Beta-Carotene Reduces Body Adiposity of Mice via BCMO1

Evidence from cell culture studies indicates that β-carotene-(BC)-derived apocarotenoid signaling molecules can modulate the activities of nuclear receptors that regulate many aspects of adipocyte physiology. Two BC metabolizing enzymes, the BC-15,15′-oxygenase (Bcmo1) and the BC-9′,10′-oxygenase (Bcdo2) are expressed in adipocytes. Bcmo1 catalyzes the conversion of BC into retinaldehyde and Bcdo2 into β-10′-apocarotenal and β-ionone. Here we analyzed the impact of BC on body adiposity of mice. To genetically dissect the roles of Bcmo1 and Bcdo2 in this process, we used wild-type and Bcmo1-/- mice for this study. In wild-type mice, BC was converted into retinoids. In contrast, Bcmo1-/- mice showed increased expression of Bcdo2 in adipocytes and β-10′-apocarotenol accumulated as the major BC derivative. In wild-type mice, BC significantly reduced body adiposity (by 28%), leptinemia and adipocyte size. Genome wide microarray analysis of inguinal white adipose tissue revealed a generalized decrease of mRNA expression of peroxisome proliferator-activated receptor γ (PPARγ) target genes. Consistently, the expression of this key transcription factor for lipogenesis was significantly reduced both on the mRNA and protein levels. Despite β-10′-apocarotenoid production, this effect of BC was absent in Bcmo1-/- mice, demonstrating that it was dependent on the Bcmo1-mediated production of retinoids. Our study evidences an important role of BC for the control of body adiposity in mice and identifies Bcmo1 as critical molecular player for the regulation of PPARγ activity in adipocyte

Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: a literature review

Purpose: Given that the relationship between vitamin D status and metabolic diseases such as obesity and type 2 diabetes (T2D) remains unclear, this review will focus on the genetic associations, which are less prone to confounding, between vitamin D-related single nucleotide polymorphisms (SNPs) and metabolic diseases. Methods: A literature search of relevant articles was performed on PubMed up to December 2019. Those articles that had examined the association of vitamin D-related SNPs with obesity and/or T2D were included. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. In total, 73 articles were included in this review. Results: There is a lack of research focussing on the association of vitamin D synthesis-related genes with obesity and T2D; however, the limited available research, although inconsistent, is suggestive of a protective effect on T2D risk. While there are several studies that investigated the vitamin D metabolism-related SNPs, the research focussing on vitamin D activation, catabolism and transport genes is limited. Studies on CYP27B1, CYP24A1 and GC genes demonstrated a lack of association with obesity and T2D in Europeans; however, significant associations with T2D were found in South Asians. VDR gene SNPs have been extensively researched; in particular, the focus has been mainly on BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and FokI (rs2228570) SNPs. Even though the association between VDR SNPs and metabolic diseases remain inconsistent, some positive associations showing potential effects on obesity and T2D in specific ethnic groups were identified. Conclusion: Overall, this literature review suggests that ethnic-specific genetic associations are involved. Further research utilizing large studies is necessary to better understand these ethnic-specific genetic associations between vitamin D deficiency and metabolic diseases

Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors

International audienc

Cholesterol dependent downregulation of mouse and human apical sodium dependent bile acid transporter (ASBT) gene expression: molecular mechanism and physiological consequences

BACKGROUND AND AIMS: Faecal bile acid elimination greatly contributes to cholesterol homeostasis. Synthesised from cholesterol in the liver, bile acids are actively reclaimed in the ileum by the apical sodium dependent bile acid transporter (ASBT). Although the expression level of ASBT affects body cholesterol balance, the impact of cholesterol on ASBT gene expression remains unclear. In this study, the effect of cholesterol on ASBT expression and ileal bile acid uptake was explored in vivo and in vitro. METHODS: ASBT gene expression was assessed by real time quantitative polymerase chain reaction and northern or western blotting, or both, in mice subjected to a 2% cholesterol diet for two weeks, in mouse ileal explants, or in human enterocyte‐like Caco‐2 cells cultured in sterol enriched or depleted media. Bile acid uptake was determined by measuring [(3)H]‐taurocholic acid influx into in situ isolated ileal loops from mice or into differentiated Caco‐2 cells. Molecular analysis of mouse and human ASBT promoters was undertaken with reporter assays, site directed mutagenesis, and electrophoretic mobility shift assays. RESULTS: In mice, cholesterol enriched diet triggered a downregulation of ASBT expression (mRNA and protein), a fall in ileal bile acid uptake, and a rise in the faecal excretion of bile acids. This effect was direct as it was reproduced ex vivo using mouse ileal explants and in vitro in differentiated Caco‐2 cells. CONCLUSIONS: This regulation, which involves an original partnership between SREBP‐2 and HNF‐1α transcription factors, affects ileal bile acid recycling and thus might participate in the maintenance of body cholesterol homeostasis

ß-carotene conversion products and their effects on adipose tissue

Recent epidemiological data suggest that ß-carotene may be protective against metabolic diseases in which adipose tissue plays a key role. Adipose tissue constitutes the major ß-carotene storage tissue and its functions have been shown to be modulated in response to ß-carotene breakdown products, especially retinal produced after cleavage by ß-carotene 15,15'-monooxygenase (BCMO1), and retinoic acid arising from oxidation of retinal. However, the possibility exists that ß-carotene in its intact form can also affect adipocyte function. Development of a knock out model and identification of a loss-of-function mutation have pointed out BCMO1 as being probably the sole enzyme responsible for provitamin A conversion into retinal in mammals. The utilisation of BCMO1-/-mice should provide insights on ß-carotene effect on its own in the future. In humans, intervention studies have highlighted the huge interindividual variation of ß-carotene conversion efficiency, possibly due to genetic polymorphisms, which might impact on response to ß-carotene. This brief review discusses the processes involved in ß-carotene conversion and the effect of cleavage products on body fat and adipose tissue functio

Gene expression response of mouse lung, liver and white adipose tissue to ß-carotene supplementation, knockout of Bcmo1 and sex.

Scope: Little information is available on differences, commonalities and especially interactions in overall gene expression responses as a result of diet, differences in sex (male and female) and effects induced by differences in metabolism. Moreover, it is unknown whether such effects are tissue specific. Methods and results: We investigated the gene expression effects induced by beta-carotene (BC) supplementation, knockout of beta-carotene 15,15'-monooxygenase 1 (Bcmo1) and differences between male and female mice in lung, liver and inguinal white adipose tissue (iWAT). Unsupervised principal component analysis showed that lung gene expression was most affected by knockout of Bcmo1. Liver was most affected by knockout of Bcmo1 and differences in sex. iWAT was most affected by differences in sex. Hardly any genes were commonly influenced by BC among the three tissues. The effect of BC supplementation and knockout of Bcmo1 were relatively sex specific, especially in iWAT. Conclusion: These data demonstrate that gene expression differences induced by BC are limited to the tissue and sex that is analyzed, and that differences in metabolism induced by for example single nucleotide polymorphisms, should be taken into account as much as possible. Moreover, our results indicate that translation from one tissue to the other should be done with caution for any nutritional intervention

Relationship of cardiac remodeling and perfusion alteration with hepatic lipid metabolism in a prediabetic high fat high sucrose diet female rat model

Background and Aims: Cardiovascular disease (CVD) is known to be linked with metabolic associated fatty liver disease and type 2 diabetes, but few studies assessed this relationship in prediabetes, especially among women, who are at greater risk of CVD. We aimed to evaluate cardiac alterations and its relationship with hepatic lipid metabolism in prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). Methods and Results: Wistar female rats were divided into 2 groups fed for 5 months with standard or HFS diet. We analyzed cardiac morphology, function, perfusion and fibrosis by Magnetic Resonance Imaging. Hepatic lipid contents along with inflammation and lipid metabolism gene expression were assessed. Five months of HFS diet induced glucose intolerance (p<0.05), cardiac remodeling characterized by increased left-ventricular volume, wall thickness and mass (p<0.05). No significant differences were found in left-ventricular ejection fraction and cardiac fibrosis but increased myocardial perfusion (p<0.01) and reduced cardiac index (p<0.05) were shown. HFS diet induced hepatic lipid accumulation with increased total lipid mass (p<0.001) and triglyceride contents (p<0.05), but also increased mitochondrial (CPT1a, MCAD; (p<0.001; p<0.05) and peroxisomal (ACO, LCAD; (p<0.05; p<0.001) β-oxidation gene expression. Myocardial wall thickness and perfusion were correlated with hepatic β-oxidation genes expression. Furthermore, myocardial perfusion was also correlated with hepatic lipid content and glucose intolerance. Conclusion: This study brings new insights on the relationship between cardiac su