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  • In this study we report a novel

    2019-07-08

    In this study, we report a novel role of the intestinal vitamin D-VDR axis as an important metabolic regulator of obesity in mice. Using a villin promoter-driven human VDR transgene in a Vdr deficient background, we show that gut-specific VDR enhances weight gain, adipose tissue inflammation and the development of hepatic steatosis induced by high-fat diet feeding. With respect to the underlying mechanism, our data indicate that VDR modulates the AS1517499 of intestinal factors controlling lipid metabolism in peripheral organs thus providing an unexpected physiological link between VDR signaling in the gut and systemic lipid homeostasis.
    Materials and methods
    Results
    Discussion This study addresses the importance of the vitamin D-VDR axis as metabolic regulator in obesity. Our data demonstrate that complete loss of VDR expression in Vdr−/− mice is associated with a lean phenotype which is in line with similar observations that have been reported previously [24,25]. Extending these findings, we observed that this is accompanied by reduced hepatic fat accumulation and reduced inflammation in adipose tissue and liver of Vdr−/− mice. Whether the reduced inflammation in adipose tissue and liver is mainly a result of reduced adiposity of Vdr−/− mice or is based on specific functions of VDR in these tissues will require further analysis in future studies. As a further major finding of the current study, the intestine-specific re-expression of VDR could partly reverse the lean phenotype of Vdr−/− mice. This effect occurred in conjunction with increased expression of pro-inflammatory genes in adipose tissue and with increased hepatic steatosis. These findings therefore strongly argue for an important and so far unexpected role of intestinal VDR signaling in the control of lipid metabolism in extra-intestinal tissues (Fig. 7F). The physiological relevance of this signaling axis is further supported by the finding that high-dose vitamin D treatment in C57BL/6J wild-type mice reproduced the general metabolic effects of intestinal VDR over-expression. With regard to the underlying mechanism, our data indicate that VDR-dependent modulation of Angptl4 expression is an important contributing factor. The ability of Angptl4 to control lipid metabolism by inhibiting lipase activities in multiple organs is well documented [38]. In line with this model, up-regulation of Angptl4 in the intestines of Vdr−/− mice was associated with a decrease of adipose tissue LPL activity resulting in a reduced ability to extract lipids from the blood and, concomitantly, less adipose tissue mass and smaller adipocytes. There is an ongoing debate on whether gut-derived Angptl4 serves as a classical endocrine factor or rather acts in a locally restricted manner [38,39,46,47]. However, direct evidence from mice with liver-specific overexpression demonstrates that liver-derived Angptl4 can in fact act as a bona fide endocrine hormone regulating LPL activity on a systemic level [48]. Noteworthy, in our scenario increased expression of Angptl4 was also evident in the liver of Vdr−/− mice and may therefore additionally contribute to the inhibition of peripheral LPL in these animals (1.01 ± 0.08 in Vdr+/− vs. 1.55 ± 0.18 in Vdr−/−, P < 0.05), particularly if the rather short time period of HFD treatment is taken into consideration. Our data identify angiopoietin-like 4 as a VDR regulated gene and suggest that the in vivo changes of intestinal Angptl4 expression in Vdr−/− mice are due to the lack of gene repression in the absence of VDR. Since this repression also occurred in cultured cells and in reporter gene assays, cell-autonomous effects on the transcriptional level are likely to operate. However, ChIP analyses of the corresponding promoter regions and the use of respective deletion mutants did not confirm the presence of a bona fide VDRE in the angiopoietin-like 4 gene. Although the exact molecular mechanism underlying the VDR-mediated repression of angiopoietin-like 4 requires further analysis, our data obtained from intestinal samples of patients suggest that a similar regulation may also occur in humans.