Diet- and time-of-day-dependent regulation of heart and adipose tissue during obesity

High-fat diet (HFD) feeding rewires circadian rhythms of feeding behavior and peripheral organs. While the liver has been extensively studied, it remains largely unknown how other peripheral organs adapt their circadian rhythms upon diet-induced obesity and the flexibility towards weight loss after dietary intervention. Here, we took a systems approach to profile diurnal transcriptome of adipose tissue and heart in diet-induced obese mice either put on low-fat diet (LFD) that reduces weight or still fed HFD. We found that diet reversal specifically restores diurnal difference in Clock transcripts in heart and adipose tissue without altering the rhythmicity of other clock genes. Pathway analysis showed that LFD activates mitochondrial energy metabolism and suppresses chronic low-grade metabolic inflammation in the heart. In addition, LFD promotes cell proliferation pathway while inhibiting cell differentiation pathway in adipose tissue. We further profiled neutral lipids by quantitative lipidomics in adipose tissue, and performed transcript-lipid network integration. Remarkably, multi-omics analysis identified three clusters of biological molecules. Cluster 1 is composed of signatures that restore diurnal rhythm upon LFD, including triglyceride hydrolase Ces1d and many triglyceride species. Cluster 2 is composed of molecules that remain largely unaltered, e.g., circadian clock genes. Together, our work defines the circadian and molecular signatures in non-hepatic organs during diet-induced obesity and their flexibility upon dietary intervention.