2023.03.22
Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism
Sci Rep. 2022 Sep 1;12(1):14883. doi: 10.1038/s41598-022-19245-x.
Yoshida Y#,1,2, Shimizu I#,3,4, Shimada A5, Nakahara K5, Yanagisawa S6, Kubo M6, Fukuda S7,8,9, Ishii C7, Yamamoto H7, Ishikawa T7, Kano K10, Aoki J10, Katsuumi G1, Suda M1, Ozaki K11, Yoshida Y12, Okuda S13, Ohta S14, Okamoto S15, Minokoshi Y16, Oda K17, Sasaoka T17, Abe M18,19, Sakimura K18,19, Kubota Y20, Yoshimura N21,22, Kajimura S23, Zuriaga M23, Walsh K25, Soga T26, Minamino T27, 28, 29.
1Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
2Department of Advanced Senotherapeutics, Juntendo University Graduate School of Medicine
3Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
4Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
5Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University
6Graduate School of Science, University of Hyogo
7Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata
8Intestinal Microbiota Project, Kanagawa Institute of Industrial Science and Technology
9Transborder Medical Research Center, University of Tsukuba
10Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
11Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences
12Department of Structural Pathology, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences
13Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences
14Department of Neurology, Juntendo University Graduate School of Medicine
15Second Department of Internal Medicine (Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology), Graduate School of Medicine, University of the Ryukyus
16Department of Homeostatic Regulation, Division of Endocrinology and Metabolism, National Institutes of Natural Sciences, National Institute for Physiological Sciences
17Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University
18Department of Cellular Neurobiology, Brain Research Institute, Niigata University
19Department of Animal Model Development, Brain Research Institute, Niigata University
20Department of Anatomy, Keio University School of Medicine
21Department of Radiology and Radiation Oncology, Niigata University Graduate School of Medical and Dental Sciences
22Department of Radiology, Niigata City General Hospital
23Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
24Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
25Division of Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
26Institute for Advanced Biosciences, Keio University
27Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
28Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development
29Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
#Contributed equally.
Abstract
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.
*Reprinted under the terms of the Creative Commons Attribution License (CC BY).
