TY - JOUR
T1 - Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox
AU - Song, Shiyang
AU - Tien, Chih Liang
AU - Cui, Hao
AU - Basil, Paul
AU - Zhu, Ningxia
AU - Gong, Yingyun
AU - Li, Wenbo
AU - Li, Hui
AU - Fan, Qiying
AU - Min Choi, Jong
AU - Luo, Weijia
AU - Xue, Yanfeng
AU - Cao, Rui
AU - Zhou, Wenjun
AU - Ortiz, Andrea R.
AU - Stork, Brittany
AU - Mundra, Vatsala
AU - Putluri, Nagireddy
AU - York, Brian
AU - Chu, Maoping
AU - Chang, Jiang
AU - Yun Jung, Sung
AU - Xie, Liang
AU - Song, Jiangping
AU - Zhang, Lilei
AU - Sun, Zheng
N1 - Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/2/8
Y1 - 2022/2/8
N2 - 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.
AB - 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.
KW - cardiomyopathy, dilated
KW - circadian clocks
KW - diet, high-fat
KW - heart failure
KW - lipid metabolism
KW - obesity
UR - http://www.scopus.com/inward/record.url?scp=85124438582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124438582&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.121.056076
DO - 10.1161/CIRCULATIONAHA.121.056076
M3 - Article
C2 - 35034472
AN - SCOPUS:85124438582
SN - 0009-7322
VL - 145
SP - 448
EP - 464
JO - Circulation
JF - Circulation
IS - 6
ER -