Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.
Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.
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DOI：
10.1038/s41598-022-19245-x
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发表时间：
2022-09-01
影响因子：
4.6
通讯作者：
Minamino, Tohru
中科院分区：
文献类型：
--
作者：
Yoshida, Yohko;Shimizu, Ippei;Shimada, Atsuhiro;Nakahara, Keita;Yanagisawa, Sachiko;Kubo, Minoru;Fukuda, Shinji;Ishii, Chiharu;Yamamoto, Hiromitsu;Ishikawa, Takamasa;Kano, Kuniyuki;Aoki, Junken;Katsuumi, Goro;Suda, Masayoshi;Ozaki, Kazuyuki;Yoshida, Yutaka;Okuda, Shujiro;Ohta, Shigeo;Okamoto, Shiki;Minokoshi, Yasuhiko;Oda, Kanako;Sasaoka, Toshikuni;Abe, Manabu;Sakimura, Kenji;Kubota, Yoshiaki;Yoshimura, Norihiko;Kajimura, Shingo;Zuriaga, Maria;Walsh, Kenneth;Soga, Tomoyoshi;Minamino, Tohru
低体温预示心力衰竭患者预后不良，但其潜在的病理机制和意义尚不清楚。棕色脂肪组织（BAT）最初被描述为产热器官，最近的研究表明它在维持全身代谢健康方面起着至关重要的作用。虽然这些报告表明BAT和心力衰竭之间存在潜在联系，但尚未研究BAT功能障碍在心力衰竭中的潜在作用。在这里，我们证明了BAT功能的改变有助于通过胆碱代谢中的定向障碍来发展心力衰竭。胸主动脉缩窄（TAC）或心肌梗死（MI）降低了小鼠BAT的产热能力，导致冷暴露时体温显著降低。BAT与TAC或MI成为缺氧，缺氧应激诱导棕色脂肪细胞凋亡。BAT功能的增强改善了TAC小鼠的产热和心脏功能。相反，在遗传性BAT功能障碍的小鼠模型中，收缩功能受损，与TAC后的低存活率相关。代谢组学分析表明，减少BAT产热与血浆三甲胺N-氧化物（TMAO）水平升高。给小鼠施用TMAO通过抑制线粒体复合物IV活性导致心脏组织中磷酸肌酸和ATP水平显著降低。对含黄素单加氧酶的遗传或药理学抑制可降低小鼠血浆TMAO水平，并改善左心室压力超负荷动物的心功能障碍。在扩张型心肌病患者中，体温沿着降低，同时血浆胆碱和TMAO水平升高。这些结果表明，维持BAT体内平衡和减少TMAO的产生可能是心力衰竭的潜在下一代疗法。
Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.
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影响因子：
7.7
作者：
Sacks H;Symonds ME
通讯作者：
Symonds ME
影响因子：
14.9
作者：
Okuda S;Watanabe Y;Moriya Y;Kawano S;Yamamoto T;Matsumoto M;Takami T;Kobayashi D;Araki N;Yoshizawa AC;Tabata T;Sugiyama N;Goto S;Ishihama Y
通讯作者：
Ishihama Y
影响因子：
14.8
作者：
Frezza, Christian;Cipolat, Sara;Scorrano, Luca
通讯作者：
Scorrano, Luca
影响因子：
6
作者：
Ahmed, Amany;Aboshady, Ibrahim;Casscells, S. Ward
通讯作者：
Casscells, S. Ward
DOI：
10.1007/978-1-60761-322-0_15
发表时间：
2009-01-01
期刊：
LIPIDOMICS: VOL 1: METHODS AND PROTOCOLS
影响因子：
--
作者：
Nakanishi, Hiroki;Ogiso, Hideo;Taguchi, Ryo
通讯作者：
Taguchi, Ryo