A predictive model of the dynamics of body weight and food intake in rats submitted to caloric restrictions.

International audienceDynamics of body weight and food intake can be studied by temporally perturbing food availability. This perturbation can be obtained by modifying the amount of available food over time while keeping the overall food quantity constant. To describe food intake dynamics, we developed a mathematical model that describes body weight, fat mass, fat-free mass, energy expenditure and food intake dynamics in rats. In addition, the model considers regulation of food intake by leptin, ghrelin and glucose. We tested our model on rats experiencing temporally variable food availability. Our model is able to predict body weight and food intake variations by taking into account energy expenditure dynamics based on a memory of the previous food intake. This model allowed us to estimate this memory lag to approximately 8 days. It also explains how important variations in food availability during periods longer than these 8 days can induce body weight gains

Role of lipotoxicity in insulin resistance in subtotally nephrectomized mouse model

Chronic kidney disease (CKD) is associated with a large range of metabolic alterations among which insulin resistance and dyslipidemia. We hypothesize that a phenomenon of lipotoxicity and ectopic fat redistribution could be responsible for the insulin-resistance associated to CKD.C57BL/6 mice underwent a 5/6 nephrectomy and were compared to pair fed sham-operated mice. Insulin sensitivity was estimated through intra-peritoneal insulin (ipITT) and glucose tolerance (ipGTT) tests. Anthropometric (body weight, lean and fad pad mass) and metabolic parameters (glycemia, insulin, cholesterol, triglycerides) were measured. The phosphorylation of a key protein of insulin signaling pathway (protein kinase B, PKB/Akt) was studied by Western blot. The intra-muscular and intra-hepatic lipids were extracted using Chloroform-Methanol (2:1, v/v).The CKD mice exhibited a marked decrease in insulin sensitivity (−76%, p<0.01) and altered glucose tolerance (+24%, p<0.001). CKD mice exhibited a profile of insulin resistance. CKD mice exhibited a significant decrease in white adipose tissue accretion (−57%, p< 0.001) associated with increased muscle (+138%, p<0.05) and liver (+38%, P<0.05) lipid contents compared to sham-operated mice. The CKD mice presented a blunted insulin-induced Akt phosphorylation (−34%, p<0.05) in gastrocnemius muscle.In subtotally nephrectomized mouse model we showed an ectopic intramuscular and intrahepatic lipid redistribution concomitant with insulin resistance. Insulin resistance and lipotoxicity may represent the missing links (beyond the classical cardiovascular risk factors) that may help explain the increased risk of cardiovascular disease in CKD

Exploring docking methods for virtual screening: application to the identification of neuraminidase and Ftsz potential inhibitors

Virtual screenings based on molecular docking play a major role in medicinal chemistry for the identification of new bioactive molecules. For this purpose, several docking methods can be used. Here, using Arguslab as software and a Gold Platinum subset library of commercially available compounds from Asinex, two docking methods associated to the scoring function Ascore were employed to investigate virtual screenings. One method is based on a genetic algorithm and the other based on a shape-based method. As case studies, both docking techniques were explored by targeting the PC190723 binding site of FtsZ protein from Staphylococcus aureus and the active site of N8 neuraminidase from Influenza virus. Following four docking sequences for each docking engine, the genetic algorithm led to multiple docking results, whereas the shape-based method gave reproducible results. The present study shows that the stochastic nature of the genetic algorithm will require the biological evaluation of more compounds than the shape-based method. This study showed that both methods are complementary and also led to the identification of neuraminidase and FtsZ potential inhibitors

The impact of dietary nutrient intake on gut microbiota in the progression and complications of chronic kidney disease

International audienceLa maladie rénale chronique a été associée à des changements dans la fonction et la composition du microbiote intestinal. L'écosystème de l'intestin humain se compose de milliards de micro-organismes formant un authentique organe métaboliquement actif qui est alimenté par des nutriments pour produire des composés bioactifs. Ces métabolites dérivés du microbiote peuvent être protecteurs pour la fonction rénale (par exemple, les acides gras à chaîne courte issus de la fermentation des fibres alimentaires) ou délétères (par exemple, les toxines urémiques dérivées de l'intestin telles que le N-oxyde de triméthylamine, le sulfate de p-crésyle et le sulfate d'indoxyle de la fermentation des acides aminés). Bien que l'alimentation soit la pierre angulaire de la prise en charge du patient atteint d'insuffisance rénale chronique, elle reste une composante relativement sous-utilisée de l'arsenal thérapeutique du clinicien. Dans cette revue, nous décrivons les dernières avancées dans la compréhension de la diaphonie alimentation-microbiote dans le contexte urémique et comment cette communication pourrait contribuer à la progression et aux complications de la maladie rénale chronique. Nous discutons ensuite de la manière dont ces connaissances pourraient être exploitées pour des stratégies nutritionnelles personnalisées afin d'empêcher les patients atteints d'insuffisance rénale chronique de progresser vers l'insuffisance rénale et ses conséquences néfastes

Abnormalities in myo-inositol metabolism associated with type 2 diabetes in mice fed a high-fat diet: benefits of a dietary myo-inositol supplementation

International audienceWe previously reported that a chronic supplementation with myo-inositol (MI) improved insulin sensitivity and reduced fat accretion in mice. We then tested the potency of such dietary intervention in the prevention of insulin resistance in C57BL/6 male mouse fed a high-fat diet (HFD). In addition, some abnormalities in inositol metabolism were reported to be associated with insulin resistance in several animal and human studies. We then investigated the presence of such anomalies (i.e. inosituria and an inositol intra-tissue depletion) in this diet-induced obesity (DIO) mouse model, as well as the potential benefit of a MI supplementation for inositol intra-tissue deficiency correction. HFD (60 % energy from fat) feeding was associated with inosituria and inositol intra-tissue depletion in the liver and kidneys. MI supplementation (0.58 mg/g per d) restored inositol pools in kidneys (partially) and liver (fully). HFD feeding for 4 months induced ectopic lipid redistribution to liver and muscles, fasting hyperglycaemia and hyperinsulinaemia, insulin resistance and obesity that were not prevented by MI supplementation, despite a significant improvement in insulin sensitivity parameter K insulin tolerance test and a reduction in white adipose tissue (WAT) mass ( - 17 %, P\textless 0.05). MI supplementation significantly reduced fatty acid synthase activity in epididymal WAT, which might explain its beneficial, but modest, effect on WAT accretion in HFD-fed mice. Finally, we found some abnormalities in inositol metabolism in association with a diabetic phenotype (i.e. insulin resistance and fasting hyperglycaemia) in a DIO mouse model. Dietary MI supplementation was efficient in the prevention of inositol intra-tissue depletion, but did not prevent insulin resistance or obesity efficiently in this mouse model

Modified lipids and lipoproteins in chronic kidney disease: A new class of uremic toxins

Chronic kidney disease (CKD) is associated with an enhanced oxidative stress and deep modifications in lipid and lipoprotein metabolism. First, many oxidized lipids accumulate in CKD and were shown to exert toxic effects on cells and tissues. These lipids are known to interfere with many cell functions and to be pro-apoptotic and pro-inflammatory, especially in the cardiovascular system. Some, like F2-isoprostanes, are directly correlated with CKD progression. Their accumulation, added to their noxious effects, rendered their nomination as uremic toxins credible. Similarly, lipoproteins are deeply altered by CKD modifications, either in their metabolism or composition. These impairments lead to impaired effects of HDL on their normal effectors and may strongly participate in accelerated atherosclerosis and failure of statins in end-stage renal disease patients. This review describes the impact of oxidized lipids and other modifications in the natural history of CKD and its complications. Moreover, this review focuses on the modifications of lipoproteins and their impact on the emergence of cardiovascular diseases in CKD as well as the appropriateness of considering them as actual mediators of uremic toxicity

New clinical evidence for urea toxicity

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Model of adipose tissue cellularity dynamics during food restriction

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Rôle des hydroxy-alkénals, dérivés de peroxydation lipidique, dans la physiopathologie de l'insulino-résistance (effets du 4-hydroxy-2-hexénal et du 4-hydroxy-2-nonénal sur les voies de signalisation et la fonction biologique de l'insuline)

Le stress oxydant semble impliqué dans le développement de la résistance périphérique à l'insuline conduisant au diabète de type 2. Les membranes biologiques, par leur richesse en acides gras polyinsaturés, constituent des cibles privilégiées pour les espèces oxydantes. La peroxydation des membranes biologiques est ainsi à l'origine de la production de nombreuses espèces réactives parmi lesquelles les aldéhydes 4-hydroxy-2-hexénal (HHE) et 4-hydroxy- 2- nonénal (HNE), dérivant respectivement de la peroxydation des acides gras polyinsaturés des familles omega-3 et omega-6. La présente étude démontre que la concentration plasmatique de HHE est augmentée chez l'homme et chez le rat au cours du diabète et qu'une injection intraveineuse de HHE conduit au développement d'une résistance à l'insuline chez le rat. Sur des lignées de cellules musculaires (L6C5) et d'adipocytes (3T3-Ll) en culture, HHE et HNE provoquent une carbonylation massive des protéines cellulaires et induisent une insulino-résistance en perturbant le transport de glucose ainsi que les voies de signalisation de l'insuline. Ces effets délétères peuvent être contrecarrés par une augmentation du glutathion réduit ou par des traitements antioxydants. HHE et HNE peuvent également former des adduits covalents sur l'insuline, diminuant ainsi son effet hypoglycémiant in vivo et la stimulation du transport de glucose in vitro. HHE et HNE sont impliqués dans le développement de l'insulino-résistance en perturbant à la fois les voies intracellulaires de signalisation et la fonction biologique de l'insuline. Ils constituent donc des cibles pharmacologiques potentielles pour la prévention du diabète de type 2.Oxidative stress appears to be involved in the development of peripheral insulin resistance leading to type 2 diabetes. Biological membranes, because of their high polyunsaturated fatty acids, are prime targets for oxidant species. Peroxidation of biological membranes is responsible for the production of many reactive species including aldehydes 4- hydroxy-2-hexenal (HHE) and 4-hydroxy-2-nonenal (HNE), respectively derived from the peroxidation of omega-3 and omega-6 polyunsaturated fatty acids. This study demonstrates that plasma concentration of HHE is increased in humans and rats during diabetes, and that intravenous injection of HHE lead to the development of insulin resistance in rats. In muscle cells (L6C5) and adipocytes (3T3-Ll), HHE and HNE cause massive carbonylation of cellular proteins and induce insulin resistance by disrupting glucose transport and the signaling pathways of insulin. These disorders can be reversed by an increase of reduced glutathione or by antioxidant treatment. HHE and HNE can also form covalent adducts on insulin, thereby reducing its hypoglycemic effect in vivo and stimulation of glucose transport in vitro. HHE and HNE are involved in the development of insulin resistance by disrupting both the intracellular signaling pathways and biological function of insulin. They are therefore potential drug targets for the prevention of type 2 diabetes.VILLEURBANNE-DOC'INSA LYON (692662301) / SudocSudocFranceF