Moscalu, A. | Search bioRxiv

bioRxiv2025

Vitamin D receptor is necessary for metabolic health after sleeve gastrectomy

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

physiology↗

bioRxiv2025

Alterations in glucocorticoid homeostasis following sleeve gastrectomy

Elevated intra-tissue levels of active glucocorticoids in obese patients are associated with insulin resistance, diabetes, impaired immune regulation, and other adverse effects. Sleeve gastrectomy (SG) induces significant weight loss and improves metabolic outcomes, including insulin resistance and hyperlipidemia. Among the enzymes controlling intracellular concentrations of active glucocorticoids, 11{beta}-hydroxysteroid dehydrogenase type 1 (HSD11B1, SDR26C1) has been extensively studied concerning obesity and post-gastric surgery interventions. However, most studies focused on either a single tissue, circulating glucocorticoid levels, or HSD11B1 activity. In this work, we showed that circulating active/inactive glucocorticoid ratio (corticosterone (B)/11-dehydrocorticosterone (A)) negatively correlated with glucose tolerance; SG in male C57BL/6 mice slightly reduced circulating mineralocorticoids and reversed the elevated ratio of B/A seen in sham-operated mice after high-fat diet, while improving glucose tolerance. This change was likely due to increased renal 11{beta}-hydroxysteroid dehydrogenase type 2 (HSD11B2, SDR9C3) activity after SG. To provide a comprehensive overview of the systemic effects post-surgery, we evaluated enzymes involved in glucocorticoid homeostasis across tissues on mRNA, protein, and activity level. Moreover, mRNA expression of transcription factors CCAAT enhancer binding protein alpha (Cebpa), Cebpb and nuclear factor kappa b (Nf{kappa}b (p50)), as well as cytokines influencing Hsd11b1 and Hsd11b2 gene expression were analyzed. The results emphasize stronger influence of renal HSD11B2 than hepatic HSD11B1 activity on the circulating B/A ratio, supported by intrarenal and intrahepatic B/A ratios. The improved glucocorticoid homeostasis following SG, indicated by decreased B/A ratios, proposes a lower risk for glucocorticoid-mediated adverse health effects, including chronic kidney disease, hypertension, and metabolic disturbances. NEW & NOTEWORTHYThis study revealed improved glucocorticoid homeostasis after sleeve gastrectomy (SG), with lower circulating ratios of active (corticosterone, B)/inactive (11-dehydrocorticosterone, A) glucocorticoids and a better glucose tolerance compared to Sham mice. SG enhanced renal HSD11B2 activity, while hepatic HSD11B1 oxoreductase activity was unchanged. These findings suggest that SG reverses some adverse metabolic effects of high-fat diet by enhancing renal HSD11B2 activity, potentially lowering the risk of chronic kidney disease, hypertension, and metabolic disease.

physiology↗