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In this early 21st century, one of the most problematic pathology is the metabolic syndrome. Development of cardiovascular disorders represents one of the major consequences of this syndrome. Insulin resistance, which is characterized by the loss of metabolic responses to insulin, is one of the events defining the metabolic syndrome. For instance, we observed a decrease in glucose uptake and oxidation which is implicated in the development of diabetic cardiomyopathy. Insulin resistance represent also a major risk of developing other cardiovascular diseases such as cardiac hypertrophy, myocardial infarction, heart failure. A way of resensitizing the cardiac tissue is considered as an interesting therapy in order to reduce the apparition of the conditions and to improve the recovery of function after an eventual ischemic event. The Stimulation of AMP-dependent kinase (AMPK) is able to sensitize the heart to insulin by molecular mechanisms that are not yet totally understood. In opposition to what has commonly be approved in the literature, the host laboratory proved that the inhibition of the insulin negative feedback is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake and proposed that this effect might involved the actin cytoskeleton rearrangement which is under the control of the small G protein Rac.We focused on Rac and showed that Rac can be activated by insulin as well as by phenformin, an AMPK activator. Rac pharmacological inhibition leads to the loss of the implication of the Rac in this effect. We are currently developing some genetic methods such as silencing RNA and overexpression of a dominant negative form of Rac to definitively demonstrate the role of this small G protein. In parallel, we are also developing the HAGLUT4-GFP fusion protein expression in adult rat cardiomyocytes. This tool will help up studying the AMPK and the small G protein Rac in the translocation, docking and fusion of GLUT4 with the plasma membrane. Le syndrome métabolique est une des pathologies les plus préoccupantes en ce début de 21ème siècle. Une des conséquences majeures de ce syndrome est l'apparition de troubles cardiovasculaires. Il se définit par plusieurs phénomènes dont l'insulino-résistance cardiaque qui se caractérise par une perte de réponse métabolique à l'insuline. On observe, par exemple, une diminution du captage et de l'oxydation du glucose impliquée dans l'apparition de cardiomyopathies diabétiques. Cette résistance présente également un risque majeur de développer d'autres maladies cardiovasculaires telles que l'hypertrophie, l'infarctus et l'insuffisance cardiaque.Une resensibilisation du tissus cardiaque à l'insuline permettrait de diminuer l'apparition de ces maladies et d'améliorer la récupération de fonction après un épisode ischémique éventuel. La stimulation de I'AMP-activated protein kinase (AMPK) sensibilise le cœur à l'insuline par des mécanismes moléculaires encore partiellement incompris. L'indentification de ces mécanismes a fait l'objet de ce travail. Contrairement à ce qui a été récemment proposé dans le muscle squelettique, nous avons montré que la diminution du cholestérol membranaire induite par l'activation de I'AMPK ne permet pas d'expliquer l'effet insulino-sensibilisateur de cette dernière sur le transport de glucose cardiomyocytaire. Nous nous sommes par la suite intéressés à la petite protéine G Rac.En effet, le laboratoire d'accueil ava it précédemment montré que la réorganisation du cytosquelette d'actine, connue pour être sous le contrôle de Rac,sembla it impliquée dans l'effet insulino-sensibilisateur de I'AMPK.Nous avons montré que Rac est activée à la fois par l'insuline et par la phenformine, un activateur de I'AMPK. En outre, nous avons montré que l'inhibition pharmacologique de Rac, par deux molécules différentes,entraine une perte de l'effet insulino-sensibilisateur de I'AMPK sur le transport de glucose myocardique. Des modèles génétiques,tels que la diminution de l'expression de Rac par ARN interférent et la surexpression d'une forme dominante négative de Rac, ont également été mis au point afin de pouvoir démontrer dans un futur proche le rôle de cette protéine G dans les phénomènes qui nous intéressent . En parallèle, nous avons mis au point l'expression d'une protéine chimérique HA-GLUT4-GFP dans le cardiomyocyte de rat adulte. Cet outil nous permettra d'étudier la translocation, l'ancrage et la fusion de la protéine GLUT4 avec la membrane plasmique. Nous pourrons ainsi étudier l'implication de I'AMPK et de la petite protéine G Rac dans ces trois mouvements de GLUT4.

Metabolic Syndrome X --- AMP-Activated Protein Kinases

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Metabolic Syndrome X --- Fetus --- Pregnant Women

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The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines, cytokines, and chemokines but also by alterations in insulin and leptin signaling, oxidative stress, and chronic low grade inflammation. These changes affect immune responses and mediate chronic inflammation leading to alterations in the hypothalamic ‘bodyweight/appetite/satiety set point’. It is becoming increasingly evident that metabolic syndrome is a risk factor for neurological disorders such as stroke, depression, and Alzheimer disease (AD). Family history, age, environmental and lifestyle factors (diet and physical inactivity, and exposure to toxins) are closely associated with predisposition for the development of metabolic syndrome as well as neurological disorders. The incidences of stroke are 2 to 4-fold higher in patients with metabolic syndrome and cardiovascular diseases compared to normal subjects of the same age. Similarly, patients with metabolic syndrome have a 2 to 3-fold increased risk for developing dementia and AD. Metabolic syndrome doubles the risk of depression. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, biochemical alterations observed in metabolic syndrome like induction of chronic inflammation and oxidative stress, impairment of endothelial cell function, induction of insulin and leptin resistance, hyperglycemia-related increase in advanced glycation end-products, and micro-vascular injury may represent a pathological bridge between metabolic syndrome and neurological disorders. It is hoped that Metabolic Syndrome: An important risk factor for stroke, Alzheimer disease, and depression will be useful to postgraduate students, faculty, research scientists, pharmacologists, nutritionists, and physicians, who are curious about the molecular mechanisms that link metabolic syndrome with stroke, Alzheimer disease, and depression.

Medicine. --- Metabolic syndrome. --- Neurosciences. --- Metabolic syndrome --- Diseases --- Risk --- Metabolic Phenomena --- Mood Disorders --- Insulin Resistance --- Probability --- Hyperinsulinism --- Mental Disorders --- Phenomena and Processes --- Glucose Metabolism Disorders --- Statistics as Topic --- Psychiatry and Psychology --- Metabolic Diseases --- Epidemiologic Methods --- Nutritional and Metabolic Diseases --- Investigative Techniques --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Metabolic Syndrome X --- Metabolism --- Nervous System Diseases --- Depressive Disorder --- Risk Factors --- Medicine --- Health & Biological Sciences --- Neurology --- Neurochemistry. --- Neurology. --- Neural sciences --- Neurological sciences --- Neuroscience --- Clinical sciences --- Medical profession --- Cardiovascular syndrome, Metabolic --- Dysmetabolic syndrome X --- Insulin resistance syndrome --- Metabolic cardiovascular syndrome --- Metabolic syndrome X --- Biomedicine. --- Nervous system --- Neuropsychiatry --- Biochemistry --- Neurosciences --- Medical sciences --- Human biology --- Life sciences --- Pathology --- Physicians --- Insulin resistance --- Syndromes --- Disorders --- Neurology .