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Edited by Joseph S. Takahashi, Howard Hughes Medical Institute and University of Texas Southwestern Medical Center, Dallas, TX, and approved April 23, 2018 (received for review August 22, 2017)
Significance
Circadian misalignment (i.e., behavioral processes such as food intake or sleep occurring at inappropriate endogenous circadian times) commonly occurs during shift work and is associated with health problems. Identifying mechanisms underlying health problems associated with circadian misalignment will help develop precision medicine countermeasures. Thus, we investigated the impact of circadian misalignment on the human plasma proteome using a simulated nightshift protocol in healthy volunteers. We demonstrate that circadian and/or behavioral wake–sleep/food intake–fasting cycles regulate 24-h time-of-day patterns of the human plasma proteome. Further, we show that proteins altered during circadian misalignment are associated with biological pathways involved in immune function, metabolism, and cancer and with altered glucose and energy metabolism, identifying potential mechanisms contributing to metabolic dysregulation.
Abstract
Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake–sleep/food intake–fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.
Footnotes
- ↵1To whom correspondence may be addressed. Email: christopher.depner{at}colorado.edu or kenneth.wright{at}colorado.edu.
Author contributions: E.L.M., A.W.M., and K.P.W. designed research; C.M.D., E.L.M., A.W.M., and K.P.W. performed research; C.M.D., E.L.M., A.W.M., and K.P.W. analyzed data; and C.M.D. and K.P.W. wrote the paper.
Conflict of interest statement: E.L.M. has received grants/research support from Philips Inc. and Somalogics, Inc. K.P.W. has received grants/research support from CurAegis Technologies (formerly known as Torvec, Inc.), Philips Inc., and Somalogics, Inc. K.P.W. has received consulting fees or has served as a paid member of the scientific advisory boards for CurAegis Technologies, the NIH, and Circadian Therapeutics. K.P.W. has received speaker honoraria from the American Academy of Sleep Medicine, the American College of Chest Physicians, the American Diabetes Association, The Obesity Society, and Philips, Inc. K.P.W. holds stock options for CurAegis Technologies.
This article is a PNAS Direct Submission.
Data deposition: Raw protein abundance data expressed as relative florescence units have been deposited in Figshare (https://figshare.com/) and are publicly available at the following DOI: 10.6084/m9.figshare.5752650.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1714813115/-/DCSupplemental.
Published under the PNAS license.
Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome
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