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Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity

BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In s...

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Autores principales: Lin, Yi-Hsuan, Luck, Helen, Khan, Saad, Schneeberger, Pierre H. H., Tsai, Sue, Clemente-Casares, Xavier, Lei, Helena, Leu, Yann-Lii, Chan, Yi Tao, Chen, Hsing-Yu, Yang, Sien-Hung, Coburn, Bryan, Winer, Shawn, Winer, Daniel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892742/
https://www.ncbi.nlm.nih.gov/pubmed/30944419
http://dx.doi.org/10.1038/s41366-019-0340-1
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author Lin, Yi-Hsuan
Luck, Helen
Khan, Saad
Schneeberger, Pierre H. H.
Tsai, Sue
Clemente-Casares, Xavier
Lei, Helena
Leu, Yann-Lii
Chan, Yi Tao
Chen, Hsing-Yu
Yang, Sien-Hung
Coburn, Bryan
Winer, Shawn
Winer, Daniel A.
author_facet Lin, Yi-Hsuan
Luck, Helen
Khan, Saad
Schneeberger, Pierre H. H.
Tsai, Sue
Clemente-Casares, Xavier
Lei, Helena
Leu, Yann-Lii
Chan, Yi Tao
Chen, Hsing-Yu
Yang, Sien-Hung
Coburn, Bryan
Winer, Shawn
Winer, Daniel A.
author_sort Lin, Yi-Hsuan
collection PubMed
description BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. METHODS: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation. RESULTS: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT. CONCLUSIONS: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation.
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spelling pubmed-68927422019-12-06 Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity Lin, Yi-Hsuan Luck, Helen Khan, Saad Schneeberger, Pierre H. H. Tsai, Sue Clemente-Casares, Xavier Lei, Helena Leu, Yann-Lii Chan, Yi Tao Chen, Hsing-Yu Yang, Sien-Hung Coburn, Bryan Winer, Shawn Winer, Daniel A. Int J Obes (Lond) Article BACKGROUND/OBJECTIVES: Low-grade chronic inflammation in visceral adipose tissue and the intestines are important drivers of obesity associated insulin resistance. Bioactive compounds derived from plants are an important source of potential novel therapies for the treatment of chronic diseases. In search for new immune based treatments of obesity associated insulin resistance, we screened for tissue relevant anti-inflammatory properties in 20 plant-based extracts. METHODS: We screened 20 plant-based extracts to assess for preferential production of IL-10 compared to TNFα, specifically targetting metabolic tissues, including the visceral adipose tissue. We assessed the therapeutic potential of the strongest anti-inflammatory compound, indigo, in the C57BL/6J diet-induced obesity mouse model with supplementation for up to 16 weeks by measuring changes in body weight, glucose and insulin tolerance, and gut barrier function. We also utilized flow cytometry, quantitative PCR, enzyme-linked immunosorbent assay (ELISA), and histology to measure changes to immune cells populations and cytokine profiles in the intestine, visceral adipose tissue (VAT), and liver. 16SrRNA sequencing was performed to examine gut microbial differences induced by indigo supplementation. RESULTS: We identifed indigo, an aryl hydrocarbon receptor (AhR) ligand agonist, as a potent inducer of IL-10 and IL-22, which protects against high-fat diet (HFD)-induced insulin resistance and fatty liver disease in the diet-induced obesity model. Therapeutic actions were mechanistically linked to decreased inflammatory immune cell tone in the intestine, VAT and liver. Specifically, indigo increased Lactobacillus bacteria and elicited IL-22 production in the gut, which improved intestinal barrier permeability and reduced endotoxemia. These changes were associated with increased IL-10 production by immune cells residing in liver and VAT. CONCLUSIONS: Indigo is a naturally occurring AhR ligand with anti-inflammatory properties that effectively protects against HFD-induced glucose dysregulation. Compounds derived from indigo or those with similar properties could represent novel therapies for diseases associated with obesity-related metabolic tissue inflammation. Nature Publishing Group UK 2019-04-03 2019 /pmc/articles/PMC6892742/ /pubmed/30944419 http://dx.doi.org/10.1038/s41366-019-0340-1 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lin, Yi-Hsuan
Luck, Helen
Khan, Saad
Schneeberger, Pierre H. H.
Tsai, Sue
Clemente-Casares, Xavier
Lei, Helena
Leu, Yann-Lii
Chan, Yi Tao
Chen, Hsing-Yu
Yang, Sien-Hung
Coburn, Bryan
Winer, Shawn
Winer, Daniel A.
Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title_full Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title_fullStr Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title_full_unstemmed Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title_short Aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
title_sort aryl hydrocarbon receptor agonist indigo protects against obesity-related insulin resistance through modulation of intestinal and metabolic tissue immunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892742/
https://www.ncbi.nlm.nih.gov/pubmed/30944419
http://dx.doi.org/10.1038/s41366-019-0340-1
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