In the paper, titled “Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock,” researchers found that the liver’s circadian clock controls the timing of protein release, identifying hundreds of proteins that are secreted differently throughout the day and help regulate metabolism. A key discovery was that the liver releases more endostatin during fasting periods. Endostatin signals fat tissue to increase fat breakdown and alter energy use, revealing how the liver and adipose tissue coordinate metabolism according to the body’s daily biological rhythm.
Christopher Litwin is a Biology of Aging PhD student in the lab of Kevin Koronowski, PhD. Dr. Koronowski is an Assistant Professor with the Department of Biochemistry & Structural Biology and a Principal Investigator with the Sam and Ann Barshop Institute for Longevity and Aging Studies.
Timed secreted proteomes reveal regulation of hepatokines by the liver circadian clock
Christopher Litwin, Qing Zhang, Ioannis Tsialtas, Zhihong Li, Sophia Hernandez, Steffi Prem, Kristi Dietert, Mallory Keating, Tomoki Sato, Jiyoon Ryu, Lily Q Dong, Kevin F Bieniek, Kevin B Koronowski
Nat Commun. 2026 Jun 2. doi: 10.1038/s41467-026-73840-4. Online ahead of print.
Abstract
Here, we use an ex vivo approach compatible with the circadian timescale to interrogate protein secretion from liver, revealing several findings. Proteomic analyses in male and female mice identify hundreds of proteins that exhibit time-of-day-dependent or clock-dependent secretion involved in extracellular matrix, immune, redox, xenobiotic, and fatty acid functions. Among these, the liver secretes more endostatin, a cleavage product of collagen type XVIII alpha 1 (COL18A1), during the inactive, fasting phase of the diurnal cycle. Temporal regulation of COL18A1/endostatin is dysregulated upon loss of Bmal1 through combined effects on Col18a1 transcriptional repression and proteolytic processing. Functional experiments in vivo and in vitro reveal that endostatin suppresses mitochondrial gene expression in white adipose tissue in a time-dependent manner and reduces mitochondrial respiration in adipocytes, while enhancing lipolysis. These results support a mechanism of inter-organ crosstalk whereby hepatically derived, temporally-restricted endostatin tunes adipocytes toward metabolic activities required during the fasting phase.