The liver may do more than process nutrients and help manage the body’s energy supply. New research suggests it also follows a daily schedule for sending signals to other parts of the body.
In a study published in Nature Communications, researchers found that hundreds of proteins released by the livers of mice changed depending on the time of day or the liver’s internal clock. One protein, called endostatin, appeared to help coordinate activity in fat tissue during the animals’ usual fasting period. The findings offer a closer look at how metabolism may be organized across the day, but they do not show that people should eat at a certain time or that changing meal timing improves metabolic health.
The body runs on roughly 24-hour biological rhythms known as circadian rhythms. These rhythms help regulate sleep, hormones, digestion and metabolism. While the brain helps keep the body’s overall clock on schedule, individual organs also have timing systems of their own.
“Any cell with a nucleus is likely to express the molecular clock. We are interested in how cells work together and coordinate their activities,” said Kevin Koronowski, Ph.D., an assistant professor at UT Health San Antonio and senior author of the study. “The clock is one way the body can organize physiology in an efficient and appropriate manner.”
Researchers focused on the liver because it plays a major role in how the body handles carbohydrates, fats and other nutrients. It also releases proteins that can travel through the bloodstream and send messages to other tissues.
The team wanted to know whether those signals change depending on the time of day.
Using liver tissue from male and female mice, researchers tracked proteins released at different points in the daily cycle. They found hundreds whose release changed over time or depended on the liver’s internal clock.
They then took a closer look at endostatin. Mouse livers released more of the protein during the animals’ inactive, fasting period.
Because mice are nocturnal, that period occurs mostly during the day. Humans typically have the opposite activity pattern, so the findings cannot simply be translated into recommendations about when people should eat.
Additional experiments in mice and fat cells suggested that endostatin may help fat tissue adjust during fasting. It increased the breakdown of stored fat and changed several processes involved in how fat cells use energy.
“We thought the time-dependent release of proteins may be important for coordinating metabolism in tissues like fat or muscle,” said first author Christopher Litwin, a doctoral student in Koronowski’s lab. “The core idea is that the clock regulates protein secretion and can influence metabolism across the day, and in other tissues.”
Researchers also disrupted part of the liver’s internal clock and found that doing so changed the normal timing of endostatin. That added evidence that the liver’s circadian rhythm helps control when the protein is released.
Together, the findings suggest the liver may not send the same metabolic signals at the same levels throughout the day. Instead, some of those signals may be timed to help other tissues respond differently during active, resting, eating and fasting periods.
That could eventually help scientists better understand why metabolism changes with time of day. It may also help explain why researchers studying sleep, eating schedules and metabolic health increasingly pay attention not only to what happens in the body, but when it happens.
Still, this study cannot tell people when they should eat.
Researchers did not test early versus late meals, time-restricted eating or different eating schedules in people. Most of the experiments involved mice, mouse tissues and cultured cells. Researchers also do not yet know whether endostatin follows the same pattern in humans or whether it meaningfully affects body weight, blood sugar or the risk of metabolic disease.
The findings also do not establish endostatin as a treatment for obesity or other metabolic conditions. Although the research team is interested in whether timed metabolic signals might eventually lead to new therapies, that possibility remains far from established.
The research and supporting laboratory resources received funding from several National Institutes of Health institutes and programs, including the National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging and National Cancer Institute. Additional support came from the Max and Minnie Tomerlin Voelcker Fund, American Heart Association, Baptist Health Foundation of San Antonio and Cancer Prevention and Research Institute of Texas, along with institutional and shared research-resource grants.