Summary: Both food timing and the integrity of the liver’s internal clock change metabolic rhythms in mice. Nearly half of the genes that cycle across the day are influenced by both the liver clock and when food is eaten.
Source: University of Pennsylvania
Every cell in the body carries its own roughly 24-hour circadian clock, and new research from the Perelman School of Medicine at the University of Pennsylvania shows how interactions between these clocks shape metabolic health. It has long been observed that shift workers face higher rates of obesity and diabetes, often linked to misaligned internal clocks and irregular eating times. Still, the precise ways that internal clocks in peripheral tissues—like the liver—respond to eating schedules and communicate with one another have been unclear.
A team led by Mitchell Lazar, MD, PhD, Willard and Rhoda Ware Professor in Diabetes and Metabolic Diseases and director of Penn’s Institute for Diabetes, Obesity, and Metabolism, published a study in Science that clarifies parts of this relationship. The work, driven by postdoctoral fellow Dongyin Guan, PhD, used a targeted mouse model to disrupt the internal clock specifically in hepatocytes, the primary metabolic cells of the liver.
When the hepatocyte clock was disrupted, mice developed measurable metabolic changes, including elevated blood triglycerides—an indicator linked to greater risk for cardiovascular disease, diabetes, and stroke. These findings underscore the liver’s internal clock as a key player in maintaining metabolic homeostasis and suggest that proper clock function in peripheral tissues is necessary for healthy systemic metabolism.
“Our discovery of clock communication between different cell types is very exciting as it suggests a previously unappreciated way that the body’s rhythms are coordinated,” said Guan.
Unexpectedly, disrupting the clock of hepatocytes did not only affect those cells. The researchers observed that other cell types within the liver underwent widespread reprogramming of their metabolic activities, indicating intercellular communication of timing information. This cross-talk among cell-specific clocks reveals an additional layer of circadian organization inside an organ that serves as a metabolic hub.
The researchers also examined how feeding schedules interact with the liver’s clocks. While light-dark cycles coordinate central clocks in the brain and influence behavior such as sleep, feeding times are powerful synchronizers of peripheral clocks. In this study, altering when the mice consumed food changed the patterns of metabolic rhythms, and the team found that timing of food intake and the hepatocyte clock together controlled gene expression cycles. In fact, nearly half of the genes that showed daily rhythmic expression were jointly regulated by both the liver’s internal clock and feeding time.
These results connect two areas of growing interest in metabolic research: the circadian regulation of physiology and the metabolic effects of time-restricted eating or intermittent fasting. The Penn team’s findings suggest that aligning meal timing with healthy circadian patterns could strengthen peripheral clock function and improve metabolic outcomes, a consideration that may be particularly valuable for people whose schedules disrupt normal day-night cycles, such as shift workers.
Lazar notes that a clearer picture of how food timing interacts with tissue clocks could inform practical strategies: optimized meal schedules might serve as preventive measures for those at risk and as therapeutic approaches for patients with metabolic disorders such as obesity and diabetes. The work highlights the potential for lifestyle-based interventions, alongside medical treatments, to reinforce the body’s natural rhythms and protect metabolic health.
Penn co-authors on the paper include Ying Xiong, Trang Minh Trinh, Yang Xiao, Wenxiang Hu, Chunjie Jiang, and Pieterjan Dierickx. Collaborators Joshua D. Rabinowitz and Cholsoon Jang from Princeton University also contributed to the study.
Funding: The research was supported by the National Institutes of Health (R01-DK045586, DK19525, and F32DK116519), the JPB Foundation, American Diabetes Association Training Grants (1-17-PDF-076 and 1-18-PDF-132), and an American Heart Association Training Grant (20POST35210738).
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University of Pennsylvania
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Abbey Hunton – University of Pennsylvania
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The image is in the public domain.
Original Research: The study will appear in Science.