A Daily Liver Clock May Tell the Body When to Burn Fat
The liver may not simply release metabolic signals whenever they are needed. New research from UT Health San Antonio suggests that it follows a carefully timed daily program, sending proteins into the bloodstream at specific points in the 24-hour cycle. These signals, known as hepatokines, can influence distant tissues including fat and muscle, potentially helping the body coordinate how it stores, mobilizes and uses energy. The findings, published June 2 in Nature Communications, offer a detailed look at how the liver’s circadian clock may act as a biological communications system—and raise the possibility that some metabolic treatments could become more effective when administered at precisely chosen times.
The study was led by Kevin Koronowski, PhD, assistant professor in the Department of Biochemistry and Structural Biology at the Joe R. and Teresa Lozano Long School of Medicine and the Sam and Ann Barshop Institute for Longevity and Aging Studies. Christopher Litwin, a fourth-year doctoral student in Koronowski’s laboratory, is the paper’s first author. Their work focused on a fundamental question in chronobiology: how does an internal cellular clock control not only the production of proteins, but also their secretion from a tissue into the circulation? Although scientists have known that the liver regulates the release of some metabolic proteins, researchers lacked a broad way to measure how secretion changes over the course of an entire day.
Nearly every nucleated cell contains a molecular timekeeping mechanism built around interconnected gene and protein feedback loops. Core clock proteins accumulate and decline in rhythmic cycles, controlling the activity of numerous downstream genes. In the liver, this clock is closely linked to feeding, fasting, glucose production, lipid metabolism and detoxification. The new research indicates that its influence extends beyond the liver’s own cells: the clock also helps determine when signaling proteins are exported into the bloodstream. In effect, the liver appears to use time as part of its biological language, transmitting different metabolic instructions during different phases of the day.
To investigate this process, the researchers examined the liver’s secreted proteome—the complete set of proteins released by liver cells—at multiple times across the daily cycle. This approach is distinct from measuring gene expression alone. A gene may be active without its protein being secreted immediately, and a protein’s release can depend on processing, packaging and transport through the cell’s secretory machinery. By tracking secreted proteins over time, the team could identify signals whose abundance outside liver cells rose and fell according to a daily rhythm. These time-dependent patterns revealed that secretion itself is a regulated biological event rather than a passive consequence of protein production.
The researchers found that many liver-derived proteins were released according to defined schedules. Such timing could allow the liver to synchronize metabolism in organs that cannot directly monitor the liver’s internal state. Fat tissue, for example, must determine when to store energy and when to release fatty acids into the bloodstream, while muscle must adjust fuel use according to activity and nutritional status. A circulating hepatokine released at the appropriate time could act as a systemic cue, connecting the liver’s clock with metabolic programs in other tissues. This type of communication may be especially important during the normal transition between feeding and fasting, when the body must rapidly change its preferred energy sources.
One of the most striking examples involved endostatin, a protein best known for its effects on blood-vessel formation but also associated with metabolic regulation. In the study, endostatin was most effective at promoting the breakdown of fat when it was released in accordance with the liver’s natural daily schedule. The observation suggests that the biological impact of a protein may depend not only on how much is present, but also on when it reaches its target tissues. A dose delivered at the wrong time could therefore produce a weaker response than the same dose delivered during a phase when fat cells are more receptive or when downstream metabolic pathways are already primed for action.
That possibility has direct implications for the emerging field of chronotherapy, which aims to align medical treatment with the body’s biological rhythms. Drugs and hormone-based therapies are often evaluated primarily by dose and chemical properties, but circadian biology suggests that timing can influence absorption, distribution, target engagement and side effects. If future studies confirm that endostatin or related peptides work best during a particular metabolic window, treatment schedules could eventually be designed around the liver’s secretion rhythms. The researchers emphasize that such applications remain prospective; the current findings do not establish a clinical therapy or demonstrate that changing protein timing will treat obesity or diabetes in people.
The work also helps explain why irregular sleep and eating patterns are repeatedly linked to metabolic disease. Artificial light, shift work, late-night meals and constantly changing schedules can disturb the alignment between the brain’s central clock, clocks in peripheral organs and the timing of nutrient intake. When the liver receives food-related signals at biologically unusual times, its metabolic programs may become uncoupled from those in adipose tissue, muscle and other organs. Over time, this internal misalignment could contribute to impaired glucose control, abnormal lipid handling and weight gain. The new study does not prove that disrupted hepatokine secretion causes these conditions, but it provides a plausible molecular route through which daily routines could influence whole-body physiology.
Koronowski’s laboratory is now exploring novel peptides and their potential metabolic effects, with the broader goal of identifying signals that could lead to improved therapies. The researchers describe the search as an effort to find the next generation of metabolic drugs, including candidates that might complement or surpass existing treatments such as GLP-1-based medicines. Any future drug development will require extensive testing to determine how these molecules act, how long they remain in circulation, whether they affect multiple organs, and whether their timing can be safely controlled in humans. The liver-clock findings provide a framework for those investigations by showing that secreted proteins should be studied as dynamic, time-dependent signals rather than as static molecules.
The study ultimately presents the liver as both a metabolic factory and a precisely timed broadcasting station. Its internal clock appears to organize the release of a broad collection of proteins, allowing messages about energy availability and fuel use to travel through the bloodstream on a daily schedule. By mapping these timed secretomes, scientists may be able to uncover new links between circadian disruption and metabolic disease, while identifying opportunities to coordinate meals, medicines and biological rhythms more intelligently. The next challenge will be determining whether the timing patterns observed in laboratory research can be translated into reliable strategies for preventing or treating obesity, diabetes and related disorders.
Subject of Research: The liver’s circadian clock and its time-dependent secretion of hepatokines that regulate whole-body metabolism.
Article Title: “Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock”
News Publication Date: August 12, 2026
Web References: https://news.uthscsa.edu/ut-san-antonio-researchers-uncover-how-livers-internal-clock-may-influence-metabolism/ ; https://www.nature.com/articles/s41467-026-73840-4
References: Nature Communications, article published June 2, 2026. DOI: 10.1038/s41467-026-73840-4
Keywords: Liver, circadian clock, biological rhythms, metabolism, hepatokines, secreted proteins, endostatin, obesity, diabetes, chronotherapy, metabolic disease, fat metabolism
