Advisory Committee Chair
Girish Melkani
Advisory Committee Members
Jarrod Barnes
Nicole Riddle
Adam Wende
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Circadian disruption caused by aging, genetic, environmental, and lifestyle factors can lead to compromised cardiac and skeletal muscle function and potentially accelerate the progression of metabolic diseases. Time-restricted feeding/eating (TRF/TRE, referred to as TRF hereafter), a dietary intervention that confines food intake within a consistent window of the day, has pleiotropic benefits from flies and mice to humans. However, the effectiveness of TRF on heart and muscle in the context of various metabolic challenges such as circadian disruption and obesity is largely unknown. Current insights into the mechanisms of TRF are primarily based on multi-omics approaches, particularly transcriptomes; however, limited studies have validated the contribution of candidate genes/pathways to TRF-mediated benefits. Here, we demonstrate that TRF maintains cardiac performance and myofibrillar organization, and modulates lipid accumulation in Drosophila when the circadian rhythm is disrupted by constant light. Time-series cardiac transcriptome analysis shows that TRF induces oscillations in the expression of genes associated with triglyceride metabolism. In particular, TRF induces elevated expression of diacylglycerol O-acyltransferase 2 (Dgat2) during the feeding period. Heart-specific manipulation of Dgat2 modulates cardiac function and lipid droplet accumulation. Notably, heart-specific overexpression of human Dgat2 at ZT 0-10 improves cardiac performance in circadian-disrupted flies. We next examined the time-series IFM (indirect flight muscle in Drosophila, equivalent to skeletal muscle in mammals, referred to as muscle hereafter) transcriptome data and we found that TRF induces downregulation of Dgat2 expression in the Drosophila models of both diet- and genetic-induced obesity. Muscle-specific manipulation of Dgat2 affects muscle performance and lipid droplet accumulation. Notably, TRF continues to improve muscle function in conjunction with muscle-specific suppression of Dgat2 or overexpression of human Dgat2. Overall, our data suggest that modulation of Dgat2 contributes, at least partially, to TRF-mediated benefits in the heart and muscle under various metabolic challenges (i.e. circadian disruption and obesity). These findings provide valuable insights into potential targets and strategies for the mitigation of metabolic disorders associated with cardiac and skeletal muscle.
Recommended Citation
Livelo, Yiming Guo, "Time-Restricted Feeding Modulates Dgat2 Expression In Cardiac And Skeletal Muscle" (2023). All ETDs from UAB. 3514.
https://digitalcommons.library.uab.edu/etd-collection/3514