Calcipotriol and iBRD9 reduce obesity in Nur77 knockout mice by regulating the gut microbiota, improving intestinal mucosal barrier function

Abstract

Objective The orphan nuclear receptor Nur77 is an important factor regulating metabolism. Nur77 knockout mice become obese with age, but the cause of obesity in these mice has not been fully ascertained. We attempted to explain the cause of obesity in Nur77 knockout mice from the perspective of the gut microbiota and to investigate the inhibitory effect of calcipotriol combined with BRD9 inhibitor (iBRD9) on obesity. Methods Eight-week-old wild-type mice and Nur77 knockout C57BL/6J mice were treated with calcipotriol combined with iBRD9 for 12 weeks. Mouse feces were collected and the gut microbiota was assessed by analyzing 16S rRNA gene sequences. The bacterial abundance difference was analyzed, and the intestinal mucosal tight junction protein, antimicrobial peptide, and inflammatory cytokine mRNA levels of the colon and serum LPS and inflammatory cytokine levels were measured. Results Calcipotriol combined with iBRD9 treatment reduced the body weight and body fat percentage in Nur77 knockout mice. In the gut microbiota of Nur77 knockout mice, the relative abundances of Lachnospiraceae and Prevotellaceae decreased, and Rikenellaceae increased; while Rikenellaceae decreased after treatment (p < 0.05). Correspondingly, the mRNA levels of intestinal mucosal tight junction proteins (occludin (Ocln), claudin3 (Cldn3)) in the colons of Nur77 knockout mice were significantly decreased, and they increased significantly after treatment (p < 0.001). The mRNA levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)) were significantly increased in Nur77 knockout mice, and TNF-α and IL-6 levels were significantly decreased after treatment (p < 0.05, <0.01, or <0.001). The levels of serum LPS, TNF-α, and IL-1β in Nur77 knockout mice were significantly increased (p < 0.05). Serum LPS, TNF-α, and IL-6 levels were significantly decreased after treatment (p < 0.05 or <0.01). Conclusions Calcipotriol combined with iBRD9 can regulate the gut microbiota, improve intestinal mucosal barrier function, reduce LPS absorption into the blood, and alleviate obesity in Nur77 knockout mice.

The Prebiotic‐Like Effects of Coprinus comatus Polysaccharides on Gut Microbiota in Normal Mice and Those with Acute Alcoholic Liver Injury: A Comparative Study

“…e previous study showed Nur77 knockout mice became obese accompanied with the relative abundances of increased Rikenellaceae [33]. At the same time, the abundance of Rikenellaceae was positively correlated with the hepatic inflammation [34].…”

Vitamin D3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D

“…For the calcipotriol treatment study, four groups were injected intraperitoneally with calcipotriol (60 μg per kg body weight) (SWT-cal, SKO-cal), or vehicle (SWT-veh, SKO-veh) three times a week for 12 weeks. 25 Those four groups feed the standard diet containing 1000 IU kg −1 VD 3 , which was provided by Trophic Animal Feed High-Tech Co., Ltd (Nantong, China) (TP 2230G-A). The chemical structures of VD 3 and calcipotriol, and the schematic diagram of the experimental procedure, are shown in Fig.…”

“…6 VD is a fat-soluble steroid hormone, with VD 3 primarily produced by the photochemical conversion of 7-dehydrocholesterol in the skin and also acquired directly through dietary intakes. VD 3 undergoes hydroxylation in the liver by 25-hydroxylase to form 25(OH)D 3 and then is further converted into its hormonally active form, 1,25(OH) 2 D 3 , in the proximal renal tubules by 1α-hydroxylase. 7 This hormonally active form exerts both genomic and non-genomic effects by ligand binding the vitamin D receptor (VDR).…”

Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

“…As BRD9-deficient Tregs were also defective in the context of tumor immunity, the authors suggested that small-molecule drugs could be useful to fight cancer. Interestingly, a study by Qingqing Lv et al showed that calcipotriol combined with I-BRD9 can regulate the gut microbiota, improve intestinal mucosal barrier function, and reduce LPS absorption into the blood [ 130 ].…”