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.

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.

Chronic exercise reduces hypothalamic transforming growth factor-ß1 in middle-aged obese mice.

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-ß (TGF-ß1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-ß1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-ß1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-ß1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-ß1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

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.

Effects of taurine supplementation upon food intake and central insulin signaling in malnourished mice fed on a high-fat diet.

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.

Taurine supplementation improves liver glucose control in normal protein and malnourished mice fed a high-fat diet.

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.