Impact of obesity on day‐night differences in cardiac metabolism

Abstract

An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24‐hours day, in association with diurnal sleep‐wake and fasting‐feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day‐night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet‐induced obesity disrupts cardiac “diurnal metabolic flexibility”, which is normalized by time‐of‐day‐restricted feeding. Chronic high fat feeding (20‐wk)‐induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24‐hours rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day‐night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day‐night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18‐wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12‐hours dark (active) phase, for a 2‐wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day‐night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for nonoxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity‐induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.

Short-term high fat diet alters genes associated with metabolic and vascular dysfunction during adolescence in rats: a pilot study

“…Though, it is unclear if this would be similar in the vasculature. In relation, time-restricted feeding in alignment with light and dark cycles has been found to partially restore day-night differences in cardiac remodeling, triglyceride synthesis, lipidome, and metabolic flexibility in mice ( Mia et al, 2021 ). Therefore, future work should investigate HFD cessation, as well as time-restricted feeding models on circadian-related genes in the vasculature.…”

Boosting circadian autophagy by means of intermittent time-restricted feeding: a novel anti-ageing strategy?

“…These results suggest that these interventions act through distinct mechanisms and may be combined to achieve an enhanced effect. Ulgherait et al [7] also observed a reduction in markers of ageing in the gut and muscles of Drosophila, and an increase in climbing activity, indicating that iTRF not only increased lifespan, but was also associated with increased healthspan.…”

“…The authors observed that 30 days of iTRF, from day 10 to day 40 of age, extends lifespan and improves functional capacities in flies. Unlike with other dietary restriction regimens, Ulgherait et al [7] observed that iTRF-induced longevity is independent of calorie restriction, reduction of protein intake, or inhibition of insulin-like signalling. In fact, flies undergoing iTRF combined with dietary protein restriction or inhibition of insulin-like signalling showed a significant additional increase in longevity, similar to the percentage of lifespan increase observed in iTRF alone versus control groups.…”

“…However, the molecular mechanisms by which TRF exerts its protective effects remain unclear. In a recent paper published in Nature, Ulgherait et al [7] , after several attempts, developed a TRF protocol, named intermittent TRF (iTRF), able to robustly and consistently extend lifespan in Drosophila. This new dietary protocol was a night-biased iTRF and consisted of 20-h fasting every other day (starting at mid-morning), with a recovery day of ad libitum diet between fast days [Figure 1].…”

“…In order to explore the molecular mechanisms by which iTRF induces longevity, the circadian clock components were investigated [7] . iTRF enhanced night-time expression of the circadian clock components period (per) and timeless (tim), and iTRF-mediated lifespan extension required a functional circadian clock.…”