Chinese scholars elucidate the obesity paradox, the treatment of "heart power" should follow the circadian rhythm

Circadian rhythms naturally change in 24-hour cycles, and disrupting the circadian rhythm has been linked to heart disease, but it's unclear how it causes it
.

Rev-erbα/β in cardiomyocytes mediates a normal metabolic rhythm that makes cells prefer lipids as an energy source during animal rest periods (daytime in mice), the team reports in the journal Circulation
.

"We investigated how the Rev-erbα/β gene affects cardiometabolism by specifically knocking out mouse cardiomyocytes," said co-corresponding author Zheng Sun, Ph.
D.
, professor of Endocrinology, Diabetes and Metabolism and Molecular and Cellular at Baylor University Associate Professor of Medicine of Biology
.

To understand how Rev-erbα/β mediates its effects, the team analyzed gene and protein expression during wakefulness and sleep, as well as a comprehensive panel of metabolites and lipids
.

"The heart responds differently to different energy sources, depending on the time of day," explains co-corresponding author Dr.
Lilei Zhang
.

"We suspect that when Rev-erbα/β knockout hearts don't burn fatty acids efficiently during the resting phase, they don't have enough energy to beat
.

To test this hypothesis, the researchers determined whether restoring fatty acid use would improve the situation
.

"We know that fatty acid use can be controlled by lipid-sensing metabolic pathways
.

The researchers fed Rev-erbα/β knockout mice one of two high-fat diets
.

"These findings support that the metabolic defect, which prevents heart cells from using fatty acids as fuel, is responsible for most of the cardiac dysfunction we see in Rev-erbα/β knockout mice
.
Importantly, we also show that correcting the metabolic defect Helps improve the condition
.
"

The obesity paradox and clinical implications of chronotherapy

"This work has three clinical implications," Sun said
.
First, we analyzed molecular clock function in cardiac tissue from dilated cardiomyopathy patients undergoing heart transplantation to explore whether clock function correlates with the severity of human cardiac dilation
.
Tissue samples were collected at different times of the day, and the gene expression ratios of the circadian genes Rev-erbα/β and Bmal1 were calculated to obtain the temporal pattern
.
We found that cardiac chronotype was associated with the severity of cardiac dilation
.
"

"The second implication is that obesity and insulin resistance, well-known clinical risk factors for heart failure, can paradoxically protect against heart failure, for a certain time window, possibly by providing fatty acids during the resting phase," Sun said
.

Finally, the researchers explored the possibility of improving the condition by controlling fatty acid and sugar metabolism with drugs
.
They found that while drugs can help restore altered metabolic pathways, it is important that the administration aligns with the corresponding metabolic pathway's internal circadian rhythm
.
Treatment does not improve heart conditions if the route of administration is out of sync with the route they want to restore
.
"

These findings highlight the importance of chronotherapy, the scheduling of drug treatments according to circadian rhythms, not only in this study but for many other drugs as well
.

"At least half of the 100 most-prescribed drugs in the U.
S.
have a circadian rhythm-related target," Zhang said
.
This suggests that these drugs need to be taken at specific times in order to be effective
.
Unfortunately, This is not the case
.
We want to stress the importance of taking circadian rhythms into account when scheduling medication
.
"

Reference: "Chronotype Myocardial Rev-erb-mediated diurnal metabolic rhythm and obesity paradox" 17 January 2022, Circulation .
DOI: 10.
1161/CIRCULATIONAHA.
121.
056076