Role of micro-RNAs associated with adipose-derived extracellular vesicles in metabolic disorders.

Micro-RNAs have emerged as important actors in the onset of metabolic disorders including obesity or type 2 diabetes. Particularly, several micro-RNAs are known to be key modulators of lipid metabolism, glucose homeostasis, or feeding behavior. Interestingly, the role of extracellular vesicles containing micro-RNAs, especially adipose-derived extracellular vesicles, are well-documented endocrine signals and disease biomarkers. However, the role of adipose-derived extracellular vesicles on the different tissues is different and highly related to the micro-RNA content. This review provides recent data about the potential involvement of adipose-derived extracellular vesicle-containing micro-RNAs in metabolic diseases.

Vitamin D metabolism is altered during aging alone or combined with obesity in male mice.

Aging and obesity are associated with a decrease in plasma 25-hydroxyvitamin D (25(OH)D) levels. In the context of a growing aging population and the rising incidence of obesity, we hypothesized that aging process, either independently or in combination with obesity, could influence vitamin D (VD) metabolism, consequently resulting in the reduced 25(OH)D plasma concentrations. C57BL/6JRJ young (6 months) and old (23 months) mice fed with control (CD) or high fat diet (HF) were compared. Plasma and adipose concentration of cholecalciferol and 25(OH)D and mRNA expression of genes coding for the main VD actors were analyzed. Aging was associated with a decrease in plasma 25(OH)D levels, whereas combined effect of obesity and aging did not generate a cumulative effect on plasma 25(OH)D levels. The mRNA expression of Cyp27a1, Cyp3a11, and Cyp2j6 were decreased in the liver during aging. Together, these regulations could explain the reduced 25-hydroxylation. Interestingly, the lack of cumulative reduction of 25(OH)D in aged and obese mice could be related to the strong induction of Cyp2j6. In kidneys, a complex modulation of Cyp27b1 and Cyp24a1 could contribute to the reduced 25-hydroxylation in the liver. In white adipose tissue, an induction of Cyp2r1 was observed during aging and obesity, together with an increase of 25(OH)D quantity, suggesting an exacerbated storage that may participated to the reduced plasma 25(OH)D levels. These findings support the notion that aging alone or combined with obesity, induces regulation of VD metabolism in the organs, beyond the classical reduction of epidermal VD precursor, which may contribute to the decrease in 25(OH)D levels.

Vitamin D Modulates Lipid Composition of Adipocyte-Derived Extracellular Vesicles Under Inflammatory Conditions.

SCOPE: Adipocyte-derived extracellular vesicles (AdEVs) convey lipids that can play a role in the energy homeostasis. Vitamin D (VD) has been shown to limit the metabolic inflammation as it decreases inflammatory markers expression in adipose tissue (AT). However, VD effect on adipocytes-derived EVs has never been investigated. METHODS AND RESULTS: Thus, the aim of this study is to evaluate the AdEVs lipid composition by LC-MS/MS approach in 3T3-L1 cells treated with VD or/and pro-inflammatory factor (tumor necrosis factor α [TNFα]). Among all lipid species, four are highlighted (glycerolipids, phospholipids, lysophospholipids, and sphingolipids) with a differential content between small (sEVs) and large EVs (lEVs). This study also observes that VD alone modulates EV lipid species involved in membrane fluidity and in the budding of membrane. EVs treated with VD under inflammatory conditions have different lipid profiles than the control group, which is more pronounced in lEVs. Indeed, 25 lipid species are significantly modulated in lEVs, compared with only seven lipid species in sEVs. CONCLUSIONS: This study concludes that VD, alone or under inflammatory conditions, is associated with specific lipidomic signature of sEVs and lEVs. These observations reinforce current knowledge on the anti-inflammatory effect of VD.

Proposal of a bioinformatics approach to predict molecular mechanisms involved in inflammatory response: case of ATRA and 1,25(OH)2D in adipocytes.

Several inflammatory markers such as cytokines, chemokines, and microRNAs (miRNAs) are well known to be induced during obesity and are strongly linked to their comorbidities. Among many others factors, the micronutrient status is suspected to reduce obesity-associated inflammation via blunting inflammatory signalling pathways. This is notably the case for active forms of vitamin A (all-trans retinoic acid ATRA) and vitamin D (1,25(OH)2D) as previously shown. In the present study, we aimed to implement a new bioinformatics approach to unveil commonly regulated signalling pathways through a combination of gene and miRNA expression sets impacted by ATRA and 1,25(OH)2D in adipocytes. In a first set of experiments, we focused only our attention on ATRA and demonstrated that it reduced LPS-mediated miRNA expression (miR-146a, miR-150, and miR-155) in mouse adipose tissue, in adipocyte cultures, and in adipocyte-derived vesicles. This result was confirmed in TNFα-induced miRNA in human adipocytes. Then, bioinformatic analysis highlighted that both ATRA and 1,25(OH)2D-regulated genes and miRNA converge to the canonical 'nuclear factor Kappa B (NF-κB) signalling pathway.' Altogether, these results showed that ATRA has anti-inflammatory effects on miRNA expression. In addition, the proposed bioinformatic model converges to NF-κB signalling pathway that has been previously demonstrated to be regulated by ATRA and 1,25(OH)2D, thus confirming the interest of such approach.