ABSTRACT
OBJECTIVE: Intriguingly, hyperinsulinemia, and hyperglycemia can predispose insulin resistance, obesity, and type 2 diabetes, leading to metabolic disturbances. Conversely, physical exercise stimulates skeletal muscle glucose uptake, improving whole-body glucose homeostasis. Therefore, we investigated the impact of short-term physical activity in a mouse model (Slc2a4+/-) that spontaneously develops hyperinsulinemia and hyperglycemia even when fed on a chow diet. METHODS: Slc2a4+/- mice were used, that performed 5 days of endurance or strength exercise training. Further analysis included physiological tests (GTT and ITT), skeletal muscle glucose uptake, skeletal muscle RNA-sequencing, mitochondrial function, and experiments with C2C12 cell line. RESULTS: When Slc2a4+/- mice were submitted to the endurance or strength training protocol, improvements were observed in the skeletal muscle glucose uptake and glucose metabolism, associated with broad transcriptomic modulation, that was, in part, related to mitochondrial adaptations. The endurance training, but not the strength protocol, was effective in improving skeletal muscle mitochondrial activity and unfolded protein response markers (UPRmt). Moreover, experiments with C2C12 cells indicated that insulin or glucose levels could contribute to these mitochondrial adaptations in skeletal muscle. CONCLUSIONS: Both short-term exercise protocols were efficient in whole-body glucose homeostasis and insulin resistance. While endurance exercise plays an important role in transcriptome and mitochondrial activity, strength exercise mostly affects post-translational mechanisms and protein synthesis in skeletal muscle. Thus, the performance of both types of physical exercise proved to be a very effective way to mitigate the impacts of hyperglycemia and hyperinsulinemia in the Slc2a4+/- mouse model.
Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Insulin Resistance , Mice , Animals , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Muscle, Skeletal/metabolism , Hyperglycemia/genetics , Hyperglycemia/metabolism , Glucose/metabolism , Glucose Transporter Type 4/metabolismABSTRACT
Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome-wide level. Transcriptomic meta-analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of 'hyperinsulinemia' and 'starvation' programs. Consistently, we observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.
Subject(s)
Antigens, CD/biosynthesis , Down-Regulation , Hyperinsulinism/metabolism , Insulin Resistance , Muscle, Skeletal/metabolism , RNA, Messenger/biosynthesis , Receptor, Insulin/biosynthesis , Animals , Antigens, CD/genetics , Cell Line , Humans , Hyperinsulinism/genetics , Mice , Mice, Knockout , RNA, Messenger/genetics , RNA-Seq , Receptor, Insulin/geneticsABSTRACT
Hyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here we investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1+/+ or Ins1+/- littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 wk, starting at 8 wk of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1+/- mice had significantly lower circulating insulin compared with Ins1+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe robust significant differences in liver or skeletal muscle. In mesenteric WAT, Ins1+/- mice had reduced Ndufb8 and Sdhb, while Ucp1 was increased in the context of HFD. HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1+/- mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, whereas in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and helps explain the increased energy expenditure previously reported in Ins1+/- mice.
Subject(s)
Adipose Tissue/metabolism , Insulin/genetics , Insulin/metabolism , Mitochondria/metabolism , Uncoupling Protein 1/biosynthesis , 3T3-L1 Cells , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Animals , Blood Glucose/metabolism , Body Weight/genetics , Diet, High-Fat , Hyperinsulinism/genetics , Hyperinsulinism/metabolism , Mice , Mice, Knockout , Oxidative Phosphorylation , Oxygen Consumption , Up-RegulationABSTRACT
The obesity is a result of energy imbalance and the increase in thermogenesis seems an interesting alternative for the treatment of this disease. The mechanism of energy expenditure through thermogenesis is tightly articulated in the hypothalamus by leptin. The hypothalamic extracellular signal-regulated kinase-1/2 (ERK1/2) is a key mediator of the thermoregulatory effect of leptin and mediates the sympathetic signal to the brown adipose tissue (BAT). In this context, physical exercise is one of the main interventions for the treatment of obesity. Thus, this study aimed to verify the effects of acute physical exercise on leptin-induced hypothalamic ERK1/2 phosphorylation and thermogenesis in obese mice. Here we showed that acute physical exercise reduced the fasting glucose of obese mice and increased leptin-induced hypothalamic p-ERK1/2 and uncoupling protein 1 (UCP1) content in BAT ( P < 0.05). These molecular changes are accompanied by an increased oxygen uptake (VO 2 ) and heat production in obese exercised mice ( P < 0.05). The increased energy expenditure in the obese exercised animals occurred independently of changes in spontaneous activity. Thus, this is the first study demonstrating that acute physical exercise can increase leptin-induced hypothalamic ERK1/2 phosphorylation and energy expenditure of obese mice.
Subject(s)
Hypothalamus/metabolism , Leptin/pharmacology , MAP Kinase Signaling System/drug effects , Obesity/metabolism , Physical Conditioning, Animal , Thermogenesis/physiology , Adipose Tissue, Brown/metabolism , Animals , Body Weight , Diet, High-Fat/adverse effects , Energy Metabolism/physiology , Injections, Intraperitoneal , Leptin/administration & dosage , Mice , Mice, Obese , Oxygen Consumption/physiology , Phosphorylation/drug effects , Uncoupling Protein 1/metabolismABSTRACT
Adiponectin is an adipokine that acts in the control of energy homeostasis. The adaptor protein containing the pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is a key protein in the adiponectin signaling. The APPL1 mediates a positive effect on the insulin signaling through the interaction with the phosphoinositide 3-kinase (PI3K). Thus, the present study aimed to explore the effects of an acute physical exercise session on the hypothalamic adiponectin signaling. Firstly, using bioinformatics analysis, we found a negative correlation between hypothalamic APPL1 mRNA levels and food consumption in several strains of genetically diverse BXD mice. Also, the mice and the human database revealed a positive correlation between the levels of APPL1 mRNA and PI3K mRNA. At the molecular level, the exercised mice showed increased APPL1 and PI3K (p110) protein contents in the hypothalamus of Swiss mice. Furthermore, the exercise increases co-localization between APPL1 and PI3K p110 predominantly in neurons of the arcuate nucleus of hypothalamus (ARC). Finally, we found an acute exercise session reduced the food intake 5 hr after the end of fasting. In conclusion, our results indicate that physical exercise reduces the food intake and increases some proteins related to adiponectin pathway in the hypothalamus of lean mice.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Hypothalamus/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Physical Conditioning, Animal/physiology , Animals , Eating/physiology , Male , Mice , RNA, Messenger/metabolism , Signal TransductionABSTRACT
Lowering carbohydrate consumption effectively lowers glucose, but impacts on inflammation are unclear. The objectives of this study were to: 1) determine whether reducing hyperglycemia by following a low-carbohydrate, high-fat (LC) diet could lower markers of innate immune cell activation in type 2 diabetes (T2D) and 2) examine if the combination of an LC diet with strategically timed postmeal walking was superior to an LC diet alone. Participants with T2D ( n = 11) completed a randomized crossover study involving three 4-day diet interventions: 1) low-fat low-glycemic index (GL), 2) and 3) LC with 15-min postmeal walks (LC+Ex). Four-day mean glucose was significantly lower in the LC+Ex group as compared with LC (-5%, P < 0.05), whereas both LC+Ex (-16%, P < 0.001) and LC (-12%, P < 0.001) conditions were lower than GL. A significant main effect of time was observed for peripheral blood mononuclear cells phosphorylated c-Jun N-terminal kinase ( P < 0.001), with decreases in all three conditions (GL: -32%, LC: -45%, and LC+Ex: -44%). A significant condition by time interaction was observed for monocyte microparticles ( P = 0.040) with a significant decrease in GL (-76%, P = 0.035) and a tendency for a reduction in LC (-70%, P = 0.064), whereas there was no significant change in LC+Ex (0.5%, P = 0.990). Both LC (-27%, P = 0.001) and LC+Ex (-35%, P = 0.005) also led to significant reductions in circulating proinsulin. An LC diet improved 4-day glycemic control and fasting proinsulin levels when compared with GL, with added glucose-lowering benefits when LC was combined with postmeal walking.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Dietary Carbohydrates/metabolism , Hyperglycemia/metabolism , Inflammation/metabolism , Walking , Adult , Aged , Blood Glucose/metabolism , Diet, Carbohydrate-Restricted , Diet, Fat-Restricted , Diet, High-Fat/adverse effects , Fasting , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Postprandial PeriodABSTRACT
Adiponectin is considered an adipokine that has essential anti-inflammatory and insulin-sensitivity actions. The adaptor protein containing the pleckstrin homology domain, the phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is a protein involved in adiponectin signaling that plays a role in many physiological and pathophysiological processes. In the central nervous system, adiponectin can potentiate the effects of leptin in the arcuate proopiomelanocortin (POMC) neurons. However, the role of APPL1 in the hypothalamus is not well understood. Therefore, in this study, we explored the effects of acute physical exercise on APPL1 protein content in the hypothalamus and food intake control in leptin stimulated-obese mice. Here we show that acute exercise increased serum adiponectin levels and APPL1 content in the hypothalamus, which were followed by reduced food intake in obese mice. Further, at the molecular level, the exercised obese mice increased the protein kinase B (Akt) signaling in the hypothalamus and attenuated the mammalian homolog of Drosophila tribbles protein 3 (TRB3) levels. In conclusion, the results indicate physical exercise is capable of increasing APPL1 protein content in the hypothalamus of leptin stimulated-obese mice and modulating food intake.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Hypothalamus/metabolism , Physical Conditioning, Animal/physiology , Adiponectin/metabolism , Animals , Cell Cycle Proteins/metabolism , Eating/physiology , Insulin/metabolism , Insulin Resistance/physiology , Leptin/metabolism , Mice , Mice, Obese , Neurons/metabolism , Neurons/physiology , Obesity/metabolism , Obesity/physiopathology , Phosphorylation/physiology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/physiologyABSTRACT
Preclinical Research Metabolic disorders are responsible for more than 60% of all deaths worldwide. Calcitriol or vitamin D (vitD) deficiency is associated with a large proportion of these diseases is an important therapeutic target for exploration. This study evaluated the administration of high doses of vitD (3000 IU/kg) in obese and insulin-resistant C57BL/6J mice. Our results demonstrated that although high doses of vitD provided metabolic benefits such as increased insulin sensitivity and decreased body mass, this was associated with significant damage in the kidneys of obese mice. These findings support the role of vitD as a therapeutic strategy against metabolic disorders. However, caution is required with the dose administrated, and the renal damage associated still needs to be investigated. Drug Dev Res 78 : 203-209, 2017. © 2017 Wiley Periodicals, Inc.
Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Energy Metabolism/drug effects , Obesity/drug therapy , Vitamin D/administration & dosage , Animals , Body Mass Index , Chemical and Drug Induced Liver Injury/pathology , Dose-Response Relationship, Drug , Insulin Resistance , Male , Mice , Vitamin D/adverse effectsABSTRACT
BACKGROUND: In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance. METHODS: Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens. FINDINGS: Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3ß, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis. INTERPRETATION: Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance. FUNDING: Funded by Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Canada Foundations for Innovation (CFI), the Swedish Diabetes Foundation, Family Ernfors Foundation and Novo Nordisk Foundation.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin Resistance , Humans , Mice , Animals , Insulin/metabolism , Insulin Resistance/genetics , Receptor, Insulin/genetics , Receptor, Insulin/metabolism , Diabetes Mellitus, Type 2/metabolism , Mice, Knockout , Canada , Adipose Tissue/metabolism , Obesity/metabolism , Antigens, Neoplasm/metabolism , Antigens, CD/genetics , Antigens, CD/metabolismABSTRACT
The main purpose of this research was to investigate the alterations in the aerobic capacity and appearance of metabolic alterations in Wistar rats fed on fructose-rich diet. We separated twenty-eight rats into two groups according to diet: a control group (C) (balanced diet) and a fructose-rich diet group (F). The animals were fed these diets for 60 d (d 120 to 180). We performed insulin, glucose as well as a minimum lactate test, at d 120 and 180. At the end of the experiment, sixteen animals were euthanized, and the following main variables were analysed: aerobic capacity, the serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, serum and liver triglyceride concentrations, serum and liver thiobarbituric acid reactive substance (TBARS) concentrations, serum and liver catalase and superoxide dismutase (SOD) activity and haematoxylin-eosin histology (HE) in hepatocytes. The remaining twelve animals were submitted to an analysis of their hepatic lipogenic rate. The animals fed a fructose-rich diet exhibited a reduction in aerobic capacity, glucose tolerance and insulin sensitivity and increased concentrations of triglycerides and TBARS in the liver. Catalase and SOD activities were reduced in the livers of the fructose-fed animals. In addition, the serum AST/ALT ratio was higher than that of the C group, which indicates hepatic damage, and the damage was confirmed by histology. In conclusion, the fructose-rich diet caused significant liver damage and a reduction in insulin sensitivity in the animals, which could lead to deleterious metabolic effects.
Subject(s)
Dietary Carbohydrates/adverse effects , Fatty Liver/metabolism , Fructose/adverse effects , Liver/metabolism , Alanine Transaminase/blood , Animals , Area Under Curve , Aspartate Aminotransferases/blood , Blood Glucose , Catalase/blood , Catalase/metabolism , Fatty Liver/blood , Fatty Liver/etiology , Glucose/metabolism , Intra-Abdominal Fat/metabolism , Lactic Acid/blood , Lipid Metabolism , Lipid Peroxidation , Lipids/blood , Lipogenesis , Liver/pathology , Non-alcoholic Fatty Liver Disease , Oxidative Stress , Rats , Rats, Wistar , Superoxide Dismutase/blood , Superoxide Dismutase/metabolism , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic disease that is characterized by insulin resistance. Its development is directly connected with the inability of insulin to exert its action, not just on carbohydrate metabolism but also on primarily on lipid metabolism. The present study aimed to compare the effects of continuous, intermittent, and strength training on serum and tissue variables on the lipid metabolism of alloxan rats. METHODS: Wistar rats were divided into eight groups: sedentary alloxan (SA), sedentary control (SC), continuous training alloxan (CA), intermittent training alloxan (IA), strength training alloxan (StA), continuous training control (CC), intermittent training control (IC) and strength training control (StC). Alloxan (250 mg/kg bw) was injected into neonatal rats at 6 days of age. The continuous training protocol consisted of 12 weeks of swimming training for 1 uninterrupted hour/day, five days/week, supporting a load that was 5% bw. The intermittent training protocol consisted of 12 weeks of swimming training with 30 s of activity interrupted by 30 s of rest, for a total of 20 min/day, five days/week, supporting a load that was 15% bw. The strength-training protocol consisted of 12 weeks of training, five days/week with 4 sets of 10 jumps in water with 1 min rest between sets, supporting a load that was a 50% bw. RESULTS: At 28 days, the alloxan animals exhibited higher insulin resistance as measured by the disappearance of glucose serum (% Kitt/min) during the ITT. At 120 days, the sedentary alloxan animals showed higher FFA values than continuous and intermittent training alloxan. In addition, the alloxan animals that underwent intermittent and strength training showed lower FFA values compared to the corresponding controls. The continuous training protocol was less effective than the strength training protocol for reducing the levels of total cholesterol in the alloxan animals. Serum total lipid values revealed that intermittent training increased serum levels in alloxan animals CONCLUSION: Thus, it was concluded that physical training at different intensities of effort is of great importance in attenuation and control of changes in the lipid metabolism in alloxan animals.
Subject(s)
Alloxan/administration & dosage , Insulin Resistance , Lipid Metabolism , Physical Conditioning, Animal , Animals , Blood Glucose , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Experimental/therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Diabetes Mellitus, Type 2/therapy , Energy Metabolism , Male , Muscle, Skeletal/metabolism , Rats , Rats, Wistar , SwimmingABSTRACT
BACKGROUND: APPL1, an adapter protein, interact directly with adiponectin receptors mediating adiponectin signaling and acting as a critical regulator of the crosstalk between adiponectin and insulin signaling pathway. The inadequate level of physical activity, high-calorie intake, or both lead to adverse consequences on health, like insulin resistance. On the order hand, physical exercise acts positively in the insulin action. PURPOSE: Here, we investigated the effects of short-term resistance training (RT) on APPL1 content and adiponectin pathway in the liver of mice fed a long-term high-fat diet. METHODS: Swiss mice were distributed into 3 groups: Mice that fed a chow diet (CTR); Mice fed a high-fat diet for 16 months (HFD); and mice fed a high-fat diet for 16 months and submitted to a climbing ladder exercise (RT) for 7 days (HFD-EXE). RESULTS: The results show that short-term RT increases the APPL1 content but wasn't able to alter AdipoR1 and AdipoR2 content in the liver of HFD-EXE mice. However, this increase in the APPL1 content in response to RT was accompanied by improvement in the insulin sensitivity. CONCLUSION: In summary, our data suggested that short-term RT improves glycemic homeostasis and increases APPL1 in the hepatic tissue of mice treated with long-term high-fat diet.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Dietary Fats/pharmacology , Insulin Resistance , Liver/metabolism , Physical Conditioning, Animal , Animals , Mice , Time FactorsABSTRACT
Chronic/abnormal activation of endoplasmic reticulum (ER) stress is linked to the exacerbation of the inflammatory process and has been recently linked to Crohn's disease (CD) pathophysiology. We investigated the intestinal mucosa and the mesenteric adipose tissue (MAT) collected from CD patients with active disease (CD group) and from non-IBD patients (CTR group) to study ER stress activation and to address tissue-specific modulation in CD. The intestinal mucosa of CD patients showed an upregulation in the expression of ER stress related genes, including ATF3, DNAJC3, STC2, DDIT3, CALR, HSPA5 and HSP90B1. Results showed that EIF2AK3 gene was upregulated, along with increased protein expression of p-eIF2α and p-eIF2α/eIF2α ratio. Additionally, ERN1 gene expression was upregulated, along with an increased spliced/activated form sXBP1 protein. Despite the upregulation of ATF6 gene expression in the intestinal mucosa of CD patients, no differences were found in ATF6 protein expression. Lastly, the analysis of MAT revealed unchanged levels of ER stress markers along with no differences in the activation of UPR. However, chaperone gene expression was modulated in the MAT of CD patients. To conclude, our results address tissue-specific differences in UPR activation in CD and point the ER stress as an important pro-inflammatory mechanism in CD, specifically in the intestinal mucosa.
Subject(s)
Colon/pathology , Crohn Disease/immunology , Endoplasmic Reticulum Stress/immunology , Intestinal Mucosa/pathology , Intra-Abdominal Fat/pathology , Adult , Aged , Biomarkers/metabolism , Case-Control Studies , Colon/diagnostic imaging , Colon/immunology , Colonoscopy , Crohn Disease/diagnosis , Crohn Disease/pathology , Endoplasmic Reticulum Chaperone BiP , Female , Humans , Intestinal Mucosa/diagnostic imaging , Intestinal Mucosa/immunology , Intra-Abdominal Fat/immunology , Male , Mesentery/immunology , Mesentery/pathology , Middle Aged , Molecular Chaperones/metabolism , Severity of Illness Index , Symptom Flare Up , Unfolded Protein Response/immunology , Up-Regulation , Young AdultABSTRACT
The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promotes synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer's Disease (AD). The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies. In this context, our study aims to investigate the age-related changes in PTP1B content, insulin signaling, ß-amyloid content, and Tau phosphorylation in the hippocampus of middle-aged rats. Young (3â¯months) and middle-aged (17â¯months) Wistar rats were submitted to Morris-water maze (MWM) test, insulin tolerance test, and molecular analysis in the hippocampus. Aging resulted in increased body weight, and insulin resistance and decreases learning process in MWM. Interestingly, the middle-aged rats have higher levels of PTP-1B, lower phosphorylation of IRS-1, Akt, GSK3ß, mTOR, and TrkB. Also, the aging process increased Tau phosphorylation and ß-amyloid content in the hippocampus region. In summary, this study provides new evidence that aging-related PTP1B increasing, contributing to insulin resistance and the onset of the AD.
Subject(s)
Hippocampus/physiology , Insulin/physiology , Protein Tyrosine Phosphatase, Non-Receptor Type 1/physiology , Spatial Learning/physiology , Aging/physiology , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/metabolism , Insulin Resistance/physiology , Male , Maze Learning , Rats , Rats, Wistar , Signal Transduction/physiologyABSTRACT
The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice.
Subject(s)
Blood Glucose/metabolism , Hyperglycemia/therapy , Obesity/metabolism , Physical Conditioning, Animal/physiology , Pyruvate Carboxylase/metabolism , Animals , Hyperglycemia/metabolism , Liver/metabolism , Male , Mice , Mice, Obese , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Fructose consumption has been growing exponentially and, concomitant with this, the increase in the incidence of obesity and associated complications has followed the same behavior. Studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars. In this context, the liver seems to be a key organ for understanding the deleterious health effects promoted by fructose consumption. Fructose promotes complications in glucose metabolism, accumulation of triacylglycerol in the hepatocytes, and alterations in the lipid profile, which, associated with an inflammatory response and alterations in the redox state, will imply a systemic picture of insulin resistance. However, physical exercise has been indicated for the treatment of several chronic diseases. In this review, we show how each exercise protocol (aerobic, strength, or a combination of both) promote improvements in the obesogenic state created by fructose consumption as an improvement in the serum and liver lipid profile (high-density lipoprotein (HDL) increase and decrease triglyceride (TG) and low-density lipoprotein (LDL) levels) and a reduction of markers of inflammation caused by an excess of fructose. Therefore, it is concluded that the practice of aerobic physical exercise, strength training, or a combination of both is essential for attenuating the complications developed by the consumption of fructose.
Subject(s)
Exercise , Fructose/adverse effects , Liver/metabolism , Obesity/complications , Animals , Biomarkers/blood , Blood Glucose/metabolism , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Disease Models, Animal , Humans , Insulin Resistance , Obesity/therapy , Resistance Training , Triglycerides/bloodABSTRACT
Crohn's disease (CD) is a chronic inflammatory disorder, characterized by cytokine imbalance and transcription signaling pathways activation. In addition, the increase of mesenteric adipose tissue (MAT) near the affected intestinal area is a hallmark of CD. Therefore, we evaluated the transcription signaling pathways and cytokines expression in intestinal mucosa and MAT of active CD patients. Ten patients with ileocecal CD and eight with noninflammatory diseases were studied. The biopsies of intestinal mucosa and MAT were snap-frozen and protein expression was determined by immunoblotting. RNA levels were measured by qPCR. The pIkB/IkB ratio and TNFα level were significantly higher in intestinal mucosa of CD when compared to controls. However, STAT1 expression was similar between intestinal mucosa of CD and controls. Considering the MAT, the pIkB/IkB ratio was significantly lower and the anti-inflammatory cytokine IL10 was significantly higher in CD when compared to controls. Finally, the protein content of pSTAT1 was higher in MAT of CD compared to controls. These findings reinforce the predominance of the proinflammatory NF-kB pathway in CD intestinal mucosa. For the first time, we showed the activation of STAT1 pathway in MAT of CD patients, which may help to understand the physiopathology of this immune mediated disease.
ABSTRACT
The mitogen-activated kinase phosphatase-3 (MKP-3) has gained great importance in the scientific community by acting as a regulator of the cell cycle through dephosphorylation of FoxO1, an important transcription factor involved in the insulin intracellular signaling cascade. When dephosphorylated and translocated to the nuclei, FoxO1 can promote the transcription of orexigenic neuropeptides (NPY/AgRP) in the hypothalamus, whereas insulin signaling is responsible for the disruption of this process. However, it is not understood if the hypothalamic activation of MKP-3 affects FoxO1 phosphorylation, and we hypothesized that MKP-3 overexpression reduces the capacity of the insulin signal to phosphorylate FoxO1. In the present study, we overexpressed the DUSP6 gene through an injection of adenovirus directly into the hypothalamic third ventricle of Swiss mice. The colocalization of the adenovirus was confirmed by the immunofluorescence assay. Then, MKP-3 overexpression resulted in a significant reduction of hypothalamic FoxO1 phosphorylation after insulin stimulation. This effect was independent of changes in Akt phosphorylation. Thus, the role of MKP-3 in the hypothalamus is closely associated with FoxO1 dephosphorylation and may provide a potential therapeutic target against hypothalamic disorders related to obesity and unbalanced food intake control.
Subject(s)
Dual Specificity Phosphatase 6/genetics , Dual Specificity Phosphatase 6/metabolism , Forkhead Box Protein O1/metabolism , Hypothalamus/metabolism , Adenoviridae/genetics , Animals , Dual Specificity Phosphatase 6/biosynthesis , Genetic Vectors/genetics , Insulin/pharmacology , Mice , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
It is well documented that exhaustive physical exercise leads to inflammation and skeletal muscle tissue damage. With this in mind, melatonin has been acutely administered before physical exercise; nevertheless, the use of melatonin as an ergogenic agent to prevent tissue inflammation and damage remains uncertain. We evaluated the effects of melatonin on swimming performance, muscle inflammation and damage and several physiological parameters after exhaustive exercise at anaerobic threshold intensity (iLAn) performed during light or dark circadian periods. The iLAn was individually determined and two days later, the animals performed an exhaustive exercise bout at iLAn 30 minutes after melatonin administration. The exercise promoted muscle inflammation and damage, mainly during the dark period, and the exogenous melatonin promoted a high ergogenic effect. The expressive ergogenic effect of melatonin leads to longer periods of muscle contraction, which superimposes a possible melatonin protective effect on the tissue damage and inflammation.
Subject(s)
Inflammation/metabolism , Melatonin/metabolism , Muscle, Skeletal/injuries , Muscle, Skeletal/metabolism , Performance-Enhancing Substances/metabolism , Physical Conditioning, Animal , Soft Tissue Injuries/metabolism , Animals , Biomarkers , Disease Models, Animal , Inflammation/drug therapy , Melatonin/pharmacology , Mice , Muscle, Skeletal/drug effects , Performance-Enhancing Substances/pharmacology , Rats , Soft Tissue Injuries/drug therapyABSTRACT
PURPOSE: This study aims to evaluate the effects of acute exercise on tribbles homolog 3 (TRB3) protein levels and on the interaction between TRB3 and Akt proteins in the hypothalamus of obese rats. In addition, we evaluated the relationship between TRB3 and endoplasmic reticulum (ER) stress and verified whether an acute exercise session influences them. METHODS: In the first part of the study, the rats were divided into three groups: control (lean), fed standard rodent chow; DIO, fed a high-fat diet; and DIO-EXE, fed a high-fat diet and submitted to a swimming acute exercise protocol. In the second part of the study, we used three other groups: control (lean) group receiving an intracerebroventricular (i.c.v.) infusion of vehicle, lean group receiving an i.c.v. infusion of thapsigargin, and lean group receiving an i.c.v. infusion of thapsigargin and performing an acute exercise session. Four hours after the exercise session, food intake was measured, and the hypothalamus was dissected and separated for subsequent protein analysis by immunoblotting and real-time polymerase chain reaction. RESULTS: The acute exercise session reduced TRB3 protein levels, disrupted the interaction between TRB3 and Akt proteins, increased the phosphorylation of Foxo1, and restored the anorexigenic effects of insulin on the hypothalamus of DIO rats. Interestingly, the suppressive effects of acute exercise on TRB3 protein levels may be related, at least in part, to decreased ER stress (evaluated though pancreatic ER kinase phosphorylation and C/EBP homologous protein levels) in the hypothalamus. CONCLUSION: Exercise-mediated reduction of hypothalamic TRB3 protein levels may be associated with reduction of ER stress. These data provide a new mechanism by which an acute exercise session improves insulin sensitivity in the hypothalamus and restores food intake control in obesity.