The 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.

No abstract

Scope A main risk factor of atherosclerosis is a Western diet (WD) rich in n‐6 polyunsaturated fatty acids (PUFAs) sensitive to oxidation. Their oxidation can be initiated by heme iron of red meat leading to the formation of 4‐hydroxy‐2‐nonenal (4‐HNE), a cytotoxic aldehyde. An increased 4‐HNE production is implicated in endothelial dysfunction and atherosclerosis. By contrast, a diet rich in proanthocyanidins reduces oxidative stress and arterial diseases. This study evaluates the effects of a WD on vascular integrity in ApolipoproteinE (ApoE−/−) mice and the protective capacity of apple extract and puree rich in antioxidant proanthocyanidins. Methods and results ApoE‐/‐ mice are fed during 12 weeks with a WD with or without n‐6 PUFAs. Moreover, two WD + n‐6 PUFAs groups are supplemented with apple puree or phenolic extract. An increase in digestive 4‐HNE production associated with a rise in plasmatic 4‐HNE and oxidized LDL concentrations is reported. Oxidizable n‐6 PUFAs consumption is associated with a worsened endothelial dysfunction and atherosclerosis. Interestingly, supplementations with apple polyphenol extract or puree prevented these impairments while reducing oxidative stress. Conclusion n‐6 lipid oxidation during digestion may be a key factor of vascular impairments. Nevertheless, an antioxidant strategy can limit 4‐HNE formation during digestion and thus durably protect vascular function.

In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

Purpose: 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.