Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy

Moscalu, A.; Stupalkowska, W.; Zhao, L.; Li, Y.; Roberts, C. F.; Chen, Y.; Ye, F.; Gold, R.; Bewick, G.; Rubino, F.; Tavakkoli, A.; Devlin, A. S.; Sheu, E. G.

doi:10.1101/2025.10.24.684160

bioRxiv · 10.1101/2025.10.24.684160

Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy

Moscalu, A.·Stupalkowska, W.·Zhao, L.·Li, Y.·Roberts, C. F.·Chen, Y.·Ye, F.·Gold, R.·Bewick, G.·Rubino, F.·Tavakkoli, A.·Devlin, A. S.·Sheu, E. G.

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Abstract

BackgroundThe vitamin D receptor (VDR) regulates insulin sensitivity. Metabolic bariatric surgery (MBS) remains the most effective treatment for obesity and T2D. However, whether its metabolic effects are VDR-dependent is unknown. Here, we assessed VDR role in the metabolic response to sleeve gastrectomy (SG). MethodsWhole body VDR knockout (KO) and wild type (WT) C57BL/6J mice with diet-induced obesity (DIO) were assigned to either SG or sham procedure. Postoperatively, animals underwent glucose and insulin tolerance tests. On sacrifice, serum, white adipose tissue (WAT), liver and colonic contents were collected for further biochemical, histological and bile acid analysis. Separately, human VDR gene expression was assessed in subcutaneous adipose tissue (SAT) biopsies collected from patients with/without MBS history. ResultsKO SG mice exhibited delayed glucose utilization after an oral challenge and progressive loss of insulin sensitivity, despite the same magnitude of surgery-induced weight change between the two genotypes. WAT in KO SG mice had lower mass, smaller adipocytes and increased inflammation. SG had a differential effect on colonic levels of the glucoregulatory cholic acid 7-sulfate (CA7S): increasing CA7S concentration in the WT mice but decreasing it in the KO mice. Finally, patients with MBS history had higher VDR expression in SAT as compared to those without MBS history. ConclusionVDR is necessary for metabolic health after SG in DIO mice due to its role in WAT function, insulin sensitivity and inflammatory response after surgery. Increased expression of VDR in patients post-MBS suggests that it may also contribute to metabolic responses in humans. HighlightsO_LIVDR KO results in delayed glucose utilization following SG in DIO mice C_LIO_LIVDR KO results in progressive loss of improved insulin sensitivity after SG C_LIO_LIVDR KO results in white adipose tissue inflammation and remodeling after SG C_LIO_LIVDR expression increases in human subcutaneous adipose tissue after bariatric surgery C_LI

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Moscalu, A., Stupalkowska, W., Zhao, L., Li, Y., Roberts, C. F., Chen, Y., Ye, F., Gold, R., Bewick, G., Rubino, F., Tavakkoli, A., Devlin, A. S., Sheu, E. G.. 2025-10-24. Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy. https://doi.org/10.1101/2025.10.24.684160

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