Myocardial Rev-erb–Mediated Diurnal Metabolic Rhythm and Obesity Paradox

Author:

Song Shiyang12,Tien Chih-Liang3,Cui Hao4ORCID,Basil Paul5ORCID,Zhu Ningxia6,Gong Yingyun1ORCID,Li Wenbo1,Li Hui3ORCID,Fan Qiying7,Min Choi Jong8,Luo Weijia9,Xue Yanfeng1,Cao Rui1,Zhou Wenjun1ORCID,Ortiz Andrea R.8ORCID,Stork Brittany8,Mundra Vatsala1,Putluri Nagireddy8,York Brian8ORCID,Chu Maoping2,Chang Jiang9,Yun Jung Sung8ORCID,Xie Liang1,Song Jiangping4ORCID,Zhang Lilei39,Sun Zheng1ORCID

Affiliation:

1. Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism (S.S., P.B., N.Z., Y.G., W. Li, Y.X., R.C., W.Z., V.M., Z.S.), Baylor College of Medicine, Houston, TX.

2. Children’s Heart Center, Institute of Cardiovascular Development and Translational Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, China (S.S., M.C.).

3. Department of Molecular and Human Genetics (C.-L.T., H.L., L.Z.), Baylor College of Medicine, Houston, TX.

4. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China (H.C., J.S.).

5. Department of Critical Care, Division of Anesthesiology, Critical Care, and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX (P.B.).

6. Department of Pathology and Physiopathology, Guilin Medical University, Guilin, China (N.Z.).

7. Department of Medicine, Division of Atherosclerosis and Vascular Medicine, Cardiovascular Research Institute (CVRI), Houston, TX (Q.F., L.X.).

8. Department of Molecular and Cellular Biology (J.M.C., A.R.O., B.S., N.P., B.Y., S.Y.J.), Baylor College of Medicine, Houston, TX.

9. Center for Genomic and Precision Medicine, Texas A&M University, Institute of Biosciences and Technology, Houston (W. Luo, J.C., L.Z.).

Abstract

Background: The nuclear receptor Rev-erbα/β, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. Methods: We generated mouse lines with cardiac-specific Rev-erbα/β knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. Results: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/β in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. Conclusions: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3