Prenatal maternal vitamin D deficiency sex-dependently programs adipose tissue metabolism and energy homeostasis in offspring.

In utero environment is crucial to ensure normal development of the fetus and to program metabolic health throughout the life. Beside macronutrients, the role of micronutrients, including vitamin D, begins to be explore. The aim of this study was to decipher the impact of maternal vitamin D deficiency (VDD), in normal and high-fat (HF) diet context, on adipose tissue metabolism and energy homeostasis in offspring, considering sex-specific responses. Body weight, energy expenditure, and spontaneous activity was differential impacted in juvenile male and female offspring born from VDD mice. In adulthood, a HF diet combined with maternal VDD disrupted glucose homeostasis and adiposity in male offspring but not in females. Such phenotypes were associated to different transcriptomic profiles in adipose tissue, which could be related to differential modulation of plasma 17ß-estradiol concentrations. Thus, maternal VDD sex-dependently modulated metabolic fate of the offspring, especially when associated with HF diet in adulthood.

Plasma Retinol Concentration Is Mainly Driven by Transthyretin in Hemodialysis Patients.

OBJECTIVE: Micronutrients deficiencies in hemodialysis patients are due to low dietary intakes and intradialytic losses for hydrophilic micronutrients. Conversely, lipophilic nondialyzable compounds might accumulate because of a lack of elimination through renal metabolism or dialysis. Other compounds have complex metabolism: their concentration is not explained by these phenomenons. The aim of this study was to report plasma concentrations of lipophilic micronutrients in hemodialysis patients and to analyze if these concentrations were predictive of mortality. DESIGN: The design was monocentric observational longitudinal study. SUBJECTS: A total of 123 hemodialysis patients included in this observational study. MAIN OUTCOME MEASURE: Plasma concentration of lipophilic micronutrients retinol and its two co-transporters transthyretin and retinol-binding protein 4, tocopherol, and carotenoids (α-carotene and ß-carotene, ß-cryptoxanthin, lycopene, lutein, and zeaxanthin), and all factors associated with 1-year mortality. RESULTS: Within the 123 patients of the study, median age (interquartile range) was 77.5 (69.5-84.5) years and 58.5% were male. Median retinol plasma concentration was 4.07 (2.65-5.51) µmol/L, and 91.9% of patient had high plasma retinol concentrations. In monovariate analysis, retinol levels were inversely correlated with mortality (hazard ratio = 0.57 [0.45-0.72]; P < .001). This effect remained significant after adjustment with several parameters. Nevertheless, the correlation between retinol and mortality disappeared as soon as transthyretin was added in the statistical model, suggesting an effect of transthyretin as confusing bias. Median tocopherol plasma concentration was 34.8 (28.3-42.9) µmol/L and 72.4% of patients had high plasma tocopherol concentration. Neither tocopherol plasma levels nor carotenoids concentrations were correlated with death in multivariate analysis. CONCLUSIONS: In hemodialysis patients, the correlation between retinol plasma concentration and mortality represents the nutritional status but not a direct biological effect of retinol. Retinol is only a surrogate predictor of mortality. It might not represent vitamin A levels, but likely the transthyretin level. Plasma retinol levels should be interpreted cautiously in hemodialysis patients.

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.

Structure factor model for understanding the measured backscatter coefficients from concentrated cell pellet biophantoms.

Ultrasonic backscatter coefficient (BSC) measurements were performed on K562 cell pellet biophantoms with cell concentrations ranging from 0.006 to 0.30 in the 10-42 MHz frequency bandwidth. Three scattering models, namely, the fluid-filled sphere model (FFSM), the particle model (PM), and the structure factor model (SFM), were compared for modeling the scattering from an ensemble of concentrated cells. A parameter estimation procedure was developed in order to estimate the scatterer size and relative impedance contrast that could explain the measured BSCs from all the studied cell concentrations. This procedure was applied to the BSC data from K562 cell pellet biophantoms in the 10-42 MHz frequency bandwidth and to the BSC data from Chinese hamster ovary cell pellet biophantoms in the 26-105 MHz frequency bandwidth given in Han, Abuhabsah, Blue, Sarwate, and O'Brien [J. Acoust. Soc. Am. 130, 4139-4147 (2011)]. The data fitting quality and the scatterer size estimates show that the SFM was more suitable than the PM and the FFSM for modeling the responses from concentrated cell pellet biophantoms.

CD36 and SR-BI are involved in cellular uptake of provitamin A carotenoids by Caco-2 and HEK cells, and some of their genetic variants are associated with plasma concentrations of these micronutrients in humans.

Scavenger receptor class B type I (SR-BI) and cluster determinant 36 (CD36) have been involved in cellular uptake of some provitamin A carotenoids. However, data are incomplete (e.g., there are no data on α-carotene), and it is not known whether genetic variants in their encoding genes can affect provitamin A carotenoid status. The objectives were 1) to assess the involvement of these scavenger receptors in cellular uptake of the main provitamin A carotenoids (i.e., ß-carotene, α-carotene, and ß-cryptoxanthin) as well as that of preformed vitamin A (i.e., retinol) and 2) to investigate the contribution of genetic variations in genes encoding these proteins to interindividual variations in plasma concentrations of provitamin A carotenoids. The involvement of SR-BI and CD36 in carotenoids and retinol cellular uptake was investigated in Caco-2 and human embryonic kidney (HEK) cell lines. The involvement of scavenger receptor class B type I (SCARB1) and CD36 genetic variants on plasma concentrations of provitamin A carotenoids was assessed by association studies in 3 independent populations. Cell experiments suggested the involvement of both proteins in cellular uptake of provitamin A carotenoids but not in that of retinol. Association studies showed that several plasma provitamin A carotenoid concentrations were significantly different (P < 0.0083) between participants who bore different genotypes at single nucleotide polymorphisms and haplotypes in CD36 and SCARB1. In conclusion, SR-BI and CD36 are involved in cellular uptake of provitamin A carotenoids, and genetic variations in their encoding genes may modulate plasma concentrations of provitamin A carotenoids at a population level.

Effect of type of TAG fatty acids on lutein and zeaxanthin bioavailability.

The xanthophylls lutein and zeaxanthin probably play a role in visual function and may participate in the prevention of age-related eye diseases. Although a minimum amount of TAG is required for an optimal bioavailability of these carotenoids, the effect of the type of TAG fatty acids (FA) is less clear. The aim was to assess the effect of the type of TAG FA on bioavailability of these xanthophylls. A total of three complementary models were used: an in vitro digestion model to study bioaccessibility, Caco-2 cells to study uptake efficiency and orally administered rats to study in vivo bioavailability. Results showed that lutein and zeaxanthin bioaccessibility was greater (about 20-30 %, P< 0·05) with butter and palm oil than with olive and fish oils. Mixed micelle size, which was significantly lower (about 8 %, P< 0·05) with SFA than with unsaturated FA, was inversely related to lutein and zeaxanthin bioaccessibility. There was no significant effect of the type of TAG FA on xanthophyll uptake by Caco-2 cells, but some compounds present in natural oils significantly affected xanthophyll uptake. Oral administration of rats with spinach and butter over 3 d led to a higher fasting plasma lutein concentration than oral administration with olive or fish oils. In conclusion, dietary fats rich in SFA lead to a higher bioavailability of lutein and zeaxanthin, as compared with fats rich in MUFA and PUFA. This is due partly to the higher bioaccessibility of these xanthophylls in the smaller mixed micelles produced when SFA are incorporated into mixed micelles.

Four days high fat diet modulates vitamin D metabolite levels and enzymes in mice.

Obesity is classically associated with low serum total and free 25(OH)D. Hypotheses have been advanced to explain this observation but mechanisms remain poorly understood, and notably priming events that could explain such association. We investigated the impact of short-term high fat (HF) diet to investigate early events occurring in vitamin D metabolism. Male C57BL/6J mice were fed with a control diet (control group) and HF diet for 4 days. HF fed mice displayed similar body weight to control mice but significantly increased adiposity, together with a decrease of free 25(OH)D concentrations, which could be explained at least in part by a decrease of Cyp2r1 and Cyp3a11 expression in the liver. An increase of 1,25(OH)2D concentration was also observed and could be explained by a decrease of Cyp24a1 expression observed in the kidney. In white adipose tissue (WAT), no modification of vitamin D metabolites quantity detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Nevertheless, an increase of Cyp2r1 and Cyp27a1 mRNA expression and a decrease of Cyp27b1 mRNA expression could suggest a possible storage of 25(OH)D in WAT at long-term. Our data are supportive of an active role of HF diet in mediating a priming effect leading the well-established perturbation of the vitamin D metabolism associated with obesity, including a decrease of free 25(OH)D and modulation of expression of genes involved in vitamin D metabolism.

Botanic Origin of Propolis Extract Powder Drives Contrasted Impact on Diabesity in High-Fat-Fed Mice.

Propolis extracts are considered as nutraceutical products with potentialities towards obesity and comorbidities management. Nevertheless, propolis extracts composition is highly variable and depends on the botanic origin of plants used by the bees to produce propolis. This study aims to evaluate the differential effect of poplar propolis extract powder (PPEP), Baccharis propolis extract powder (BPEP), and/ or Dalbergia propolis extract powder (DPEP) on obesity and glucose homeostasis in high-fat-fed mice. PPEP supplementation reduced high-fat (HF)-mediated body weight gain, adiposity index, and improved glucose homeostasis in male C57Bl/6J mice that were submitted to a high-fat diet for 12 weeks, whereas BPEP, DPEP, or a mix of the three PEPs did not modify those parameters. Adipose tissue (AT) gene expression profiling highlighted an induction of mRNA related to lipid catabolism and an inhibition of mRNA coding for inflammatory markers. Several Nrf2 target genes, coding for antioxidant enzymes, were induced in AT under PPEP effect, but not by other PEP. Interestingly, representative PPEP polyphenols mediated the induction of Nrf2 target genes cell-autonomously in adipocytes, suggesting that this induction may be related to the specific polyphenol content of PPEP. Whereas PPEP supplementation has demonstrated a clear potential to blunt the onset of obesity and associated comorbidities, other PEPs (from Baccharis and Dalbergia) were inefficient to support their role in preventive nutrition.

The Brassica napus (oilseed rape) seeds bioactive health effects are modulated by agronomical traits as assessed by a multi-scale omics approach in the metabolically impaired ob-mouse.

Beside oil, oilseed rape (Brassica napus) seeds contains nutritional bioactives such as polyphenols and glucosinolates. However, to date their nutritional properties have been overlooked in the new "double zero" breeds. Seed alcoholic extracts from two B. napus cultivars most contrasting in their phytochemical contents as measured by mass-spectrometry were given to ob-mice. Biological outcomes including clinical metrics, gut and plasma metabolomes, liver transcriptome and metabolome were compared to ob-mice given a similar broccoli extract (Brassica oleracea). One B. napus extract induced a reduction of the oxidative stress indicated by the decrease of plasma isoprostanoids. This was associated to the regulation of the antioxidant stress defense Nrf2 pathway, to 'omic' oxidative stress functions, metabolic and cell process regulations, and the metabolomics microbiota profile. Extracts of B. napus seeds demonstrated health effects that may be improved by selecting appropriate agronomical traits, highlighting the potential benefits of better utilizing agronomy for improved human and animal nutrition.

Poplar Propolis Ethanolic Extract Reduces Body Weight Gain and Glucose Metabolism Disruption in High-Fat Diet-Fed Mice.

SCOPE: Current evidence supports the beneficial effect of polyphenols on the management of obesity and associated comorbidities. This is the case for propolis, a polyphenol-rich substance produced by bees. The aim of the present study is to evaluate the effect of a poplar propolis ethanolic extract (PPEE) on obesity and glucose homeostasis, and to unveil its putative molecular mechanisms of action. METHODS AND RESULTS: Male high-fat (HF) diet-fed mice are administered PPEE for 12 weeks. PPEE supplementation reduces the HF-mediated adiposity index, adipocyte hypertrophy, and body weight gain. It also improves HOMA-IR and fasting glucose levels. Gene expression profiling of adipose tissue (AT) shows an induction of mRNA related to lipid catabolism and mitochondrial biogenesis and inhibition of mRNA coding for inflammatory markers. Interestingly, several Nrf2-target genes are induced in AT following administration of PPEE. The ability of PPEE to induce the expression of Nrf2-target genes is studied in adipocytes. PPEE is found to transactivate the Nrf2 response element and the Nrf2 DNA-binding, suggesting that part of the effect of PPEE can be mediated by Nrf2. CONCLUSION: PPEE supplementation may represent an interesting preventive strategy to tackle the onset of obesity and associated metabolic disorders.

A Probiotic Mixture Induces Anxiolytic- and Antidepressive-Like Effects in Fischer and Maternally Deprived Long Evans Rats.

A role of the gut microbiota in psychiatric disorders is supported by a growing body of literature. The effects of a probiotic mixture of four bacterial strains were studied in two models of anxiety and depression, naturally stress-sensitive Fischer rats and Long Evans rats subjected to maternal deprivation. Rats chronically received either the probiotic mixture (1.109 CFU/day) or the vehicle. Anxiety- and depressive-like behaviors were evaluated in several tests. Brain monoamine levels and gut RNA expression of tight junction proteins (Tjp) and inflammatory markers were quantified. The gut microbiota was analyzed in feces by 16S rRNA gene sequencing. Untargeted metabolite analysis reflecting primary metabolism was performed in the cecal content and in serum. Fischer rats treated with the probiotic mixture manifested a decrease in anxiety-like behaviors, in the immobility time in the forced swimming test, as well as in levels of dopamine and its major metabolites, and those of serotonin metabolites in the hippocampus and striatum. In maternally deprived Long Evans rats treated with the probiotic mixture, the number of entries into the central area in the open-field test was increased, reflecting an anxiolytic effect. The probiotic mixture increased Tjp1 and decreased Ifnγ mRNA levels in the ileum of maternally deprived rats. In both models, probiotic supplementation changed the proportions of several Operational Taxonomic Units (OTU) in the gut microbiota, and the levels of certain cecal and serum metabolites were correlated with behavioral changes. Chronic administration of the tested probiotic mixture can therefore beneficially affect anxiety- and depressive-like behaviors in rats, possibly owing to changes in the levels of certain metabolites, such as 21-deoxycortisol, and changes in brain monoamines.

Anti-Obesity Effect of Carotenoids: Direct Impact on Adipose Tissue and Adipose Tissue-Driven Indirect Effects.

This review summarizes current knowledge on the biological relevance of carotenoids and some of their metabolites in obesity management. The relationship between carotenoids and obesity is considered in clinical studies and in preclinical studies. Adipose tissue is a key organ in obesity etiology and the main storage site for carotenoids. We thus first describe carotenoid metabolism in adipocyte and adipose tissue and the effects of carotenoids on biological processes in adipose tissue that may be linked to obesity management in in vitro and preclinical studies. It is also now well established that the brain is strongly involved in obesity processes. A section is accordingly devoted to the potential effect of carotenoids on obesity via their direct and/or adipose tissue-driven indirect biological effects on the brain.

Quantification of trans-resveratrol and its metabolites in human plasma using ultra-high performance liquid chromatography tandem quadrupole-orbitrap mass spectrometry.

Trans-resveratrol is a stilbene polyphenol with a large spectrum of biological activities. This is why it is widely studied in terms of activities, bioavailability and quantitation in different foods, beverages and biological matrices. Different analytical methods are employed for its quantitation. In this study a quadrupole-orbitrap tandem mass spectrometer coupled to a reverse phase ultra-high performance liquid chromatography is applied to a quantitation of trans-resveratrol and its metabolites trans-resveratrol-3-O-ß-d-glucuronide, trans-resveratrol-4'-O-ß-d-glucuronide, trans-resveratrol-3-O-sulfate, a,b-dihydroresveratrol, a,b-dihydroresveratrol-glucuronide, a,b-dihydroresveratrol-glucuronide-sulfate, a,b-dihydroresveratrol-sulfate, trans-resveratrol-3,5-O-ß-d-diglucuronide, trans-resveratrol-3,4'-O-d-ß-diglucuronide, trans-resveratrol-3-O-ß-d-glucuronide-sulfate and trans-resveratrol-4'-O-ß-d-glucuronide-sulfate in human plasma. MS/MS experiments coupled to a high resolving power and accurate mass measurements as well as the use of labeled internal standards enabled the achievement of linear calibration curves across the four orders of magnitude concentration ranges. The method was validated in terms of specificity and selectivity, accuracy and precision, sensitivity and matrix effect and can be now applied to pharmacokinetic studies or routine analysis. In addition, the application of quadrupole-orbitrap mass spectrometer to the quantitation of trans-resveratrol and its metabolites provides acquisition of full collision induced dissociation spectra of analyzed compounds giving place to the structural characterization and sensitivity and linear concentration ranges respecting the accuracy and precision, specificity and selectivity requirements.

A Two-Week Treatment with Plant Extracts Changes Gut Microbiota, Caecum Metabolome, and Markers of Lipid Metabolism in ob/ob Mice.

SCOPE: Targeting gut microbiota dysbiosis by prebiotics is effective, though side effects such as abdominal bloating and flatulence may arise following high prebiotic consumption over weeks. The aim is therefore to optimize the current protocol for prebiotic use. METHODS AND RESULTS: To examine the prebiotic properties of plant extracts, two independent studies are conducted in ob/ob mice, over two weeks. In the first study, Porphyra umbilicalis and Melissa officinalis L. extracts are evaluated; in the second study, a high vs low dose of an Emblica officinalis Gaertn extract is assessed. These plant extracts affect gut microbiota, caecum metabolome, and induce a significant lower plasma triacylglycerols (TG) following treatment with P. umbilicalis and significantly higher plasma free fatty acids (FFA) following treatment with the low-dose of E. officinalis Gaertn. Glucose- and insulin-tolerance are not affected but white adipose tissue and liver gene expression are modified. In the first study, IL-6 hepatic gene expression is significantly (adjusted p = 0.0015) and positively (r = 0.80) correlated with the bacterial order Clostridiales in all mice. CONCLUSION: The data show that a two-week treatment with plant extracts affects the dysbiotic gut microbiota and changes both caecum metabolome and markers of lipid metabolism in ob/ob mice.

Diet induced obesity modifies vitamin D metabolism and adipose tissue storage in mice.

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.

(all-E)- and (5Z)-Lycopene Display Similar Biological Effects on Adipocytes.

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.

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.

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.

MicroRNAs are involved in the hypothalamic leptin sensitivity.

The central nervous system monitors modifications in metabolic parameters or hormone levels (leptin) and elicits adaptive responses such as food intake and glucose homeostasis regulation. Particularly, within the hypothalamus, pro-opiomelanocortin (POMC) neurons are crucial regulators of energy balance. Consistent with a pivotal role of the melanocortin system in the control of energy homeostasis, disruption of the Pomc gene causes hyperphagia and obesity. Pomc gene expression is tightly controlled by different mechanisms. Interestingly, recent studies pointed to a key role for micro ribonucleic acid (miRNAs) in the regulation of gene expression. However, the role of miRNAs in the leptin sensitivity in hypothalamic melanocortin system has never been assessed. We developed a transgenic mouse model (PDKO) with a partial deletion of the miRNA processing enzyme DICER specifically in POMC neurons. PDKO mice exhibited a normal body weight but a decrease of food intake. Interestingly, PDKO mice had decreased metabolic rate by reduction of VO2 consumption and CO2 production which could explain that PDKO mice have normal weight while eating less. Interestingly, we observed an increase of leptin sensitivity in the POMC neurons of PDKO mice which could explain the decrease of food intake in this model. We also observed an increase in the expression of genes involved in the function of brown adipose tissue that is in polysynaptic contact with the POMC neurons. In summary, these results support the hypothesis that Dicer-derived miRNAs may be involved in the effect of leptin on POMC neurons activity.

Gene Expression Pattern in Response to Cholecalciferol Supplementation Highlights Cubilin as a Major Protein of 25(OH)D Uptake in Adipocytes and Male Mice White Adipose Tissue.

It is well established that the active form of vitamin D (i.e., 1,25-dihydroxyvitamin D [1,25(OH)2D]) regulates the expression of genes involved in its own metabolism and transport in the kidney and possibly in the liver. However, little is known about the transcriptional impact of cholecalciferol supplementation on white adipose tissue (WAT) and adipocytes, which are a major site of vitamin D and 25-hydroxyvitamin D [25(OH)D] storage in the organism. To fill this gap, we investigated the impact of cholecalciferol supplementation in WAT via a panel of genes coding for enzymes and proteins involved in vitamin D metabolism and uptake. Mice supplemented with cholecalciferol (15,000 IU/kg of body weight per day) for 4 days showed decreased messenger RNA (mRNA) levels of proteins involved in cholecalciferol metabolism (Cyp24a1, Cyp27a1) and decreased cubilin mRNA levels in WAT. These data were partly confirmed in 3T3-L1 adipocytes incubated with 1,25(OH)2D. The downregulation of cubilin mRNA observed in WAT and in 3T3-L1 was confirmed at the protein level in WAT and at the mRNA level in human primary adipocytes. Vitamin D receptor (VDR) agonist (EB1089) and RNA interference approaches demonstrated that VDR was involved in this regulation. Furthermore, chemical inhibitor and RNA inference analysis demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes. This study established an overall snapshot of the genes regulated by cholecalciferol in mouse WAT and cell-autonomously in adipocytes. We highlighted that the regulation of cubilin expression was mediated by a VDR-dependent mechanism, and we demonstrated that cubilin was involved in 25(OH)D uptake by adipocytes.

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.