com TAU e o EF, associados ou isolados, não influenciam no acúmulo de gordura dos camundongos obesos-MSG, porém, diminuem a trigliceridemia e a resistência à insulina.

Taurine supplementation prevents morpho-physiological alterations in high-fat diet mice pancreatic ß-cells.

Taurine (Tau) is involved in beta (ß)-cell function and insulin action regulation. Here, we verified the possible preventive effect of Tau in high-fat diet (HFD)-induced obesity and glucose intolerance and in the disruption of pancreatic ß-cell morpho-physiology. Weaning Swiss mice were distributed into four groups: mice fed on HFD diet (36 % of saturated fat, HFD group); HTAU, mice fed on HFD diet and supplemented with 5 % Tau; control (CTL); and CTAU. After 19 weeks of diet and Tau treatments, glucose tolerance, insulin sensitivity and islet morpho-physiology were evaluated. HFD mice presented higher body weight and fat depots, and were hyperglycemic, hyperinsulinemic, glucose intolerant and insulin resistant. Their pancreatic islets secreted high levels of insulin in the presence of increasing glucose concentrations and 30 mM K(+). Tau supplementation improved glucose tolerance and insulin sensitivity with a higher ratio of Akt phosphorylated (pAkt) related to Akt total protein content (pAkt/Akt) following insulin administration in the liver without altering body weight and fat deposition in HTAU mice. Isolated islets from HTAU mice released insulin similarly to CTL islets. HFD intake induced islet hypertrophy, increased ß-cell/islet area and islet and ß-cell mass content in the pancreas. Tau prevented islet and ß-cell/islet area, and islet and ß-cell mass alterations induced by HFD. The total insulin content in HFD islets was higher than that of CTL islets, and was not altered in HTAU islets. In conclusion, for the first time, we showed that Tau enhances liver Akt activation and prevents ß-cell compensatory morpho-functional adaptations induced by HFD.

Decreased TNF-α gene expression in periodontal ligature in MSG-obese rats: a possible protective effect of hypothalamic obesity against periodontal disease?

The prevalence of obesity is increasing globally. There is evidence that the uncontrolled energetic metabolism in obese patients can accelerate periodontal disease. Therefore, the aim of this study was evaluate the possible relationship between hypothalamic obesity induced by neonatal treatment with MSG and experimental periodontal disease. Newborn male Wistar rats received subcutaneous injections in the cervical region, of 4g/Kg/day of body weight (BW) of MSG (MSG group) or hypertonic saline solution, 1.25/kg/day BW (control group, CTL). At 70 days of life periodontal disease was induced in these animals. After they were sacrificed, radiographic analyses of alveolar bone resorption and Tumor Necrosis Factor α (TNFα) gene expression in gingival tissue were performed. The neonatal treatment with MSG did not affect the concentration of plasma glucose and cholesterol (CHOL). However, plasma insulin, non-esterified fatty acids (NEFA) and triglycerides (TG) leves were higher in MSG compared with CTL group. The alveolar bone resorption was 44% lower in MSG-obese rats compared with CTL rats. In the presence of periodontal ligature, there was an increase in this parameter in all groups. The TNFα gene expression, an inflammatory marker, in periodontal tissue was similar in obese and CTL rats. The presence of ligature increased TNFα gene expression in both groups, but in a lower extension in MSG-obese rats. In conclusion these results suggested that hypothalamic obesity may produce a protective effect against periodontal disease, however further research is needed to understand the mechanisms involved in this process.

Decreased insulin secretion in islets from protein malnourished rats is associated with impaired glutamate dehydrogenase function: effect of leucine supplementation.

We herein studied the role of glutamate dehydrogenase (GDH), in response to leucine (LEU) supplementation, upon insulin secretion of malnourished rats. Weaned male Wistar rats were fed normal-protein (17%) or low-protein diet (6%, LP) for 8 weeks. Half of the rats of each group were supplemented with LEU (1.5%) in the drinking water for the following 4 weeks. Gene and protein expressions, static insulin secretion, and cytoplasmic Ca(2+) oscillations were measured. Glutamate dehydrogenase messenger RNA was 58% lower in LP islets, and LEU supplementation augmented it in 28%. The LP islets secreted less insulin when exposed to 20 mmol/L LEU, 20 mmol/L LEU + 2 mmol/L glutamine (with or without 5 mmol/L aminooxyacetic acid, a branched chain aminotransferase inhibitor, or 20 µmol/L epigallocatechin gallate, a GDH inhibitor), 20 mmol/L α-ketoisocaproate, glutamine + 20 mmol/L ß-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (a GDH activator), and 22.2 mmol/L glucose. Leucine supplementation augmented insulin secretion to levels found in normal-protein islets in all the above conditions, an effect that was blunted when islets were incubated with epigallocatechin gallate. The glutamine + ß-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid-induced increased [Ca(2+)](i) and oscillations were higher than those for LP islets. Leucine supplementation normalized these parameters in LP islets. Impaired GDH function was associated with lower insulin release in LP islets, and LEU supplementation normalized insulin secretion via restoration of GDH function. In addition, GDH may contribute to insulin secretion through ameliorations of Ca(2+) handling in LP islets.

Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats.

The aim of the present study was to evaluate the preventive effects of taurine (TAU) supplementation upon monosodium glutamate (MSG)-induced obesity. Rats treated during the first 5 days of life with MSG or saline were distributed into the following groups: control (CTL), CTL-treated with TAU (CTAU), MSG and MSG-supplemented with TAU (MTAU). CTAU and MTAU received 2.5% of TAU in their drinking water from 21 to 90 days of life. At the end of treatment, MSG and MTAU rats were hyperinsulinemic, glucose intolerant and insulin resistant, as judged by the HOMA index. MSG and MTAU rat islets secreted more insulin at 16.7 mM glucose compared to CTL. MSG rats also showed higher triglycerides (TG) and non-esterified fatty acids (NEFA) plasma levels, Lee Index, retroperitoneal and periepidydimal fat pads, compared with CTL, whereas plasma lipid concentrations and fat depots were lower in MTAU, compared with MSG rats. In addition, MSG rats had a higher liver TG content compared with CTL. TAU decreased liver TG content in both supplemented groups, but fat content only in MTAU rats. TAU supplementation did not change glucose homeostasis, insulin secretion and action, but reduced plasma and liver lipid levels in MSG rats.