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Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity
BACKGROUND: Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life‐threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828814/ https://www.ncbi.nlm.nih.gov/pubmed/23902639 http://dx.doi.org/10.1161/JAHA.113.000312 |
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author | Maeda, Akinobu Tamura, Kouichi Wakui, Hiromichi Dejima, Toru Ohsawa, Masato Azushima, Kengo Kanaoka, Tomohiko Uneda, Kazushi Matsuda, Miyuki Yamashita, Akio Miyazaki, Nobuko Yatsu, Keisuke Hirawa, Nobuhito Toya, Yoshiyuki Umemura, Satoshi |
author_facet | Maeda, Akinobu Tamura, Kouichi Wakui, Hiromichi Dejima, Toru Ohsawa, Masato Azushima, Kengo Kanaoka, Tomohiko Uneda, Kazushi Matsuda, Miyuki Yamashita, Akio Miyazaki, Nobuko Yatsu, Keisuke Hirawa, Nobuhito Toya, Yoshiyuki Umemura, Satoshi |
author_sort | Maeda, Akinobu |
collection | PubMed |
description | BACKGROUND: Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life‐threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity‐related metabolic disorders, moving the tissue toward a proinflammatory phenotype. METHODS AND RESULTS: Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(−/−)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(−/−) mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap(−/−) recipient mice improved the systemic metabolic dysfunction. CONCLUSIONS: These results demonstrate that Agtrap(−/−) mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function. |
format | Online Article Text |
id | pubmed-3828814 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-38288142013-11-19 Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity Maeda, Akinobu Tamura, Kouichi Wakui, Hiromichi Dejima, Toru Ohsawa, Masato Azushima, Kengo Kanaoka, Tomohiko Uneda, Kazushi Matsuda, Miyuki Yamashita, Akio Miyazaki, Nobuko Yatsu, Keisuke Hirawa, Nobuhito Toya, Yoshiyuki Umemura, Satoshi J Am Heart Assoc Original Research BACKGROUND: Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life‐threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity‐related metabolic disorders, moving the tissue toward a proinflammatory phenotype. METHODS AND RESULTS: Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(−/−)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(−/−) mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap(−/−) recipient mice improved the systemic metabolic dysfunction. CONCLUSIONS: These results demonstrate that Agtrap(−/−) mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function. Blackwell Publishing Ltd 2013-08-23 /pmc/articles/PMC3828814/ /pubmed/23902639 http://dx.doi.org/10.1161/JAHA.113.000312 Text en © 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research Maeda, Akinobu Tamura, Kouichi Wakui, Hiromichi Dejima, Toru Ohsawa, Masato Azushima, Kengo Kanaoka, Tomohiko Uneda, Kazushi Matsuda, Miyuki Yamashita, Akio Miyazaki, Nobuko Yatsu, Keisuke Hirawa, Nobuhito Toya, Yoshiyuki Umemura, Satoshi Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title | Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title_full | Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title_fullStr | Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title_full_unstemmed | Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title_short | Angiotensin Receptor–Binding Protein ATRAP/Agtrap Inhibits Metabolic Dysfunction With Visceral Obesity |
title_sort | angiotensin receptor–binding protein atrap/agtrap inhibits metabolic dysfunction with visceral obesity |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828814/ https://www.ncbi.nlm.nih.gov/pubmed/23902639 http://dx.doi.org/10.1161/JAHA.113.000312 |
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