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Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice
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 ha...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585951/ https://www.ncbi.nlm.nih.gov/pubmed/33045433 http://dx.doi.org/10.1016/j.molmet.2020.101095 |
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author | Lontchi-Yimagou, Eric Kang, Sona Goyal, Akankasha Zhang, Kehao You, Jee Y. Carey, Michelle Jain, Swati Bhansali, Shobhit Kehlenbrink, Sylvia Guo, Peng Rosen, Evan D. Kishore, Preeti Hawkins, Meredith |
author_facet | Lontchi-Yimagou, Eric Kang, Sona Goyal, Akankasha Zhang, Kehao You, Jee Y. Carey, Michelle Jain, Swati Bhansali, Shobhit Kehlenbrink, Sylvia Guo, Peng Rosen, Evan D. Kishore, Preeti Hawkins, Meredith |
author_sort | Lontchi-Yimagou, Eric |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7585951 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-75859512020-10-30 Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice Lontchi-Yimagou, Eric Kang, Sona Goyal, Akankasha Zhang, Kehao You, Jee Y. Carey, Michelle Jain, Swati Bhansali, Shobhit Kehlenbrink, Sylvia Guo, Peng Rosen, Evan D. Kishore, Preeti Hawkins, Meredith Mol Metab Original Article 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. Elsevier 2020-10-10 /pmc/articles/PMC7585951/ /pubmed/33045433 http://dx.doi.org/10.1016/j.molmet.2020.101095 Text en © 2020 Published by Elsevier GmbH. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Lontchi-Yimagou, Eric Kang, Sona Goyal, Akankasha Zhang, Kehao You, Jee Y. Carey, Michelle Jain, Swati Bhansali, Shobhit Kehlenbrink, Sylvia Guo, Peng Rosen, Evan D. Kishore, Preeti Hawkins, Meredith Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title | Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title_full | Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title_fullStr | Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title_full_unstemmed | Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title_short | Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice |
title_sort | insulin-sensitizing effects of vitamin d repletion mediated by adipocyte vitamin d receptor: studies in humans and mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585951/ https://www.ncbi.nlm.nih.gov/pubmed/33045433 http://dx.doi.org/10.1016/j.molmet.2020.101095 |
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