Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

Paternal Exercise Improves the Metabolic Health of Offspring via Epigenetic Modulation of the Germline.

BACKGROUND/AIMS: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease's (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. METHODS: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. RESULTS: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. CONCLUSION: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

Modulation of endothelium-derived nitric oxide production and activity by taurine and taurine-conjugated bile acids.

Taurine is a semiessential amino acid found at high concentrations in mammalian plasma and cells, where it regulates cellular functions such as ion flux, controls cell volume and serves as a substrate for conjugated bile acids (BAs). Exogenous administration of both taurine and taurine-conjugated BAs have also been implicated in the modulation of cardiovascular functions. This brief review summarizes the role of taurine and taurine-conjugated BAs in vascular relaxation through the modulation of endothelium-derived nitric oxide (NO). The effects of taurine on vascular health are controversial. However, in the presence of cardiometabolic risk factors, it has been proposed that taurine can increase vascular NO levels by increasing eNOS expression, eNOS phosphorylation on Ser1177, NO bioavailability, the level of antioxidative defense, and the l-arginine/NOS inhibitor asymmetric dimethylarginine (ADMA) ratio. The taurine-conjugated BA-mediated activation of Farnesoid X receptor (FXR), G protein-coupled BA receptor (TGR5) and/or muscarinic 3 receptor (M3) was also reported to increase vascular NO production. FXR activation increases eNOS expression and may reduce ADMA formation, while TGR5 increases mobilization of Ca2+ and phosphorylation of eNOS and Akt in endothelial cells. Furthermore, taurine and taurine-conjugated BAs might regulate NO synthesis and activity by enhancing H2S generation. Several studies have demonstrated the beneficial effects of both taurine and taurine-conjugated BAs in reversing the endothelial dysfunction associated with diabetes, atherosclerosis, hypertension, obesity, malnutrition, and smoking. In addition, taurine-conjugated BAs have emerged as a potential treatment for portal hypertension. Despite these favorable findings, there is a need to further explore the mechanisms and signaling pathways underlying the endothelial effects of taurine and taurine-conjugated BAs. Here, we summarize the main findings regarding the effects of taurine and taurine-conjugated BAs on the endothelial dysfunction associated with altered NO metabolism in cardiovascular diseases.

D-Pinitol Increases Insulin Secretion and Regulates Hepatic Lipid Metabolism in Msg-Obese Mice.

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.

Hyperinsulinemia is associated with increasing insulin secretion but not with decreasing insulin clearance in an age-related metabolic dysfunction mice model.

Human life expectancy is increasing faster lately and, consequently, the number of patients with age-related diseases such as type 2 diabetes (T2D) is rising every year. Cases of hyperinsulinemia have been extensively reported in elderly subjects and this alteration in blood insulin concentration is postulated to be a cause of insulin resistance, which in some cases triggers T2D onset. Thus, it is important to know the underlying mechanisms of age-dependent hyperinsulinemia to find new strategies to prevent T2D in elderly subjects. Two processes control blood insulin concentration: Insulin secretion by the endocrine portion of the pancreas and insulin clearance, which occurs mainly in the liver by the action of the insulin-degrading enzyme (IDE). Here, we demonstrated that 10-month-old mice (old) display increased body and fat pad weight, compared with 3-month-old mice (control), and these alterations were accompanied by glucose and insulin intolerance. We also confirm hyperinsulinemia in the old mice, which was related to increased insulin secretion but not to reduced insulin clearance. Although no changes in insulin clearance were observed, IDE activity was lower in the liver of old compared with the control mice. However, this decreased IDE activity was compensated by increased expression of IDE protein in the liver, thus explaining the similar insulin clearance observed in both groups. In conclusion, at the beginning of aging, 10-month-old mice do not display any alterations in insulin clearance. Therefore, hyperinsulinemia is initiated primarily due to a higher insulin secretion in the age-related metabolic dysfunction in mice.

Glucose intolerance in monosodium glutamate obesity is linked to hyperglucagonemia and insulin resistance in α cells.

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.

Taurine supplementation prevents endothelial dysfunction and attenuates structural changes in aortas from hypothalamic obese rats.

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.

Impact of a playful booklet about diabetes and obesity on high school students in Campinas, Brazil.

Obesity and diabetes are two of the biggest public health problems in the modern world. One possible way to combat the rising prevalence of these diseases is through the spread of awareness about its consequences and how to prevent them. Therefore, educational interventions focused on teaching the physiological basis of these conditions might be valuable tools. However, most scholar curriculums lack high-quality material devoted to this topic. Thus we developed an educational booklet, composed of playful elements, targeted toward high school students and destined for application in classrooms. The efficacy of the developed material was validated through a pretest-posttest design, in which the students had to answer a 10-question test. After booklet completion, students had better outcomes, with an increase in the percentage of correct answers in 7 out of 10 questions contained in the test (P < 0.05). Thus we developed an effective material for usage in the high school classroom to spread the awareness of the risks of metabolic diseases and how to prevent them.

Whole body ARHGAP21 reduction improves glucose homeostasis in high-fat diet obese mice.

GTPase activating proteins (GAPs) are ubiquitously expressed, and their role in cellular adhesion and membrane traffic processes have been well described. TBC1D1, which is a Rab-GAP, is necessary for adequate glucose uptake by muscle cells, whereas increased TCGAP, which is a Rho-GAP, decreases GLUT4 translocation, and consequently glucose uptake in adipocytes. Here, we assessed the possible involvement of ARHGAP21, a Rho-GAP protein, in glucose homeostasis. For this purpose, wild type mice and ARHGAP21 transgenic whole-body gene-deficiency mice (heterozygous mice, expressing approximately 50% of ARHGAP21) were fed either chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD). Het-HFD mice showed a reduction in white fat storage, reflected in a lower body weight gain. These mice also displayed an improvement in insulin sensitivity and glucose tolerance, which likely contributed to reduced insulin secretion and pancreatic beta cell area. The reduction of body weight was also observed in Het mice and this phenomenon was associated with an increase in brown adipose tissue and reduced muscle weight, without alteration in glucose-insulin homeostasis. In conclusion, the whole body ARHGAP21 reduction improved glucose homeostasis and protected against diet-induced obesity specifically in Het-HFD mice. However, the mechanism by which ARHGAP21 leads to these outcomes requires further investigation.

Reduced glucose-induced insulin secretion in low-protein-fed rats is associated with altered pancreatic islets redox status.

In the present study, we investigated the relationship between early life protein malnutrition-induced redox imbalance, and reduced glucose-stimulated insulin secretion. After weaning, male Wistar rats were submitted to a normal-protein-diet (17%-protein, NP) or to a low-protein-diet (6%-protein, LP) for 60 days. Pancreatic islets were isolated and hydrogen peroxide (H2 O2 ), oxidized (GSSG) and reduced (GSH) glutathione content, CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and catalase (CAT) gene expression, as well as enzymatic antioxidant activities were quantified. Islets that were pre-incubated with H2 O2 and/or N-acetylcysteine, were subsequently incubated with glucose for insulin secretion measurement. Protein malnutrition increased CAT mRNA content by 100%. LP group SOD1 and CAT activities were 50% increased and reduced, respectively. H2 O2 production was more than 50% increased whereas GSH/GSSG ratio was near 60% lower in LP group. Insulin secretion was, in most conditions, approximately 50% lower in LP rat islets. When islets were pre-incubated with H2 O2 (100 µM), and incubated with glucose (33 mM), LP rats showed significant decrease of insulin secretion. This effect was attenuated when LP islets were exposed to N-acetylcysteine.

Fenofibrate reverses changes induced by high-fat diet on metabolism in mice muscle and visceral adipocytes.

The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

Regulation of glucose and lipid metabolism by the pancreatic and extra-pancreatic actions of taurine.

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.

Diet-induced glucose homeostasis dysregulation is enhanced by taurine supplementation in ovariectomized mice.

Low levels of estrogens are associated with obesity-related comorbidities. Mice with lower levels of estrogens are thereby more sensitive to the effects of a high-fat-diet (HFD) for the development of glucose intolerance and insulin resistance. Studies in vivo have demonstrated that taurine (TAU) supplementation prevents glucose and insulin resistance. Thus, we aimed to investigate the potential beneficial effects of TAU supplementation on glucose homeostasis of mice with low levels of estrogens fed with a HFD. 3-month-old female C57BL/6J mice underwent bilateral ovariectomy (OVX). After 1 week of recovery, mice were divided into 4 groups and either received: a standard chow diet (OVXC), chow diet plus drinking water enriched with 3% of TAU (OVXCT), HFD (OVXH), and HFD plus supplementation of TAU (OVXHT) for 14 weeks. Exposure to the HFD increased adiposity and plasma levels of glucose and insulin. Contrary to our prediction, the addition of TAU enhanced the deleterious effects of the HFD. Glucose and insulin tolerance tests (ipGTT and ipITT) indicated that mice maintained on the HFD + TAU had worse glucose intolerance and insulin resistance that was linked to lower insulin signaling in skeletal muscle and liver. Insulin secretion of isolated pancreatic islets of OVXH mice was higher than OVXC, and the addition of TAU associated with a HFD did not modulate insulin secretion, suggesting a failure of pancreatic ß cells of OVXHT mice. These results suggest that despite the beneficial reports of TAU, it should be used cautiously in situations where the levels of estrogens are low.

Role of microRNAs on the Regulation of Mitochondrial Biogenesis and Insulin Signaling in Skeletal Muscle.

Mitochondria play a critical role in several cellular processes and cellular homeostasis. Mitochondrion dysfunction has been correlated with numerous metabolic diseases such as obesity and type 2 diabetes. MicroRNAs are non-coding RNAs that have emerged as key regulators of cell metabolism. The microRNAs act as central regulators of metabolic gene networks by leading to the degradation of their target messenger RNA or repression of protein translation. In addition, vesicular and non-vesicular circulating miRNAs exhibit a potential role as mediators of the cross-talk between the skeletal muscle and other tissues/organs. In this review, we will focus on the emerging knowledge of miRNAs controlling mitochondrial function and insulin signaling in skeletal muscle cells. J. Cell. Physiol. 232: 958-966, 2017. © 2016 Wiley Periodicals, Inc.

Propranolol treatment lowers blood pressure, reduces vascular inflammatory markers and improves endothelial function in obese mice.

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.

Benefits of L-alanine or L-arginine supplementation against adiposity and glucose intolerance in monosodium glutamate-induced obesity.

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.

Exercise increases pancreatic ß-cell viability in a model of type 1 diabetes through IL-6 signaling.

Type 1 diabetes (T1D) is provoked by an autoimmune assault against pancreatic ß cells. Exercise training enhances ß-cell mass in T1D. Here, we investigated how exercise signals ß cells in T1D condition. For this, we used several approaches. Wild-type and IL-6 knockout (KO) C57BL/6 mice were exercised. Afterward, islets from control and trained mice were exposed to inflammatory cytokines (IL-1ß plus IFN-γ). Islets from control mice and ß-cell lines (INS-1E and MIN6) were incubated with serum from control or trained mice or medium obtained from 5-aminoimidazole-4 carboxamide1-ß-d-ribofuranoside (AICAR)-treated C2C12 skeletal muscle cells. Subsequently, islets and ß cells were exposed to IL-1ß plus IFN-γ. Proteins were assessed by immunoblotting, apoptosis was determined by DNA-binding dye propidium iodide fluorescence, and NO(•) was estimated by nitrite. Exercise reduced 25, 75, and 50% of the IL-1ß plus IFN-γ-induced iNOS, nitrite, and cleaved caspase-3 content, respectively, in pancreatic islets. Serum from trained mice and medium from AICAR-treated C2C12 cells reduced ß-cell death, induced by IL-1ß plus IFN-γ treatment, in 15 and 38%, respectively. This effect was lost in samples treated with IL-6 inhibitor or with serum from exercised IL-6 KO mice. In conclusion, muscle contraction signals ß-cell survival in T1D through IL-6.

Taurine supplementation preserves hypothalamic leptin action in normal and protein-restricted mice fed on a high-fat diet.

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.

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.

Leucine supplementation does not affect protein turnover and impairs the beneficial effects of endurance training on glucose homeostasis in healthy mice.

Endurance exercise training as well as leucine supplementation modulates glucose homeostasis and protein turnover in mammals. Here, we analyze whether leucine supplementation alters the effects of endurance exercise on these parameters in healthy mice. Mice were distributed into sedentary (C) and exercise (T) groups. The exercise group performed a 12-week swimming protocol. Half of the C and T mice, designated as the CL and TL groups, were supplemented with leucine (1.5 % dissolved in the drinking water) throughout the experiment. As well known, endurance exercise training reduced body weight and the retroperitoneal fat pad, increased soleus mass, increased VO2max, decreased muscle proteolysis, and ameliorated peripheral insulin sensitivity. Leucine supplementation had no effect on any of these parameters and worsened glucose tolerance in both CL and TL mice. In the soleus muscle of the T group, AS-160(Thr-642) (AKT substrate of 160 kDa) and AMPK(Thr-172) (AMP-Activated Protein Kinase) phosphorylation was increased by exercise in both basal and insulin-stimulated conditions, but it was reduced in TL mice with insulin stimulation compared with the T group. Akt phosphorylation was not affected by exercise but was lower in the CL group compared with the other groups. Leucine supplementation increased mTOR phosphorylation at basal conditions, whereas exercise reduced it in the presence of insulin, despite no alterations in protein synthesis. In trained groups, the total FoxO3a protein content and the mRNA for the specific isoforms E2 and E3 ligases were reduced. In conclusion, leucine supplementation did not potentiate the effects of endurance training on protein turnover, and it also reduced its positive effects on glucose homeostasis.