Interesterified palm oil promotes insulin resistance and altered insulin secretion and signaling in Swiss mice.

Interesterified fats have been used to replace trans-fat in ultra-processed foods. However, their metabolic effects are not completely understood. Hence, this study aimed to investigate the effects related to glucose homeostasis in response to interesterified palm oil or refined palm oil intake. Four-week-old male Swiss mice were randomly divided into four experimental groups and fed the following diets for 8 weeks: a normocaloric and normolipidic diet containing refined palm oil (PO group) or interesterified palm oil (IPO group); a hypercaloric and high-fat diet containing refined PO (POHF group) or interesterified PO (IPOHF group). Metabolic parameters related to body mass, adiposity and food consumption showed no significant differences. As for glucose homeostasis parameters, interesterified palm oil diets (IPO and IPOHF) resulted in higher glucose intolerance than unmodified palm oil diets (PO and POHF). Euglycemic-hyperinsulinemic clamp assessment showed a higher endogenous glucose production in the IPO group compared with the PO group. Moreover, the IPO group showed significantly lower p-AKT protein content (in the muscle and liver tissues) when compared with the PO group. Analysis of glucose-stimulated static insulin secretion (11.1 mmol/L glucose) in isolated pancreatic islets showed a higher insulin secretion in animals fed interesterified fat diets (IPO and IPOHF) than in those fed with palm oil (PO and POHF). Interesterified palm oil, including in normolipidic diets, can impair insulin signaling in peripheral tissues and increase insulin secretion by ß-cells, characterizing insulin resistance in mice.

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.

Hypoglycaemic effect of resveratrol in streptozotocin-induced diabetic rats is impaired when supplemented in association with leucine.

Studies have shown synergistic and independent effects of leucine and resveratrol (RSV) as possible therapeutic agents to ameliorate metabolic disorders. Thus, the objective of this study was to investigate the effects of supplementation with leucine and RSV, alone and in combination, on metabolic changes in white adipose tissue of neonatally STZ-induced diabetic rats. After weaning, the rats were treated with trans-resveratrol (0.6 mg/kg/dose) and/or leucine (1.35 mg/kg/dose) administered orally. The animals were euthanized at age 16 weeks for blood analyses. Subcutaneous (SC), periepididymal (PE) and retroperitoneal (RP) fat pads were weighed. Adipocytes from PE and RP pads were isolated for morphometric analysis. Long-term supplementation with RSV promoted adiposity recovery, prevented hypoinsulinemia and improved the metabolic profile of the diabetic rats. However, some of these effects were impaired when RSV was associated with leucine. The diabetic rats supplemented with leucine alone showed no significant improvement in metabolic disorders.

Jaboticaba peel powder and jaboticaba peel aqueous extract reduces obesity, insulin resistance and hepatic fat accumulation in rats.

This study investigated the effects of freeze-dried jaboticaba peel (FJP) and jaboticaba tea (JE) on obesity parameters of diet-induced obese rats. Thirty-six male Wistar rats were distributed into six groups: AIN-93 M feed a normal control diet; HFF (obese control) feed a high-fat and fructose diet; Prevention FJP (P. FJP) and Treatment FJP (T. FJP) feed HFF diet with 2% of FJP powder, for 12 and 6 weeks respectively; Prevention JE (P. JE) and Treatment JE (T. JE) were feed with HFF diet and the water was substituted by JE, for 12 and 6 weeks, respectively. Lipid profile, glucose, adiponectin and leptin were measured. Glucose and insulin tolerance, also pancreatic islet insulin secretion were determined. Liver morphology and fat liver accumulation were evaluated. Results showed that HFF-diet induced weight gain, dyslipidemia, glucose intolerance, insulin resistance and hepatic steatosis. All FJP and JE treatments reduced weight gain, adiposity and improved insulin sensitivity. Twelve weeks supplementation increased HDL-cholesterol and prevented hepatic steatosis. Our results suggest that FJP and JE act as functional foods, being a dietary strategy to prevent or control obesity. FJP and JE 12 weeks supplementation can modulate important parameters of obesity and insulin metabolism, preventing liver steatosis in obese rats.

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.

Protein malnutrition after weaning disrupts peripheral clock and daily insulin secretion in mice.

Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock.

Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.

Taurine (Tau) restores ß-cell function in obesity; however, its action is lost in malnourished obese rodents. Here, we investigated the mechanisms involved in the lack of effects of Tau in this model. C57BL/6 mice were fed a control diet (CD) (14% protein) or a protein-restricted diet (RD) (6% protein) for 6 wk. Afterward, mice received a high-fat diet (HFD) for 8 wk [CD + HFD (CH) and RD + HFD (RH)] with or without 5% Tau supplementation after weaning on their drinking water [CH + Tau (CHT) and RH + Tau (RHT)]. The HFD increased insulin secretion through mitochondrial metabolism in CH and RH. Tau prevented all those alterations in CHT only. The expression of the taurine transporter (Tau-T), as well as Tau content in pancreatic islets, was increased in CH but had no effect on RH. Protein malnutrition programs ß cells and impairs Tau-induced restoration of mitochondrial metabolism and biogenesis. This may be associated with modulation of the expression of Tau-T in pancreatic islets, which may be responsible for the absence of effect of Tau in protein-malnourished obese mice.-Branco, R. C. S., Camargo, R. L., Batista, T. M., Vettorazzi, J. F., Borck, P. C., dos Santos-Silva, J. C. R., Boschero, A. C., Zoppi, C. C., Carneiro, E. M. Protein malnutrition blunts the increment of taurine transporter expression by a high-fat diet and impairs taurine reestablishment of insulin secretion.

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.

Nutritional recovery with okara diet prevented hypercholesterolemia, hepatic steatosis and glucose intolerance.

We assessed the biological value of an okara diet and its effects on the hormonal and metabolic profile of rats submitted to protein restriction during intra-uterine life and lactation and recovered after weaning. Male rats from mothers fed either 17% or 6% protein during pregnancy and lactation were maintained on 17% casein (CC, LC), 17% okara (CO, LO) or 6% casein (LL) diets over 60 d. The nutritional quality of the okara protein was similar to that of casein. The okara diet was effective in the nutritional recovery of rats in growing that were malnourished in early life. Furthermore, the okara diet reversed the hypercholesterolemia and the hepatic steatosis observed in the malnutrition and prevented glucose intolerance in an animal model prone to diabetes mellitus.

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.

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 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.

Mechanisms of insulin secretion in malnutrition: modulation by amino acids in rodent models.

Protein restriction at early stages of life reduces ß-cell volume, number of insulin-containing granules, insulin content and release by pancreatic islets in response to glucose and other secretagogues, abnormalities similar to those seen in type 2 diabetes. Amino acids are capable to directly modulate insulin secretion and/or contribute to the maintenance of ß-cell function, resulting in an improvement of insulin release. Animal models of protein malnutrition have provided important insights into the adaptive mechanisms involved in insulin secretion in malnutrition. In this review, we discuss studies focusing on the modulation of insulin secretion by amino acids, specially leucine and taurine, in rodent models of protein malnutrition. Leucine supplementation increases insulin secretion by pancreatic islets in malnourished mice. This effect is at least in part due to increase in the expression of proteins involved in the secretion process, and the activation of the PI3K/PKB/mTOR pathway seems also to contribute. Mice supplemented with taurine have increased insulin content and secretion as well as increased expression of genes essential for ß-cell functionality. The knowledge of the mechanisms through which amino acids act on pancreatic ß-cells to stimulate insulin secretion is of interest for clinical medicine. It can reveal new targets for the development of drugs toward the treatment of endocrine diseases, in special type 2 diabetes.