Combined effect of vitamin D supplementation and physical exercise in tertiary prevention on c57bl/6j mice : metabolic aspects of obesity and associated disorders

L’obésité est une maladie pandémique résultant de changements comportementaux dus à la modernisation de notre société actuelle, comprenant une augmentation de l’inactivité physique et une surconsommation d’aliments riches en graisse et en sucre mais également pauvres en micronutriments. Dans ce contexte, cette thèse a pour objectif d’évaluer les effets de l’exercice physique associé à la supplémentation en vitamine D en prévention tertiaire dans un modèle expérimental d’obésité. Tout d’abord, la consommation du régime obésogène a conduit au développement de l’obésité caractérisée par une augmentation de l’adiposité, une accumulation de lipides ectopiques dans le foie ainsi qu’à la mise en place d’une résistance à l’insuline et d’une inflammation. Dans un premier temps, nous nous sommes intéressés à l’effet de la vitamine D sur ces différents événements rencontrés au cours de l’obésité. Bien que nous n’ayons pas mis en évidence d’effet de la supplémentation en vitamine D sur les paramètres morphologiques, nous avons montré une baisse de l’inflammation du tissu adipeux par la limitation d’expression des chimiokines et de l’infiltration lipidique au niveau hépatique accompagnée d’une baisse d’expression des gènes impliqués dans la lipogenèse.Le deuxième objectif de cette thèse a été d’étudier les effets combinés de la supplémentation en vitamine D et de l’exercice physique volontaire. Contrairement à ce qui a été retrouvé par la supplémentation en vitamine D seule, l’exercice physique a induit une limitation de la prise de poids, accompagnée d’une réduction de l’adiposité médiée par une baisse de l’hypertrophie adipocytaire. De plus, la double intervention a permis de restaurer la sensibilité à l’insuline et d’abolir totalement l’infiltration lipidique au niveau hépatique. Ceci pourrait être expliqué par la diminution de l’inflammation adipocytaire et de la réduction d’infiltration macrophagique retrouvée à la fois dans le tissu adipeux et dans le foie. Ainsi, nos résultats démontrent pour la première fois l’intérêt de coupler l’exercice physique à la supplémentation en vitamine D pour lutter contre l’obésité et désordres métaboliques associés.Obesity is a pandemic disease arising from behavorial and social changes which are driven by modernization of actual society. These changes include an increase of physical inactivity and overconsumption of food rich in fat and sugar but also poor in micronutrients. In this context, the aim of this thesis was to evaluate physical exercise and vitamin D supplementation effects in tertiary prevention on an experimental model of obesity. First, obesogenic diet consumption led to obesity development characterized by increased adiposity, ectopic lipid accumulation in the liver as well as insulin resistance and inflammation. Firstly, we investigate vitamin D supplementation on these events occurring during obesity. While we did not observe modification of morphological parameters by vitamin D supplementation, we demonstrated that vitamin D supplementation decreased adipose tissue inflammation by limiting chemokine expression and hepatic lipid infiltration accompanied by decreased gene expression involved in lipogenesis.The second objective of this thesis was to investigate the combined effects of vitamin D supplementation and voluntary physical exercise. Unlike to what we observed by vitamin D supplementation alone, physical exercise induced a limitation in weight gain, accompanied by a reduction in adiposity mediated by decreased adipocyte hypertrophy. In addition, the double intervention restored insulin sensitivity and completely abolished hepatic lipid infiltration. This could be explained by decreased adipocyte inflammation and decreased macrophage infiltration found in both adipose tissue and liver. Thus, our results demonstrated for the first time the interest of combining physical exercise and vitamin D supplementation to fight obesity and associated metabolic disorders

Effet combiné de l’exercice physique et de la vitamine D en prévention tertiaire sur des souris c57bl/6j soumises à un régime riche en graisse et en sucre : aspects métaboliques de l’obésité et des désordres associés

Obesity is a pandemic disease arising from behavorial and social changes which are driven by modernization of actual society. These changes include an increase of physical inactivity and overconsumption of food rich in fat and sugar but also poor in micronutrients. In this context, the aim of this thesis was to evaluate physical exercise and vitamin D supplementation effects in tertiary prevention on an experimental model of obesity. First, obesogenic diet consumption led to obesity development characterized by increased adiposity, ectopic lipid accumulation in the liver as well as insulin resistance and inflammation. Firstly, we investigate vitamin D supplementation on these events occurring during obesity. While we did not observe modification of morphological parameters by vitamin D supplementation, we demonstrated that vitamin D supplementation decreased adipose tissue inflammation by limiting chemokine expression and hepatic lipid infiltration accompanied by decreased gene expression involved in lipogenesis.The second objective of this thesis was to investigate the combined effects of vitamin D supplementation and voluntary physical exercise. Unlike to what we observed by vitamin D supplementation alone, physical exercise induced a limitation in weight gain, accompanied by a reduction in adiposity mediated by decreased adipocyte hypertrophy. In addition, the double intervention restored insulin sensitivity and completely abolished hepatic lipid infiltration. This could be explained by decreased adipocyte inflammation and decreased macrophage infiltration found in both adipose tissue and liver. Thus, our results demonstrated for the first time the interest of combining physical exercise and vitamin D supplementation to fight obesity and associated metabolic disorders.L’obésité est une maladie pandémique résultant de changements comportementaux dus à la modernisation de notre société actuelle, comprenant une augmentation de l’inactivité physique et une surconsommation d’aliments riches en graisse et en sucre mais également pauvres en micronutriments. Dans ce contexte, cette thèse a pour objectif d’évaluer les effets de l’exercice physique associé à la supplémentation en vitamine D en prévention tertiaire dans un modèle expérimental d’obésité. Tout d’abord, la consommation du régime obésogène a conduit au développement de l’obésité caractérisée par une augmentation de l’adiposité, une accumulation de lipides ectopiques dans le foie ainsi qu’à la mise en place d’une résistance à l’insuline et d’une inflammation. Dans un premier temps, nous nous sommes intéressés à l’effet de la vitamine D sur ces différents événements rencontrés au cours de l’obésité. Bien que nous n’ayons pas mis en évidence d’effet de la supplémentation en vitamine D sur les paramètres morphologiques, nous avons montré une baisse de l’inflammation du tissu adipeux par la limitation d’expression des chimiokines et de l’infiltration lipidique au niveau hépatique accompagnée d’une baisse d’expression des gènes impliqués dans la lipogenèse.Le deuxième objectif de cette thèse a été d’étudier les effets combinés de la supplémentation en vitamine D et de l’exercice physique volontaire. Contrairement à ce qui a été retrouvé par la supplémentation en vitamine D seule, l’exercice physique a induit une limitation de la prise de poids, accompagnée d’une réduction de l’adiposité médiée par une baisse de l’hypertrophie adipocytaire. De plus, la double intervention a permis de restaurer la sensibilité à l’insuline et d’abolir totalement l’infiltration lipidique au niveau hépatique. Ceci pourrait être expliqué par la diminution de l’inflammation adipocytaire et de la réduction d’infiltration macrophagique retrouvée à la fois dans le tissu adipeux et dans le foie. Ainsi, nos résultats démontrent pour la première fois l’intérêt de coupler l’exercice physique à la supplémentation en vitamine D pour lutter contre l’obésité et désordres métaboliques associés

Artificial sweeteners impair endothelial vascular reactivity: Preliminary results in rodents

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Vitamin D Supplementation Improves Adipose Tissue Inflammation and Reduces Hepatic Steatosis in Obese C57BL/6J Mice

International audienceThe beneficial effect of vitamin D (VD) supplementation on body weight gain limitation and inflammation has been highlighted in primary prevention mice models, but the long-term effect of VD supplementation in tertiary prevention has never been reported in obesity models. The curative effect of VD supplementation on obesity and associated disorders was evaluated in high-fat- and high-sucrose (HFS)-fed mice. Morphological, histological, and molecular phenotype were characterized. The increased body mass and adiposity caused by HFS diet as well as fat cell hypertrophy and glucose homeostasis were not improved by VD supplementation. However, VD supplementation led to a decrease of HFS-induced inflammation in inguinal adipose tissue, characterized by a decreased expression of chemokine mRNA levels. Moreover, a protective effect of VD on HFS-induced hepatic steatosis was highlighted by a decrease of lipid droplets and a reduction of triglyceride accumulation in the liver. This result was associated with a significant decrease of gene expression coding for key enzymes involved in hepatic de novo lipogenesis and fatty acid oxidation. Altogether, our results show that VD supplementation could be of interest to blunt the adipose tissue inflammation and hepatic steatosis and could represent an interesting nutritional strategy to fight obesity-associated comorbidities

Combined Beneficial Effect of Voluntary Physical Exercise and Vitamin D Supplementation in Diet-induced Obese C57BL/6J Mice

International audiencePurpose Physical exercise (PE) combined with nutritional approaches has beneficial effects that are widely advocated to improve metabolic health. Here we used voluntary PE together with vitamin D (VD) supplementation, which has already shown beneficial effects in primary and tertiary prevention in obese mice models, to study their combined additive effects on body weight management, glucose homeostasis, metabolic inflammation, and liver steatosis as key markers of metabolic health. Methods Ten-week-old male C57BL/6J mice were fed a high-fat/sucrose (HFS) diet for 10 wk, then assigned to a 15-wk intervention period with PE, VD supplementation, or both PE and VD supplementation. Morphological, histological, and molecular phenotype data were characterized. Results The HFS-induced increases in body mass, adiposity, and adipocyte hypertrophy were improved by PE but not by VD supplementation. The HFS-induced inflammation (highlighted by chemokines mRNA levels) in inguinal adipose tissue was decreased by PE and/or VD supplementation. Furthermore, the intervention combining PE and VD showed additive effects on restoring insulin sensitivity and improving hepatic steatosis, as demonstrated through a normalization of size and number of hepatic lipid droplets and triglyceride content and a significant molecular-level decrease in the expression of genes coding for key enzymes in hepatic de novo lipogenesis. Conclusions Taken together, our data show beneficial effects of combining PE and VD supplementation on obesity-associated comorbidities such as insulin resistance and hepatic disease in mice. This combined exercise-nutritional support strategy could prove valuable in obesity management programs

Combined Beneficial Effect of Voluntary Physical Exercise and Vitamin D Supplementation in Diet-induced Obese C57BL/6J Mice

International audiencePurpose Physical exercise (PE) combined with nutritional approaches has beneficial effects that are widely advocated to improve metabolic health. Here we used voluntary PE together with vitamin D (VD) supplementation, which has already shown beneficial effects in primary and tertiary prevention in obese mice models, to study their combined additive effects on body weight management, glucose homeostasis, metabolic inflammation, and liver steatosis as key markers of metabolic health. Methods Ten-week-old male C57BL/6J mice were fed a high-fat/sucrose (HFS) diet for 10 wk, then assigned to a 15-wk intervention period with PE, VD supplementation, or both PE and VD supplementation. Morphological, histological, and molecular phenotype data were characterized. Results The HFS-induced increases in body mass, adiposity, and adipocyte hypertrophy were improved by PE but not by VD supplementation. The HFS-induced inflammation (highlighted by chemokines mRNA levels) in inguinal adipose tissue was decreased by PE and/or VD supplementation. Furthermore, the intervention combining PE and VD showed additive effects on restoring insulin sensitivity and improving hepatic steatosis, as demonstrated through a normalization of size and number of hepatic lipid droplets and triglyceride content and a significant molecular-level decrease in the expression of genes coding for key enzymes in hepatic de novo lipogenesis. Conclusions Taken together, our data show beneficial effects of combining PE and VD supplementation on obesity-associated comorbidities such as insulin resistance and hepatic disease in mice. This combined exercise-nutritional support strategy could prove valuable in obesity management programs

Combined Beneficial Effect of Voluntary Physical Exercise and Vitamin D Supplementation in Diet-induced Obese C57BL/6J Mice

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Combined Beneficial Effect of Voluntary Physical Exercise and Vitamin D Supplementation in Diet-induced Obese C57BL/6J Mice

International audienc

Vitamin D3 Supplementation Alleviates Left Ventricular Dysfunction in a Mouse Model of Diet-Induced Type 2 Diabetes: Potential Involvement of Cardiac Lipotoxicity Modulation

International audiencePurpose To evaluate the effectiveness of vitamin D-3 supplementation, in secondary prevention, on cardiac remodeling and function, as well as lipid profile, in a mouse model of diet-induced type 2 diabetes. Methods Mice were fed a high fat and sucrose diet for 10 weeks. Afterward, diet was maintained for 15 more weeks and two groups were formed, with and without cholecalciferol supplementation. A control group was fed with normal chow. Glucose homeostasis and cardiac function were assessed at baseline and at the 10th and 24th weeks. Animals were killed at the 10th and 25th weeks for plasma and cardiac sample analysis. Cardiac lipid profile was characterized by LC-MS/MS. Results After 10 weeks of diet, mice exhibited pre-diabetes, mild left ventricle hypertrophy, and impaired longitudinal strain, but preserved myocardial circumferential as well as global diastolic and systolic cardiac function. After 15 more weeks of diet, animals presented with well-established type 2 diabetes, pathological cardiac hypertrophy, and impaired regional myocardial function. Cholecalciferol supplementation had no effect on glucose homeostasis but improved cardiac remodeling and regional myocardial function. After 25 weeks, non-supplemented mice exhibited increased myocardial levels of ceramides and diacylglycerol, both of which were normalized by vitamin D-3 supplementation. Conclusion This work brought to light the beneficial effects of cholecalciferol supplementation, in secondary prevention, on cardiac remodeling and function in a mouse model of diet-induced type 2 diabetes. Those cardioprotective effects may be, at least in part, attributed to the modulation of myocardial levels of lipotoxic species by vitamin D