Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice

Eric Lontchi-Yimagou, Sona Kang, Akankasha Goyal, Kehao Zhang, Jee Y. You, Michelle Carey, Swati Jain, Shobhit Bhansali, Sylvia Kehlenbrink, Peng Guo, Evan D. Rosen, Preeti Kishore, Meredith Hawkins

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. Methods: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. Results: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. Conclusions: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

Original languageEnglish (US)
Article number101095
JournalMolecular Metabolism
Volume42
DOIs
StatePublished - Dec 2020

Keywords

  • Adipocyte
  • Fibrosis
  • Inflammation
  • Insulin sensitivity
  • Macrophage
  • Vitamin D

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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