CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation.

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.

ER stress activation in the intestinal mucosa but not in mesenteric adipose tissue is associated with inflammation in Crohn's disease patients.

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.

Physical training prevent and treat hepatic lipid accumulation induced by fructose-rich diet / Treinamento físico previne e trata acumulação lipídica hepática induzida por dieta rica em frutose

This study aims to examine the effects of physical training performed in early (preventive) or late (therapeutic) protocols on body weight gain, glucose tolerance, and triglycerides accumulation in rats fed on a fructoserich diet. Wistar rats were allocated into two major groups according to the diet received: Control (C- standard diet) and Fructose (F- diet containing 60% fructose) fed during 120 days. Next, these two groups were distributed into six groups: C and F that were kept inactive; CTE (Control Trained Early) and FTE (Fructose Trained Early) that were submitted to Anaerobic Threshold (AnT) training from 28 to 120 days; CTL (Control Trained Late) and FTL (Fructose Trained Late) trained from 90 to 120 days. Physical Training was composed by swimming (5 days/week) at AnT determined by maximum lactate stead state (MLSS). The Oral Glucose Tolerance Test (oGTT) was performed 48h after the last in vivo analysis and did not showed differences between the groups. After, the animals were euthanized for heart, liver, and adipose tissue extraction. The early exercised animals had lower body weight compared to their sedentary littermates. Also, the fructose-rich diet increased liver lipids content in the sedentary animals and physical training successfully reduced this parameter in both major groups. These results suggests that physical training at the AnT performed in early or late protocols are effective to prevent and treat metabolic disorders related to fructose intake.

Este estudo tem como objetivo examinar os efeitos do treinamento físico realizado em protocolos precoce (preventivo) ou tardio (terapêutico) sobre o ganho de massa corporal, tolerância à glicose e acúmulo de triglicerídeos em ratos alimentados com dieta rica em frutose. Ratos Wistar foram alocados em dois grupos principais de acordo com a dieta recebida: Controle (C, dieta padrão) e Frutose (F, dieta contendo 60% de frutose) durante 120 dias. Em seguida, esses dois grupos foram distribuídos em seis grupos: C e F que foram mantidos inativos; CET (Controle Treinado Precoce) e FTE (Frutose Treinado Precoce) que foram submetidos ao treinamento no Limiar Anaeróbio (AnT) de 28 a 120 dias; CTL (controle treinado tardio) e FTL (frutose treinado tardio) treinados de 90 a 120 dias. O treinamento físico foi composto por natação (5 dias / semana) na AnT determinado pela Máxima Fase Estável de Lactato (MLSS). O Teste Oral de Tolerância à Glicose (oGTT) foi realizado 48 horas após a última análise in vivo e não mostrou diferenças entre os grupos. Depois, os animais foram eutanasiados para extração do coração, fígado e tecido adiposo. Os animais exercitados precocemente apresentaram menor massa corporal em comparação com os sedentários. Além disso, a dieta rica em frutose aumentou o conteúdo de lipídios do fígado nos animais sedentários e o treinamento físico reduziu com sucesso este parâmetro em ambos os grupos principais. Estes resultados sugerem que o treinamento físico no AnT realizado em protocolos precoce ou tardio são eficazes para prevenir e tratar distúrbios metabólicos relacionados à ingestão de frutose.

Acute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice.

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.

Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice.

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.

Overexpression of Mitogen-activated protein kinase phosphatase-3 (MKP-3) reduces FoxO1 phosphorylation in mice hypothalamus.

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.

Hippocampal insulin signaling and neuroprotection mediated by physical exercise in Alzheimer´s disease

Abstract Epidemiological studies indicate continuous increases in the prevalence of Alzheimer’s Disease (AD) in the next few decades. The key feature of this disease is hippocampal neurodegeneration. This structure has an important role in learning and memory. Intense research efforts have sought to elucidate neuroprotective mechanisms responsible for hippocampal integrity. Insulin signaling seems to be a very promising pathway for the prevention and treatment of AD. This hormone has been described as a powerful activator of neuronal survival. Recent research showed that reduced insulin sensitivity leads to low-grade inflammation, and both phenomena are closely related to AD genesis. Concomitantly, exercise has been shown to exert anti-inflammatory effects and to promote improvement in insulin signaling in the hippocampus, which supports neuronal survival and constitutes an interesting non-pharmacological alternative for the prevention and treatment of AD. This review examines recent advances in understanding the molecular mechanisms involved in hippocampal neuroprotection mediated by exercise.(AU)

Acute Exercise Decreases Tribbles Homolog 3 Protein Levels in the Hypothalamus of Obese Rats.

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.

Consumo de frutose e exercício físico, impacto na síndrome metabólica / Fructose Consumption and physical exercise, the impact on metabolic syndrome

Nas últimas duas décadas, a síndrome metabólica está no foco das diversas agências de saúde mundiais. Compreendendo entre os aspectos mais importantes a intolerância à glicose e a resistência à insulina, outras desordens vêm sendo enquadradas nessa categoria. A esteatose hepática não alcoólica emerge como um dos componentes dessa síndrome. Diversos estudos apontam o aumento do consumo de frutose associado ao sedentarismo ao aparecimento da esteatose hepática. A partir dessa premissa, a presente revisão objetivou-se na busca de estudos que apontem o papel do exercício físico como importante arma no tratamento e na prevenção da esteatose hepática não alcoólica.

In the last two decades, the metabolic syndrome is in focus of many health agencies worldwide. Understanding among the most important glucose intolerance and insulin resistance, other disorders have been framed in this category. The non-alcoholic hepatic steatosis appears to be one of the components of this syndrome. Several studies point to the increased consumption of fructose linked to the onset of sedentary steatohepatitis. From that premise, this review aimed to the search for studies that suggest the role of exercise as an important weapon in the treatment and prevention of non-alcoholic hepatic steatosis.