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)D 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.

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 4 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 pro-inflammatory cytokine mRNA expression in the liver and in the epididymal adipose tissue. The antiinflammatory 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.

The BMP2/4 antagonist and novel adipokine Gremlin 1 is highly expressed in human adipose cells and increased in hypertrophic obesity. As a secreted antagonist, it inhibits the effect of BMP2/4 on adipose precursor cell commitment/differentiation. We examined mRNA levels of Gremlin 1 in key target tissues for insulin and also measured tissue and serum levels in several carefully phenotyped human cohorts. Gremlin 1 expression was high in adipose tissue, higher in visceral than in subcutaneous tissue, increased in obesity, and further increased in type 2 diabetes (T2D). A similar high expression was seen in liver biopsies, but expression was considerably lower in skeletal muscles. Serum levels were increased in obesity but most prominently in T2D. Transcriptional activation in both adipose tissue and liver as well as serum levels were strongly associated with markers of insulin resistance in vivo (euglycemic clamps and HOMA of insulin resistance), and the presence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We also found Gremlin 1 to antagonize insulin signaling and action in human primary adipocytes, skeletal muscle, and liver cells. Thus, Gremlin 1 is a novel secreted insulin antagonist and biomarker as well as a potential therapeutic target in obesity and its complications T2D and NAFLD/NASH.

Cross-sectional studies depict an inverse relationship between vitamin D (VD) status reflected by plasma 25-hydroxy-vitamin D and obesity. Furthermore, recent studies in vitro and in animal models tend to demonstrate an impact of VD and VD receptor on adipose tissue and adipocyte biology, pointing to at least a part-causal role of VD insufficiency in obesity and associated physiopathological disorders such as adipose tissue inflammation and subsequent insulin resistance. However, clinical and genetic studies are far less convincing, with highly contrasted results ruling out solid conclusions for the moment. Nevertheless, prospective studies provide interesting data supporting the hypothesis of a preventive role of VD in onset of obesity. The aim of this review is to summarise the available data on relationships between VD, adipose tissue/adipocyte physiology, and obesity in order to reveal the next key points that need to be addressed before we can gain deeper insight into the controversial VD-obesity relationship.Adipose tissue: Vitamin D: Obesity: Inflammation: Adipocytes: Nutrients: Nutrition Vitamin D: a brief overview Vitamin D (VD; calciferol) is a hormone mainly described for its role as a regulator of phosphate and calcium homeostasis (1) . It can be obtained through animal (VD 3 , cholecalciferol) or plant (VD 2 , ergocalciferol) food sources. Only a few foodstuffs contain significant amounts of VD, the main sources being fish liver oils, fatty fish (sardines, herring and mackerel) and egg yolk (2,3) , but small quantities are also found in fortified milk, orange juice, bread and cereals. Alternatively, VD 3 is produced endogenously in the skin after UVB irradiation from the precursor 7-dehydrocholesterol to give pre-VD 3 , which is further isomerised to VD 3 before being released into the circulation (4) . Classical estimates have assigned a majority (70-90 %) of VD supply to dermal synthesis, but a recent paper revised this figure down to just 10-25 % of VD supply (5) and posited that dietary intake of 25-hydroxy-vitamin D (25(OH)D) is a significant contributor to total VD input.Adipose tissue is a major storage site for vitamin D Despite limited data, it is widely accepted that adipose tissue is a reservoir for VD in human subjects and rats (6)(7)(8)(9)(10) . Interestingly, visceral fat was found to contain 20 % more VD than subcutaneous fat (11) . Heaney et al. (12) calculated that 65 % of total VD in the body is in the form of D 3 , for which adipose tissue and skeletal muscle appear to be the main body stores (accounting for 73 and 16 %, respectively).

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Low circulating levels of total and free 25-hydroxyvitamin D (25(OH)D) indicative of vitamin D status have been associated with obesity in humans. Moreover, obesity is thought to play a causal role in the reduction of 25(OH)D levels, and several theories have been put forward to explain this relationship. Here we tested the hypothesis that obesity disrupts vitamin D homeostasis in key organs of vitamin D metabolism. Male C57BL6 mice were fed for 7 or 11 weeks on either a control diet (control, 10% energy from fat) or a high-fat diet (HF, 60% energy from fat) formulated to provide equivalent vitamin D3 intake in both groups. After 7 weeks, there was a transient increase of total 25(OH)D together with a significant decrease of plasma vitamin D3 that could be related to the induction of hepatic genes involved in 25-hydroxylation. After 11 weeks, there was no change in total 25(OH)D but a significant decrease of free 25(OH)D and plasma vitamin D3 levels. We also quantified an increase of 25(OH)D in adipose tissue that was inversely correlated to the free 25(OH)D. Interestingly, this accumulation of 25(OH)D in adipose tissue was highly correlated to the induction of Cyp2r1, which could actively participate in vitamin D3 trapping and subsequent conversion to 25(OH)D in adipose tissue. Taken together, our data strongly suggest that the enzymes involved in vitamin D metabolism, notably in adipose tissue, are transcriptionally modified under high-fat diet, thus contributing to the obesity-related reduction of free 25(OH)D.

Scope Although about 90% of lycopene in dietary sources occurs in the linear all‐trans conformation, a large proportion of the lycopene found in human tissues is of the cis‐isomer type, notably (5Z)‐lycopene. The biological effects of this (5Z) isomer have been under‐researched. The aim of this study is to evaluate some biological functions of (5Z)‐lycopene in adipocytes and to compare them with those of (all‐E)‐lycopene. Methods and results (all‐E)‐ and (5Z)‐Lycopene displayed strong similarities in global gene expression profile and biological pathways impacted. Peroxisome proliferator‐activated receptor (PPAR) signaling is identified as a major actor mediating the effects of lycopene isomers. Transactivation assays confirmed the ability of both isomers to transactivate PPARγ. In addition, the TNFα‐induced proinflammatory cytokine mRNA expression in 3T3‐L1 adipocytes is reduced by both isomers via a reduction in the phosphorylation levels of p65. Finally, lycopene isomers restore the TNF‐α‐blunted uptake of glucose by adipocytes via a modulation of AKT phosphorylation. Conclusion These results show that lycopene isomers exert similar biological functions in adipocytes, linked to their ability to transactivate PPARγ. These findings add to our knowledge of lycopene effects in adipocyte biology and point to the possible use of lycopene in the prevention of obesity‐related disorders.

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