June 16, 2024

The Obesity Paradox and Circadian Rhythms in Heart Failure

“In the resting stage, which for humans is at night and for mice in the day, the heart utilizes fatty acids that are launched from fats as the primary source of energy. In the active stage, which is throughout the day for individuals and at night for mice, the heart has some resistance to dietary carbohydrates. We discovered that without Rev-erbα/ β, hearts have metabolic defects that limit the use of fatty acids when resting, and there is overuse of sugar in the active phase.”
“First, we analyzed the molecular clock function in heart tissues of clients with dilated cardiomyopathy who had gotten heart transplants to check out whether the clock function was associated with the intensity of cardiac dilation in human beings. We found that the heart chronotype associates with the seriousness of cardiac dilation.”

” We studied how the Rev-erbα/ β gene affected the metabolism of the heart by knocking it out particularly in mouse cardiomyocytes,” said co-corresponding author Dr. Zheng Sun, associate professor of medication, section of metabolism, endocrinology and diabetes and of cellular and molecular biology at Baylor. “Lacking the gene resulted in progressive heart damage that led to cardiac arrest.”
To find out how Rev-erbα/ β moderated its impacts, the team analyzed gene and protein expression and a comprehensive panel of lipids and metabolites, during both the awake and sleep hours. They found that the Rev-erbα/ β gene is extremely revealed only during the sleep hours, and its activity is connected with fat and sugar metabolic process.
“In the resting stage, which for people is at night and for mice in the day, the heart utilizes fatty acids that are launched from fats as the main source of energy. We found that without Rev-erbα/ β, hearts have metabolic problems that limit the use of fatty acids when resting, and there is overuse of sugar in the active stage.”
” We suspected that when Rev-erbα/ β knockout hearts can not burn fatty acids effectively in the resting stage, then they do not have enough energy to beat. That energy shortage would probably cause changes in the heart that led to progressive dilated cardiomyopathy,” said Sun, a member of Dan L Duncan Comprehensive Cancer Center.
To test this hypothesis, the researchers figured out whether bring back the defect in fat usage would enhance the condition.
” We know that fatty acid usage can be controlled by lipid-sensing metabolic pathways. We assumed that if we fed the Rev-erbα/ β knockout mice more lipids, maybe the lipid-sensing pathways would be activated, bypass the problem and as a result the heart would be able to obtain energy from lipids,” Sun discussed.
The researchers fed Rev-erbα/ β knockout mice one of two high-fat diets. “The high-fat/high-sucrose diet partly minimized the heart problems, but the high-fat diet plan did not,” Sun stated.
” These findings support that the metabolic problem that prevents the heart cells from utilizing fatty acids as fuel is triggering most of the cardiac dysfunction we see in the Rev-erbα/ β knockout mice. Notably, we also reveal that correcting the metabolic flaw can assist improve the condition,” Zhang said.
Medical implications in weight problems paradox and chronotherapy
“First, we evaluated the molecular clock function in heart tissues of clients with dilated cardiomyopathy who had gotten heart transplants to check out whether the clock function was associated with the intensity of heart dilation in human beings. We found that the heart chronotype associates with the intensity of heart dilation.”
” The 2nd ramification is that obesity and insulin resistance, long-known clinical risk factors for heart failure, can be paradoxically protective against cardiac arrest, within a specific time window, most likely by supplying fatty acids in the resting phase,” Sun stated.
Lastly, the scientists explored the possibility of pharmacologically manipulating fatty acid and sugar metabolic process to improve the condition. They found that while medications can help restore the modified metabolic paths, it was essential to provide the drugs lined up with the internal body clock of the matching metabolic pathways. If the drugs were offered out-of-sync with the path they were meant to restore, the treatment did not improve the heart condition.”
These findings highlight the value of chronotherapy, the scheduling of medications according to the circadian rhythm, not just in this study, however for lots of other medications.
” Of the top 100 most recommended drugs in the U.S., at least half of them have a target that is connected to a circadian rhythm,” Zhang stated. We want to emphasize the importance of taking the circadian rhythm into factor to consider when scheduling medications.”
Reference: “Chronotype Myocardial Rev-erb-mediated diurnal metabolic rhythm and weight problems paradox” 17 January 2022, Circulation.DOI: 10.1161/ CIRCULATIONAHA.121.056076.

Interfering with body clocks, which alter naturally on a 24-hour cycle, has actually been linked in heart illness, but it is uncertain how it causes the condition. A research study group at Baylor College of Medicine and collaborating institutions investigated the function of the protein Rev-erbα/ β, a crucial element of the circadian clock, on cardiovascular disease advancement in animal designs and human patients.
The group reports in the journal Circulation that Rev-erbα/ β in cardiomyocytes moderates a normal metabolic rhythm that makes it possible for the cells to choose lipids as a source of energy during the animals resting time, daytime for mice. Removing Rev-erbα/ β disrupts this rhythm, reduces the cardiomyocytes ability to use lipids in the resting time and results in progressive dilated cardiomyopathy and lethal heart failure.