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TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling

The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a...

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Autores principales: Lee, Hwan Hee, Jeong, Gyu Won, Ye, Byeong Jin, Yoo, Eun Jin, Son, Keoung Sun, Kim, Dong Ki, Park, Hye-Kyung, Kang, Byoung Heon, Lee-Kwon, Whaseon, Kwon, Hyug Moo, Choi, Soo Youn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862453/
https://www.ncbi.nlm.nih.gov/pubmed/36170666
http://dx.doi.org/10.2337/db21-1099
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author Lee, Hwan Hee
Jeong, Gyu Won
Ye, Byeong Jin
Yoo, Eun Jin
Son, Keoung Sun
Kim, Dong Ki
Park, Hye-Kyung
Kang, Byoung Heon
Lee-Kwon, Whaseon
Kwon, Hyug Moo
Choi, Soo Youn
author_facet Lee, Hwan Hee
Jeong, Gyu Won
Ye, Byeong Jin
Yoo, Eun Jin
Son, Keoung Sun
Kim, Dong Ki
Park, Hye-Kyung
Kang, Byoung Heon
Lee-Kwon, Whaseon
Kwon, Hyug Moo
Choi, Soo Youn
author_sort Lee, Hwan Hee
collection PubMed
description The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell–specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet–induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance–related genes and promoted induction of insulin sensitivity–related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.
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spelling pubmed-98624532023-02-03 TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling Lee, Hwan Hee Jeong, Gyu Won Ye, Byeong Jin Yoo, Eun Jin Son, Keoung Sun Kim, Dong Ki Park, Hye-Kyung Kang, Byoung Heon Lee-Kwon, Whaseon Kwon, Hyug Moo Choi, Soo Youn Diabetes Obesity Studies The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell–specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet–induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance–related genes and promoted induction of insulin sensitivity–related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity. American Diabetes Association 2022-12 2022-09-28 /pmc/articles/PMC9862453/ /pubmed/36170666 http://dx.doi.org/10.2337/db21-1099 Text en © 2022 by the American Diabetes Association https://www.diabetesjournals.org/journals/pages/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
spellingShingle Obesity Studies
Lee, Hwan Hee
Jeong, Gyu Won
Ye, Byeong Jin
Yoo, Eun Jin
Son, Keoung Sun
Kim, Dong Ki
Park, Hye-Kyung
Kang, Byoung Heon
Lee-Kwon, Whaseon
Kwon, Hyug Moo
Choi, Soo Youn
TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title_full TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title_fullStr TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title_full_unstemmed TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title_short TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling
title_sort tonebp in myeloid cells promotes obesity-induced insulin resistance and inflammation through adipose tissue remodeling
topic Obesity Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9862453/
https://www.ncbi.nlm.nih.gov/pubmed/36170666
http://dx.doi.org/10.2337/db21-1099
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