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Publication
Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin
D receptor: Studies in humans and mice.
Authors Lontchi-Yimagou E, Kang S, Goyal A, Zhang K, You JY, Carey M, Jain S, Bhansali
S, Kehlenbrink S, Guo P, Rosen ED, Kishore P, Hawkins M
Submitted By Submitted Externally on 11/10/2020
Status Published
Journal Molecular metabolism
Year 2020
Date Published 10/1/2020
Volume : Pages 42 : 101095
PubMed Reference 33045433
Abstract 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., 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., 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., 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.




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