@article{7859d78daa704c2ead63523b79c17dd2,
title = "Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice",
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.",
keywords = "Adipocyte, Fibrosis, Inflammation, Insulin sensitivity, Macrophage, Vitamin D",
author = "Eric Lontchi-Yimagou and Sona Kang and Akankasha Goyal and Kehao Zhang and You, {Jee Y.} and Michelle Carey and Swati Jain and Shobhit Bhansali and Sylvia Kehlenbrink and Peng Guo and Rosen, {Evan D.} and Preeti Kishore and Meredith Hawkins",
note = "Funding Information: This study was supported by grants from the American Diabetes Association (1-12-CT-41 to P.K. and M.H.), the National Institutes of Health (DK069861, DK079974 and DK48321, to M.H.), and by the Einstein-Montefiore NIH CTSA Grant UL1TR001073 from the National Center for Research Resources (NCRR). E.D.R. was supported by NIH R01 DK 085171, DK 102173, and DK 102170. So.K. was supported by NIH R01 DK 116008. E.L-Y. was supported by the American Diabetes Association (1-18-PMF-024) and the National Center for Advancing Translational Science Einstein-Montefiore Clinical and Translational Science Awards (UL1 TR002556).We acknowledge the assistance of Robin Sgueglia, Roger Maginley, Pooja Ragavan, Vera DesMarais, Snema Damal Villivallam and Hillary Guzik and thank the Ddrops Company for supplying vitamin D and placebo for the studies. The imaging was conducted at the Analytical Imaging Facility, which is funded by NCI Cancer Grant P30CA013330. The mouse phenotyping studies were conducted at Beth Israel Deaconess Medical Center except for the clamp studies, which were performed at the Vanderbilt University Medical Center Mouse Metabolic Phenotyping Center (DK059637). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views or policies of the FDA, NCRR, or NIH. Funding Information: We acknowledge the assistance of Robin Sgueglia, Roger Maginley, Pooja Ragavan, Vera DesMarais, Snema Damal Villivallam and Hillary Guzik and thank the Ddrops Company for supplying vitamin D and placebo for the studies. The imaging was conducted at the Analytical Imaging Facility, which is funded by NCI Cancer Grant P30CA013330 . The mouse phenotyping studies were conducted at Beth Israel Deaconess Medical Center except for the clamp studies, which were performed at the Vanderbilt University Medical Center Mouse Metabolic Phenotyping Center (DK059637). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views or policies of the FDA, NCRR, or NIH. Funding Information: This study was supported by grants from the American Diabetes Association (1-12-CT-41 to P.K. and M.H.), the National Institutes of Health ( DK069861 , DK079974 and DK48321 , to M.H.), and by the Einstein-Montefiore NIH CTSA Grant UL1TR001073 from the National Center for Research Resources (NCRR). E.D.R. was supported by NIH R01 DK 085171 , DK 102173 , and DK 102170 . So.K. was supported by NIH R01 DK 116008 . E.L-Y. was supported by the American Diabetes Association ( 1-18-PMF-024 ) and the National Center for Advancing Translational Science Einstein-Montefiore Clinical and Translational Science Awards ( UL1 TR002556 ). Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = dec,
doi = "10.1016/j.molmet.2020.101095",
language = "English (US)",
volume = "42",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier GmbH",
}
