Publications by authors named "Jean Franciesco Vettorazzi"

21 Publications

  • Page 1 of 1

Excess of glucocorticoids during late gestation impairs the recovery of offspring's β-cell function after a postnatal injury.

FASEB J 2021 08;35(8):e21828

Laboratory of Investigation in Chronic Diseases - LIDoC, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina - UFSC, Florianópolis, Brazil.

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. β-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets' function over time. This study alerts to the importance of proper management of exogenous GCs during pregnancy and a healthy postnatal lifestyle since the combination of adverse factors during the prenatal and postnatal period accentuates the predisposition to metabolic disorders in adult life.
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http://dx.doi.org/10.1096/fj.202100841RDOI Listing
August 2021

The Vagus Nerve and Spleen: Influence on White Adipose Mass and Histology of Obese and Non-obese Rats.

Front Physiol 2021 25;12:672027. Epub 2021 Jun 25.

Postgraduate Program in Applied Health Sciences, Western Paraná State University, Francisco Beltrão, Brazil.

The vagus nerve (VN) and spleen represent a complex interface between neural and immunological functions, affecting both energy metabolism and white adipose tissue (WAT) content. Here, we evaluated whether vagal and splenic axis participates in WAT mass regulation in obese and non-obese male Wistar rats. High doses of monosodium glutamate (M; 4 g/Kg) were administered during the neonatal period to induce hypothalamic lesion and obesity (M-Obese rats). Non-obese or Control (CTL) rats received equimolar saline. At 60 days of life, M-Obese and CTL rats were randomly distributed into experimental subgroups according to the following surgical procedures: sham, subdiaphragmatic vagotomy (SV), splenectomy (SPL), and SV + SPL ( = 11 rats/group). At 150 days of life and after 12 h of fasting, rats were euthanized, blood was collected, and the plasma levels of glucose, triglycerides, cholesterol, insulin, and interleukin 10 (IL10) were analyzed. The visceral and subcutaneous WAT depots were excised, weighed, and histologically evaluated for number and size of adipocytes as well as IL10 protein expression. M-Obese rats showed higher adiposity, hyperinsulinemia, hypertriglyceridemia, and insulin resistance when compared with CTL groups ( < 0.05). In CTL and M-Obese rats, SV reduced body weight gain and triglycerides levels, diminishing adipocyte size without changes in IL10 expression in WAT (< 0.05). The SV procedure resulted in high IL10 plasma levels in CTL rats, but not in the M-Obese group. The splenectomy prevented the SV anti-adiposity effects, as well as blocked the elevation of IL10 levels in plasma of CTL rats. In contrast, neither SV nor SPL surgeries modified the plasma levels of IL10 and IL10 protein expression in WAT from M-Obese rats. In conclusion, vagotomy promotes body weight and adiposity reduction, elevating IL10 plasma levels in non-obese animals, in a spleen-dependent manner. Under hypothalamic obesity conditions, VN ablation also reduces body weight gain and adiposity, improving insulin sensitivity without changes in IL10 protein expression in WAT or IL10 plasma levels, in a spleen-independent manner. Our findings indicate that the vagal-spleen axis influence the WAT mass in a health state, while this mechanism seems to be disturbed in hypothalamic obese animals.
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http://dx.doi.org/10.3389/fphys.2021.672027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269450PMC
June 2021

Vagotomy and Splenectomy Reduce Insulin Secretion and Interleukin-1β.

Pancreas 2021 04;50(4):607-616

From the Laboratory of Endocrine Physiology and Metabolism (LAFEM), Western Paraná State University (UNIOESTE).

Objectives: This study aimed to evaluate the effect of vagotomy, when associated with splenectomy, on adiposity and glucose homeostasis in Wistar rats.

Methods: Rats were divided into 4 groups: vagotomized (VAG), splenectomized (SPL), VAG + SPL, and SHAM. Glucose tolerance tests were performed, and physical and biochemical parameters evaluated. Glucose-induced insulin secretion and protein expression (Glut2/glucokinase) were measured in isolated pancreatic islets. Pancreases were submitted to histological and immunohistochemical analyses, and vagus nerve neural activity was recorded.

Results: The vagotomized group presented with reduced body weight, growth, and adiposity; high food intake; reduced plasma glucose and triglyceride levels; and insulin resistance. The association of SPL with the VAG surgery attenuated, or abolished, the effects of VAG and reduced glucose-induced insulin secretion and interleukin-1β area in β cells, in addition to lowering vagal activity.

Conclusions: The absence of the spleen attenuated or blocked the effects of VAG on adiposity, triglycerides and glucose homeostasis, suggesting a synergistic effect of both on metabolism. The vagus nerve and spleen modulate the presence of interleukin-1β in β cells, possibly because of the reduction of glucose-induced insulin secretion, indicating a bidirectional flow between autonomous neural firing and the spleen, with repercussions for the endocrine pancreas.
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http://dx.doi.org/10.1097/MPA.0000000000001809DOI Listing
April 2021

Resistance exercise training improves glucose homeostasis by enhancing insulin secretion in C57BL/6 mice.

Sci Rep 2021 Apr 21;11(1):8574. Epub 2021 Apr 21.

Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Resistance exercise exerts beneficial effects on glycemic control, which could be mediated by exercise-induced humoral factors released in the bloodstream. Here, we used C57Bl/6 healthy mice, submitted to resistance exercise training for 10 weeks. Trained mice presented higher muscle weight and maximum voluntary carrying capacity, combined with reduced body weight gain and fat deposition. Resistance training improved glucose tolerance and reduced glycemia, with no alterations in insulin sensitivity. In addition, trained mice displayed higher insulinemia in fed state, associated with increased glucose-stimulated insulin secretion. Islets from trained mice showed reduced expression of genes related to endoplasmic reticulum (ER) stress, associated with increased expression of Ins2. INS-1E beta-cells incubated with serum from trained mice displayed similar pattern of insulin secretion and gene expression than isolated islets from trained mice. When exposed to CPA (an ER stress inducer), the serum from trained mice partially preserved the secretory function of INS-1E cells, and prevented CPA-induced apoptosis. These data suggest that resistance training, in healthy mice, improves glucose homeostasis by enhancing insulin secretion, which could be driven, at least in part, by humoral factors.
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http://dx.doi.org/10.1038/s41598-021-88105-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060292PMC
April 2021

Long-term increase of insulin secretion in mice subjected to pregnancy and lactation.

Endocr Connect 2020 Apr;9(4):299-308

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas, Campinas, Brazil.

Purpose: Observational studies show that longer breastfeeding periods reduce maternal risk of type 2 diabetes mellitus. However, it is currently unknown if the long-term benefits of breastfeeding for maternal glucose homeostasis are linked to changes in the endocrine pancreas.

Methods: We presently evaluated functional, morphological and molecular aspects of the endocrine pancreas of mice subjected to two sequential cycles of pregnancy and lactation (L21). Age-matched mice not allowed to breastfeed (L0) and virgin mice were used as controls.

Results: L21 mice exhibited increased tolerance and increased glucose-stimulated insulin secretion (GSIS) by isolated islets. Pancreatic islets of L21 mice did not present evident morphological changes to justify the increased GSIS. On the other hand, islets of L21 mice exhibited a reduction in Cavb3 and Kir6.2 expression with concordant increased intracellular Ca2+ levels after challenge with glucose.

Conclusion: Altogether, the present findings show the breastfeeding exerts long-term benefits for maternal endocrine pancreas by increasing intracellular Ca2+ levels and GSIS.
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http://dx.doi.org/10.1530/EC-20-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159261PMC
April 2020

ARHGAP21 deficiency impairs hepatic lipid metabolism and improves insulin signaling in lean and obese mice.

Can J Physiol Pharmacol 2019 Nov 27;97(11):1018-1027. Epub 2019 Jun 27.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas, UNICAMP, Campinas, SP, Brazil.

ARHGAP21 is a Rho-GAP that controls GTPases activity in several tissues, but its role on liver lipid metabolism is unknown. Thus, to achieve the Rho-GAP role in the liver, control and ARHGAP21-haplodeficient mice were fed chow (Ctl and Het) or high-fat diet (Ctl-HFD and Het-HFD) for 12 weeks, and pyruvate and insulin tolerance tests, insulin signaling, liver glycogen and triglycerides content, gene and protein expression, and very-low-density lipoprotein secretion were measured. Het mice displayed reduced body weight and plasma triglycerides levels, and increased liver insulin signaling. Reduced gluconeogenesis and increased glycogen content were observed in Het-HFD mice. Gene and protein expression of microsomal triglyceride transfer protein were reduced in both Het mice, while the lipogenic genes SREBP-1c and ACC were increased. ARHGAP21 knockdown resulted in hepatic steatosis through increased hepatic lipogenesis activity coupled with decreases in CPT1a expression and very-low-density lipoprotein export. In conclusion, liver of ARHGAP21-haplodeficient mice are more insulin sensitive, associated with higher lipid synthesis and lower lipid export.
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http://dx.doi.org/10.1139/cjpp-2018-0691DOI Listing
November 2019

Whole-Body ARHGAP21-Deficiency Improves Energetic Homeostasis in Lean and Obese Mice.

Front Endocrinol (Lausanne) 2019 29;10:338. Epub 2019 May 29.

Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas/UNICAMP, Campinas, Brazil.

Inhibition of Rab-GAP TBC1 domain family member 1 (TBC1D1) reduces body weight and increases energy expenditure in mice. Here, we assessed the possible involvement of GTPase activating protein 21 (ARHGAP21), a Rho-GAP protein, in energy homeostasis. Wild-type and whole-body ARHGAP21-haplodeficient mice were fed either chow or high-fat diet for 10 weeks. These mice were analyzed for body weight, food intake, voluntary physical activity, and energy expenditure by indirect calorimetry. Real-time PCR was performed to determine changes in the expression of hypothalamic-anorexic genes. Whole-body ARHGAP21-haplodeficient mice showed lower body weight and food intake associated with increased energy expenditure. These mice also showed higher expression of hypothalamic-anorexic genes such as POMC and CART. Our data suggest that the reduction in body weight of ARHGAP21-haplodeficient mice was related to alterations in the central nervous system. This suggests a new role for ARHGAP21 in energetic metabolism and prompts us to consider GAP protein members as possible targets for the prevention and treatment of obesity and related diseases.
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http://dx.doi.org/10.3389/fendo.2019.00338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548804PMC
May 2019

The Bile Acid TUDCA Improves Beta-Cell Mass and Reduces Insulin Degradation in Mice With Early-Stage of Type-1 Diabetes.

Front Physiol 2019 15;10:561. Epub 2019 May 15.

Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.

Type 1 diabetes (T1D) is characterized by impairment in beta-cell mass and insulin levels, resulting in hyperglycemia and diabetic complications. Since diagnosis, appropriate control of glycaemia in T1D requires insulin administration, which can result in side effects, such as hypoglycemia. In this sense, some bile acids have emerged as new therapeutic targets to treat T1D and T2D, as well as metabolic diseases. The taurine conjugated bile acid, tauroursodeoxycholic (TUDCA) reduces the incidence of T1D development and improves glucose homeostasis in obese and T2D mice. However, its effects in early-stage of T1D have not been well explored. Therefore, we have assessed the effects of TUDCA on the glycemic control of mice with early-stage T1D. To achieve this, C57BL/6 mice received intraperitoneal administration of streptozotocin (STZ, 40 mg/kg) for 5 days. Once diabetes was confirmed in the STZ mice, they received TUDCA treatment (300 mg/kg) or phosphate buffered saline (PBS) for 24 days. After 15 days of treatment, the STZ+TUDCA mice showed a 43% reduction in blood glucose, compared with the STZ group. This reduction was likely due to an increase in insulinemia. This increase in insulinemia may be explained, at least in part, by a reduction in hepatic IDE activity and, consequently, reduction on insulin clearance, as well as an increase in beta-cell mass and a higher beta-cell number per islet. Also, the groups did not present any alterations in insulin sensitivity. All together, these effects contributed to the improvement of glucose metabolism in T1D mice, pointing TUDCA as a potential therapeutic agent for the glycemic control in early-stage of T1D.
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http://dx.doi.org/10.3389/fphys.2019.00561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529580PMC
May 2019

Combined oral contraceptive in female mice causes hyperinsulinemia due to β-cell hypersecretion and reduction in insulin clearance.

J Steroid Biochem Mol Biol 2019 06 25;190:54-63. Epub 2019 Mar 25.

Universidade Federal do Rio de Janeiro, Campus UFRJ-Macaé Professor Aloísio Teixeira, Macaé, RJ, Brazil. Electronic address:

Oral contraception is the most commonly used interventional method in the world. However, several women employ the continuous use of these hormones to avoid pre- and menstruation discomforts. Some studies indicate that oral contraceptives are associated with disturbances in glycemia and the effects of the use of a continuous regime are poorly elucidated. Herein, we evaluated the effects of the continuous administration of a combined oral contraceptive (COC) composed by ethinyl estradiol (EE) and drospirenone (DRSP) on glucose homeostasis in female mice. Adult Swiss mice received 0.6 μg EE and 60 μg DRSP (COC group) or vehicle [control (CTL)] daily by gavage for 35 days. COC treatment had no effect on body weight or adiposity, but increased uterus weight and induced hepatomegaly. Importantly, COC females displayed normal glycemia and glucose tolerance, but hyperinsulinemia and lower plasma C-peptide/insulin ratio, indicating reduced insulin clearance. Furthermore, COC mice displayed reduced protein content of the β subunit of the insulin receptor (IRβ) in the liver. Additionally, pancreatic islets isolated from COC mice secreted more insulin in response to increasing glucose concentrations. This effect was associated with the activity of steroid hormones, since INS-1E cells incubated with EE plus DRSP also secreted more insulin. Therefore, we provide the first evidence that the continuous administration of EE and DRSP lead to hyperinsulinemia, due to enhancement of insulin secretion and the reduction of insulin degradation, which possibly lead to the down-regulation of hepatic IRβ. These findings suggest that the continuous administration of COC could cause insulin resistance with the prolongation of treatment.
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http://dx.doi.org/10.1016/j.jsbmb.2019.03.018DOI Listing
June 2019

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

Amino Acids 2019 Apr 4;51(4):727-738. Epub 2019 Mar 4.

Universidade Federal do Rio de Janeiro, Campus UFRJ-Macaé, Avenida São José do Barreto, 764, Macaé, RJ, CEP 27965-045, Brazil.

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 β- and α-cell hypotrophy, and lower δ-cell number per islet. Paternal TAU supplementation prevented the decrease in glucose-induced insulin secretion and normalized β-cell size and δ-cell number, and increased α-cell size/islet in HTAU-F1 mice. In conclusion, HFD consumption by male founders decreases β-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.
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http://dx.doi.org/10.1007/s00726-019-02712-7DOI Listing
April 2019

Amino acid restriction increases β-cell death under challenging conditions.

J Cell Physiol 2019 08 27;234(10):16679-16684. Epub 2019 Feb 27.

Department of Structural and Functional Biology, Obesity and Comorbidities Research Center (OCRC), Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil.

Malnutrition programs metabolism, favor dysfunction of β cells. We aimed to establish an in vitro protocol of malnutrition, assessing the effect of amino acid restriction upon the β cells. Insulin-producing cells INS-1E and pancreatic islets were maintained in RPMI 1640 medium containing 1× (Ctl) or 0.25× (AaR) of amino acids. We evaluated several markers of β-cell function and viability. AaR Insulin secretion was reduced, whereas cell viability was unaltered. Calcium oscillations in response to glucose increased in AaR. AaR showed lower Ins1 RNAm, snap 25, and PKC (protein kinase C) protein content, whereas phospho-eIF2α was increased. AaR cells exposed to nutrient or chemical challenges displayed higher apoptosis rates. We showed that amino acid restriction programmed β cell and induced functional changes. This model might be useful for the study of molecular mechanisms involved with β-cell programming helping to establish novel therapeutic targets to prevent harmful outcomes of malnutrition.
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http://dx.doi.org/10.1002/jcp.28389DOI Listing
August 2019

Protein malnutrition mitigates the effects of a high-fat diet on glucose homeostasis in mice.

J Cell Physiol 2019 05 14;234(5):6313-6323. Epub 2018 Oct 14.

Department of Structural and Functional Biology, Obesity and Comorbidities Research Center (OCRC), Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Nutrient malnutrition, during the early stages of development, may facilitate the onset of metabolic diseases later in life. However, the consequences of nutritional insults, such as a high-fat diet (HFD) after protein restriction, are still controversial. We assessed overall glucose homeostasis and molecular markers of mitochondrial function in the gastrocnemius muscle of protein-restricted mice fed an HFD until early adulthood. Male C57BL/6 mice were fed a control (14% protein-control diet) or a protein-restricted (6% protein-restricted diet) diet for 6 weeks. Afterward, mice received an HFD or not for 8 weeks (mice fed a control diet and HFD [CH] and mice fed a protein-restricted diet and HFD [RH]). RH mice showed lower weight gain and fat accumulation and did not show an increase in fasting plasma glucose and insulin levels compared with CH mice. RH mice showed higher energy expenditure, increased citrate synthase, peroxisome-proliferator-activated receptor gamma coactivator 1-alpha protein content, and higher levels of malate and α-ketoglutarate compared with CH mice. Moreover, RH mice showed increased AMPc-dependent kinase and acetyl coenzyme-A (CoA) carboxylase phosphorylation, lower intramuscular triacylglycerol content, and similar malonyl-CoA levels. In conclusion, protein undernourishment after weaning does not potentiate fat accumulation and insulin resistance in adult young mice fed an HFD. This outcome seems to be associated with increased skeletal muscle mitochondrial oxidative capacity and reduced lipids accumulation.
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http://dx.doi.org/10.1002/jcp.27361DOI Listing
May 2019

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

Amino Acids 2018 Jun 19;50(6):765-774. Epub 2018 Mar 19.

Laboratory of Pancreas Endocrine and Metabolism, Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas/UNICAMP, 255, Monteiro Lobato Street, Campinas, SP, 13083-862, Brazil.

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.
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http://dx.doi.org/10.1007/s00726-018-2553-3DOI Listing
June 2018

Bile acid TUDCA improves insulin clearance by increasing the expression of insulin-degrading enzyme in the liver of obese mice.

Sci Rep 2017 11 1;7(1):14876. Epub 2017 Nov 1.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970, Campinas, SP, Brazil.

Disruption of insulin secretion and clearance both contribute to obesity-induced hyperinsulinemia, though reduced insulin clearance seems to be the main factor. The liver is the major site for insulin degradation, a process mainly coordinated by the insulin-degrading enzyme (IDE). The beneficial effects of taurine conjugated bile acid (TUDCA) on insulin secretion as well as insulin sensitivity have been recently described. However, the possible role of TUDCA in insulin clearance had not yet been explored. Here, we demonstrated that 15 days treatment with TUDCA reestablished plasma insulin to physiological concentrations in high fat diet (HFD) mice, a phenomenon associated with increased insulin clearance and liver IDE expression. TUDCA also increased IDE expression in human hepatic cell line HepG2. This effect was not observed in the presence of an inhibitor of the hepatic membrane bile acid receptor, S1PR2, nor when its downstream proteins were inhibited, including IR, PI3K and Akt. These results indicate that treatment with TUDCA may be helpful to counteract obesity-induced hyperinsulinemia through increasing insulin clearance, likely through enhanced liver IDE expression in a mechanism dependent on S1PR2-Insulin pathway activation.
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http://dx.doi.org/10.1038/s41598-017-13974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665899PMC
November 2017

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

J Nutr Biochem 2017 12 4;50:54-65. Epub 2017 Sep 4.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil.

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.
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http://dx.doi.org/10.1016/j.jnutbio.2017.08.013DOI Listing
December 2017

Vagotomy Reduces Insulin Clearance in Obese Mice Programmed by Low-Protein Diet in the Adolescence.

Neural Plast 2017 30;2017:9652978. Epub 2017 Aug 30.

University of Campinas (UNICAMP), Campinas, SP, Brazil.

The aim of this study was to investigate the effect of subdiaphragmatic vagotomy on insulin sensitivity, secretion, and degradation in metabolic programmed mice, induced by a low-protein diet early in life, followed by exposure to a high-fat diet in adulthood. Weaned 30-day-old C57Bl/6 mice were submitted to a low-protein diet (6% protein). After 4 weeks, the mice were distributed into three groups: LP group, which continued receiving a low-protein diet; LP + HF group, which started to receive a high-fat diet; and LP + HFvag group, which underwent vagotomy and also was kept at a high-fat diet. Glucose-stimulated insulin secretion (GSIS) in isolated islets, ipGTT, ipITT, in vivo insulin clearance, and liver expression of the insulin-degrading enzyme (IDE) was accessed. Vagotomy improved glucose tolerance and reduced insulin secretion but did not alter adiposity and insulin sensitivity in the LP + HFvag, compared with the LP + HF group. Improvement in glucose tolerance was accompanied by increased insulinemia, probably due to a diminished insulin clearance, as judged by the lower C-peptide : insulin ratio, during the ipGTT. Finally, vagotomy also reduced liver IDE expression in this group. In conclusion, when submitted to vagotomy, the metabolic programmed mice showed improved glucose tolerance, associated with an increase of plasma insulin concentration as a result of insulin clearance reduction, a phenomenon probably due to diminished liver IDE expression.
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http://dx.doi.org/10.1155/2017/9652978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603136PMC
June 2018

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

FASEB J 2017 09 1;31(9):4078-4087. Epub 2017 Jun 1.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.

Taurine (Tau) restores β-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 β 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.
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http://dx.doi.org/10.1096/fj.201600326RRRDOI Listing
September 2017

Protein malnutrition potentiates the amplifying pathway of insulin secretion in adult obese mice.

Sci Rep 2016 09 16;6:33464. Epub 2016 Sep 16.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, CEP: 13083-865, Brazil.

Pancreatic beta cell (β) dysfunction is an outcome of malnutrition. We assessed the role of the amplifying pathway (AMP PATH) in β cells in malnourished obese mice. C57Bl-6 mice were fed a control (C) or a low-protein diet (R). The groups were then fed a high-fat diet (CH and RH). AMP PATH contribution to insulin secretion was assessed upon incubating islets with diazoxide and KCl. CH and RH displayed increased glucose intolerance, insulin resistance and glucose-stimulated insulin secretion. Only RH showed a higher contribution of the AMP PATH. The mitochondrial membrane potential of RH was decreased, and ATP flux was unaltered. In RH islets, glutamate dehydrogenase (GDH) protein content and activity increased, and the AMP PATH contribution was reestablished when GDH was blunted. Thus, protein malnutrition induces mitochondrial dysfunction in β cells, leading to an increased contribution of the AMP PATH to insulin secretion through the enhancement of GDH content and activity.
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http://dx.doi.org/10.1038/srep33464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025848PMC
September 2016

The bile acid TUDCA increases glucose-induced insulin secretion via the cAMP/PKA pathway in pancreatic beta cells.

Metabolism 2016 Mar 17;65(3):54-63. Epub 2015 Oct 17.

Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil. Electronic address:

Objective: While bile acids are important for the digestion process, they also act as signaling molecules in many tissues, including the endocrine pancreas, which expresses specific bile acid receptors that regulate several cell functions. In this study, we investigated the effects of the conjugated bile acid TUDCA on glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells.

Methods: Pancreatic islets were isolated from 90-day-old male mice. Insulin secretion was measured by radioimmunoassay, protein phosphorylation by western blot, Ca(2+) signals by fluorescence microscopy and ATP-dependent K(+) (KATP) channels by electrophysiology.

Results: TUDCA dose-dependently increased GSIS in fresh islets at stimulatory glucose concentrations but remained without effect at low glucose levels. This effect was not associated with changes in glucose metabolism, Ca(2+) signals or KATP channel activity; however, it was lost in the presence of a cAMP competitor or a PKA inhibitor. Additionally, PKA and CREB phosphorylation were observed after 1-hour incubation with TUDCA. The potentiation of GSIS was blunted by the Gα stimulatory, G protein subunit-specific inhibitor NF449 and mimicked by the specific TGR5 agonist INT-777, pointing to the involvement of the bile acid G protein-coupled receptor TGR5.

Conclusion: Our data indicate that TUDCA potentiates GSIS through the cAMP/PKA pathway.
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http://dx.doi.org/10.1016/j.metabol.2015.10.021DOI Listing
March 2016
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