Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice

Abstract Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adip...

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Autores principales:	Maimaiti Yisireyili, Motoharu Hayashi, Hongxian Wu, Yasuhiro Uchida, Koji Yamamoto, Ryosuke Kikuchi, Mohammad Shoaib Hamrah, Takayuki Nakayama, Xian Wu Cheng, Tadashi Matsushita, Shigeo Nakamura, Toshimitsu Niwa, Toyoaki Murohara, Kyosuke Takeshita
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/738983d9e26b47f2b5f2eba04fb3afb7
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spelling	oai:doaj.org-article:738983d9e26b47f2b5f2eba04fb3afb72021-12-02T15:05:35ZXanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice10.1038/s41598-017-01366-32045-2322https://doaj.org/article/738983d9e26b47f2b5f2eba04fb3afb72017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01366-3https://doaj.org/toc/2045-2322Abstract Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes. Restraint stress in mice resulted in upregulation of XOR and xanthine oxidase activity, accumulation of ROS in VAT as well as liver and intestine, increase in serum UA levels, upregulation of NADPH oxidase subunits and downregulation of antioxidant enzymes. Immunohistochemistry and RT-PCR analysis also showed that restraint stress induced VAT monocyte accumulation and proinflammatory adipokine production, resulting in reduced insulin sensitivity and induction of plasminogen activator inhibitor-1 and tissue factor in VAT. Treatment with febuxostat, a potent XO inhibitor, suppressed stress-induced ROS production and VAT inflammation, resulting in improvement of serum UA levels, insulin sensitivity, and prothrombotic tendency. Our results suggest that stress perturbs glucose and UA metabolism, and promotes prothrombotic status, and that XO inhibition by febuxostat might be a potential therapy for stress-related disorders.Maimaiti YisireyiliMotoharu HayashiHongxian WuYasuhiro UchidaKoji YamamotoRyosuke KikuchiMohammad Shoaib HamrahTakayuki NakayamaXian Wu ChengTadashi MatsushitaShigeo NakamuraToshimitsu NiwaToyoaki MuroharaKyosuke TakeshitaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maimaiti Yisireyili Motoharu Hayashi Hongxian Wu Yasuhiro Uchida Koji Yamamoto Ryosuke Kikuchi Mohammad Shoaib Hamrah Takayuki Nakayama Xian Wu Cheng Tadashi Matsushita Shigeo Nakamura Toshimitsu Niwa Toyoaki Murohara Kyosuke Takeshita Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
description	Abstract Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported recently that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. In the present study, we hypothesized the involvement of VAT xanthine oxidoreductase (XOR), a source of reactive oxygen species (ROS) and uric acid (UA) in the above processes. Restraint stress in mice resulted in upregulation of XOR and xanthine oxidase activity, accumulation of ROS in VAT as well as liver and intestine, increase in serum UA levels, upregulation of NADPH oxidase subunits and downregulation of antioxidant enzymes. Immunohistochemistry and RT-PCR analysis also showed that restraint stress induced VAT monocyte accumulation and proinflammatory adipokine production, resulting in reduced insulin sensitivity and induction of plasminogen activator inhibitor-1 and tissue factor in VAT. Treatment with febuxostat, a potent XO inhibitor, suppressed stress-induced ROS production and VAT inflammation, resulting in improvement of serum UA levels, insulin sensitivity, and prothrombotic tendency. Our results suggest that stress perturbs glucose and UA metabolism, and promotes prothrombotic status, and that XO inhibition by febuxostat might be a potential therapy for stress-related disorders.
format	article
author	Maimaiti Yisireyili Motoharu Hayashi Hongxian Wu Yasuhiro Uchida Koji Yamamoto Ryosuke Kikuchi Mohammad Shoaib Hamrah Takayuki Nakayama Xian Wu Cheng Tadashi Matsushita Shigeo Nakamura Toshimitsu Niwa Toyoaki Murohara Kyosuke Takeshita
author_facet	Maimaiti Yisireyili Motoharu Hayashi Hongxian Wu Yasuhiro Uchida Koji Yamamoto Ryosuke Kikuchi Mohammad Shoaib Hamrah Takayuki Nakayama Xian Wu Cheng Tadashi Matsushita Shigeo Nakamura Toshimitsu Niwa Toyoaki Murohara Kyosuke Takeshita
author_sort	Maimaiti Yisireyili
title	Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
title_short	Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
title_full	Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
title_fullStr	Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
title_full_unstemmed	Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
title_sort	xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/738983d9e26b47f2b5f2eba04fb3afb7
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Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice

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