Julien Astier

Vitamin D reduces the inflammatory response and restores glucose uptake in adipocytes.

SCOPE Obesity is strongly associated with low-grade inflammation, notably due to an overproduction of proinflammatory markers by adipose tissue and adipocytes as well as a vitamin D deficiency. Whether these problems are interrelated has not been clearly established. METHODS AND RESULTS In the present report, decreases in the levels of inflammatory markers such as IL-6, MCP-1, and IL-1β (mRNA and protein level) in human adipocytes and in 3T3-L1 adipocytes were observed after 1,25-dihydroxyvitamin D3 (1,25-(OH)(2) D(3) ) treatment. Such treatment also decreased the expression of the TNF-α-mediated proinflammatory marker in 3T3-L1 and human adipocytes. A similar effect was observed in adipocyte-macrophage co-culture systems in which 1,25-(OH)(2) D(3) decreased proinflammatory marker expression under basal and TNF-α-stimulated conditions. The involvement of VDR and NF-κB was confirmed in these regulations. Incubation with 1,25-(OH)(2) D(3) also resulted in the dephosphorylation of p38, which is linked to the transcriptional induction of several Dusp family members. Functional consequences of the 1,25-(OH)(2) D(3) treatment on glucose uptake and AKT phosphorylation were observed. CONCLUSION The improvement of both proinflammatory status and glucose uptake in adipocytes under 1,25-(OH)(2) D(3) effect suggests that low-grade inflammation could be linked to vitamin D deficiency. This observation offers new perspectives in the context of obesity and associated physiopathological disorders.

Vitamin D protects against diet-induced obesity by enhancing fatty acid oxidation

Prospective studies reported an inverse correlation between 25-hydroxyvitamin D [25(OH)D] plasma levels and prevalence of obesity and type 2 diabetes. In addition, 25(OH)D status may be a determinant of obesity onset. However, the causality between these observations is not yet established. We studied the preventive effect of vitamin D3 (VD3) supplementation (15,000 IU/kg of food for 10 weeks) on onset of obesity in a diet-induced obesity mouse model. We showed that the VD3 supplementation limited weight gain induced by high-fat diet, which paralleled with an improvement of glucose homeostasis. The limitation of weight gain could further be explained by an increased lipid oxidation, possibly due to an up-regulation of genes involved in fatty acid oxidation and mitochondrial metabolism, leading to increased energy expenditure. Altogether, these data show that VD3 regulates energy expenditure and suggest that VD3 supplementation may represent a strategy of preventive nutrition to fight the onset of obesity and associated metabolic disorders.

Chemokine Expression in Inflamed Adipose Tissue Is Mainly Mediated by NF-κB

Immune cell infiltration of expanding adipose tissue during obesity and its role in insulin resistance has been described and involves chemokines. However, studies so far have focused on a single chemokine or its receptor (especially CCL2 and CCL5) whereas redundant functions of chemokines have been described. The objective of this work was to explore the expression of chemokines in inflamed adipose tissue in obesity. Human and mouse adipocytes were analyzed for expression of chemokines in response to inflammatory signal (TNF-α) using microarrays and gene set enrichment analysis. Gene expression was verified by qRT-PCR. Chemokine protein was determined in culture medium with ELISA. Chemokine expression was investigated in human subcutaneous adipose tissue biopsies and mechanism of chemokine expression was investigated using chemical inhibitors and cellular and animal transgenic models. Chemokine encoding genes were the most responsive genes in TNF-α treated human and mouse adipocytes. mRNA and protein of 34 chemokine genes were induced in a dose-dependent manner in the culture system. Furthermore, expression of those chemokines was elevated in human obese adipose tissue. Finally, chemokine expression was reduced by NF-κB inactivation and elevated by NF-κB activation. Our data indicate that besides CCL2 and CCL5, numerous other chemokines such as CCL19 are expressed by adipocytes under obesity-associated chronic inflammation. Their expression is regulated predominantly by NF-κB. Those chemokines could be involved in the initiation of infiltration of leukocytes into obese adipose tissue.

All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes.

A positive effect of all-trans retinoic acid (ATRA) on white adipose tissue (WAT) oxidative and thermogenic capacity has been described and linked to an in vivo fat-lowering effect of ATRA in mice. However, little is known about the effects of ATRA on mitochondria in white fat. Our objective has been to characterize the effect of ATRA on mitochondria biogenesis and oxidative phosphorylation (OXPHOS) capacity in mature white adipocytes. Transcriptome analysis, oxygraphy, analysis of mitochondrial DNA (mtDNA), and flow cytometry-based analysis of mitochondria density were performed in mature 3T3-L1 adipocytes after 24 h incubation with ATRA (2 µM) or vehicle. Selected genes linked to mitochondria biogenesis and function and mitochondria immunostaining were analyzed in WAT tissues of ATRA-treated as compared with vehicle-treated mice. ATRA upregulated the expression of a large set of genes linked to mtDNA replication and transcription, mitochondrial biogenesis, and OXPHOS in adipocytes, as indicated by transcriptome analysis. Oxygen consumption rate, mtDNA content, and staining of mitochondria were increased in the ATRA-treated adipocytes. Similar results were obtained in WAT depots of ATRA-treated mice. We conclude that ATRA impacts mitochondria in adipocytes, leading to increased OXPHOS capacity and mitochondrial content in these cells.

Vitamin D limits chemokine expression in adipocytes and macrophage migration in vitro and in male mice.

Vitamin D (VD) displays immunoregulatory effects and reduces adipocyte inflammation, which may participate to a reduction of adipose tissue macrophage infiltration in the context of obesity-associated low-grade inflammation. These observations have been described mainly in vitro, through the evaluation of a limited number of inflammatory markers. Here, we studied the effects of 1,25 dihydroxy-VD on chemokine network expression in adipocytes (by transcriptomic approach), and we confirm the physiological relevance of these data in vivo, by demonstrating the effect of VD on cytokine and chemokine gene expression as well as on macrophage infiltration in adipose tissue. 1,25 dihydroxy-VD down-regulated (-1.3- to -10.8-fold) the mRNA expression of 29 chemokines and limited macrophage migration in TNFα-conditioned adipocyte medium (1.5-fold; P < .05). This effect was associated with a reduction in p65 and IκB (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha) phosphorylation (2-fold compared with TNFα; P < .05). The effects of VD were confirmed in mice injected ip with lipopolysaccharide (acute inflammation) and diet-induced obese mice (metabolic inflammation), where the levels of mRNA encoding proinflammatory cytokines and chemokines (∼2-fold) were reduced in adipocytes (acute and metabolic inflammation) and adipose tissue and that macrophage infiltration was also inhibited in the adipose tissue of obese mice (metabolic inflammation). Altogether, these results showed that VD displayed a global immunoregulatory impact on adipocytes, notably via the inhibition of chemokine expression and macrophage infiltration in inflamed adipose tissue.

Lycopene and tomato powder supplementation similarly inhibit high‐fat diet induced obesity, inflammatory response, and associated metabolic disorders

SCOPE Several studies have linked the high intake of lycopene or tomatoes products with lower risk for metabolic diseases. The aim of the present study was to evaluate and to compare the effect of lycopene and tomato powder on obesity-associated disorders. METHODS AND RESULTS Male C57BL/J6 mice were assigned into four groups to receive: control diet (CD), high fat diet (HFD), high fat diet supplemented with lycopene or with tomato powder (TP) for 12 weeks. In HFD condition, lycopene and TP supplementation significantly reduced adiposity index, organ, and relative organ weights, serum triglycerides, free fatty acids, 8-iso-prostaglandin GF2α and improved glucose homeostasis, but did not affect total body weight. Lycopene and TP supplementation prevented HFD-induced hepatosteatosis and hypertrophy of adipocytes. Lycopene and TP decreased HFD-induced proinflammatory cytokine mRNA expression in the liver and in the epididymal adipose tissue. The anti-inflammatory effect of lycopene and TP was related to a reduction in the phosphorylation levels of IκB, and p65, and resulted in a decrease of inflammatory proteins in adipose tissue. CONCLUSION These results suggest that lycopene or TP supplementation display similar beneficial health effects that could be particularly relevant in the context of nutritional approaches to fight obesity-associated pathologies.

Visfatin is involved in TNFα-mediated insulin resistance via an NAD+/Sirt1/PTP1B pathway in 3T3-L1 adipocytes

Tumor necrosis factor α (TNFα) is a well-known mediator of inflammation in the context of obesity in adipose tissue. Its action appears to be directly linked to perturbations of the insulin pathway, leading to the development of insulin resistance. Visfatin has been suspected to be linked to insulin sensitivity, but the mechanism involved is still partly unknown. The aim of this study was to evaluate the role of visfatin in the impairment of the insulin pathway by TNFα activity in 3T3-L1 adipocytes and to unveil the mechanisms involved in such impairment. We demonstrated in 3T3-L1 adipocytes that visfatin was involved in TNFα-mediated insulin resistance in adipocytes. Indeed, after TNFα treatment in 3T3-L1 cells, visfatin was downregulated, leading to decreased nicotinamide adenine dinucleotide (NAD+) concentrations in cells. This decrease was followed by a decrease in Sirt1 activity, which was linked to an increase in PTP1B expression. The modulation of PTP1B by visfatin was likely responsible for the observed decreases in glucose uptake and Akt phosphorylation in 3T3-L1 adipocytes. Here, we demonstrated a complete pathway involving visfatin, NAD+, Sirt1, and PTP1B that led to the perturbation of insulin signaling by TNFα in 3T3-L1 adipocytes.

All-trans-retinoic acid represses chemokine expression in adipocytes and adipose tissue by inhibiting NF-κB signaling ☆

An effect of the Vitamin A metabolite all-trans-retinoic acid (ATRA) on body weight regulation and adiposity has been described, but little is known about its impact on obesity-associated inflammation. Our objective was to evaluate the overall impact of this metabolite on inflammatory response in human and mouse adipocytes, using high-throughput methods, and to confirm its effects in a mouse model. ATRA (2 μM for 24 h) down-regulated the mRNA expression of 17 chemokines in human adipocytes, and limited macrophage migration in a TNFα-conditioned 3 T3-L1 adipocyte medium (73.7%, P<.05). These effects were confirmed in mice (n=6-9 per group) subjected to oral gavage of ATRA (5 mg/kg of body weight) and subsequently injected intraperitoneally with lipopolysaccharide. In this model, both systemic and adipose levels of inflammatory markers were reduced. The antiinflammatory effect of ATRA was associated with a reduction in the phosphorylation levels of IκB and p65 (~50%, P<.05), two subunits of the NF-κB pathway, probably mediated by PGC1α, in 3 T3-L1 adipocytes. Taken together, these results show a significant overall antiinflammatory effect of ATRA on proinflammatory cytokine and chemokine production in adipocyte and adipose tissue and suggest that ATRA supplementation may represent a strategy of preventive nutrition to fight against obesity and its complications.

Vitamin D limits inflammation-linked microRNA expression in adipocytes in vitro and in vivo: A new mechanism for the regulation of inflammation by vitamin D.

ABSTRACT Inflammation of adipose tissue is believed to be a contributing factor to many chronic diseases associated with obesity. Vitamin D (VD) is now known to limit this metabolic inflammation by decreasing inflammatory marker expression and leukocyte infiltration in adipose tissue. In this study, we investigated the impact of VD on microRNA (miR) expression in inflammatory conditions in human and mouse adipocytes, using high-throughput methodology (miRNA PCR arrays). Firstly, we identified three miRs (miR-146a, miR-150, and miR-155) positively regulated by TNFα in human adipocytes. Interestingly, the expression of these miRs was strongly prevented by 1,25(OH)2D preincubation. These results were partly confirmed in 3T3-L1 adipocytes (for miR-146a and miR-150). The ability of VD to control the expression of these miRs was confirmed in diet-induced obese mice: the levels of the three miRs were increased following high fat (HF) diet in epididymal white adipose tissue and reduced in HF diet fed mice supplemented with VD. The involvement of NF-κB signaling in the induction of these miRs was confirmed in vitro and in vivo using aP2-p65 transgenic mice. Finally, the ability of VD to deactivate NF-κB signaling, via p65 and IκB phosphorylation inhibition in murine adipocyte, was observed and could constitute a driving molecular mechanism. This study demonstrated for the first time that VD modulates the expression of miRs in adipocytes in vitro and in adipose tissue in vivo through its impact on NF-κB signaling pathway, which could represent a new mechanism of regulation of inflammation by VD.

Hemodialysis patients with diabetes eat less than those without: a plea for a permissive diet

The main cause of malnutrition in haemodialysis patients is a spontaneous decline in energy and protein intakes. This study aims to report the dietary energy intake (DEI), dietary protein intake (DPI), and dietary micronutrient intake in a French HD population, to report factors associated with a low DPI and DEI, and to analyze if nutritional intake was correlated with nutritional status.