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. 2022 Feb 3;13(1):681.
doi: 10.1038/s41467-022-28308-6.

Circadian lipid and hepatic protein rhythms shift with a phase response curve different than melatonin

Brianne A Kent  1   2   3 , Shadab A Rahman  1   2 , Melissa A St Hilaire  1   2 , Leilah K Grant  1   2 , Melanie Rüger  1   2 , Charles A Czeisler  1   2 , Steven W Lockley  4   5
Affiliations

Circadian lipid and hepatic protein rhythms shift with a phase response curve different than melatonin

Brianne A Kent et al. Nat Commun. .

Erratum in

Abstract

While studies suggest that light and feeding patterns can reset circadian rhythms in various metabolites, whether these shifts follow a predictable pattern is unknown. We describe the first phase response curves (PRC) for lipids and hepatic proteins in response to combined light and food stimuli. The timing of plasma rhythms was assessed by constant routine before and after exposure to a combined 6.5-hour blue light exposure and standard meal schedule, which was systematically varied by ~20° between in0000dividuals. We find that the rhythms shift according to a PRC, with generally greater shifts for lipids and liver proteins than for melatonin. PRC timing varies relative to the stimulus, with albumin and triglyceride PRCs peaking at a time similar to melatonin whereas the cholesterol and high-density lipoprotein PRCs are offset by ~12 h. These data have important implications for treating circadian misalignment in shiftworkers who consume meals and are exposed to light around the clock.

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Conflict of interest statement

B.A.K., L.K.G., and M.R. declare no competing interests. S.A.R. holds patents for Prevention of Circadian Rhythm Disruption by Using Optical Filters and Improving sleep performance in subject exposed to light at night; S.A.R. owns equity in Melcort Inc.; has provided paid consulting services to Sultan & Knight Limited, Bambu Vault LLC, Lucidity Lighting Inc.; and has received honoraria as an invited speaker and travel funds from Starry Skies Lake Superior, PennWell Corp., and Seoul Semiconductor Co. Ltd. These interests were reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. M.S.H. has provided paid limited consulting for The MathWorks, Inc. M.S.H. has received honoraria and travel funds as an invited speaker from the Providence Sleep Research Interest Group and the Mayo Clinic Metabolomics Resource Core. C.A.C. reports grants to B.W.H. from NHLBI, NIA, NIOSH, and DOD; is/was a paid consultant to Bose, Boston Celtics, Boston Red Sox, Cephalon, Institute of Digital Media and Child Development, Klarman Family Foundation, Jazz Pharma, Merck, Purdue Pharma, Samsung, Teva Pharma Australia, AARP, American Academy of Dental Sleep Medicine, Eisenhower Medical Center, M. Davis and Company, Physician’s Seal, UC San Diego, University of Washington, University of Michigan, Maryland Sleep Society, National Sleep Foundation, Sleep Research Society, Tencent, and Vanda Pharmaceuticals, in which C.A.C. also holds an equity interest; receives research/education support through B.W.H. from Cephalon, Mary Ann & Stanley Snider via Combined Jewish Philanthropies, NFL Charities, Jazz Pharmaceuticals Plc Inc, Philips Respironics Inc, Regeneron Pharmaceuticals, Teva Pharmaceuticals Industries Ltd, Sanofi SA, Optum, ResMed, San Francisco Bar Pilots, Sanofi, Schneider, Simmons, Sysco, Philips, Vanda Pharmaceuticals; is/was an expert witness in legal cases, including those involving Advanced Power Technologies, Alvarado Hospital, LLC, Amtrak; Bombardier, Inc., C&J Energy Services; Casper Sleep, Inc., Columbia River Bar Pilots, Complete General Construction Company, Dallas Police Department, Delta Airlines/Comair, Enterprise Rent-A-Car, Fédération des Médecins Résidents du Québec (FMRQ), FedEx, Greyhound Lines, Inc./Motor Coach Industries/FirstGroup America, H.G. Energy LLC, Maricopa County, Arizona, Sheriff’s Office, Murrieta Valley Unified School District, Pomerado Hospital, Palomar Health District, Puckett EMS, Purdue Pharma, South Carolina Central Railroad Company, LLC., Steel Warehouse, Inc., Union Pacific Railroad, United Parcel Service, and Vanda Pharmaceuticals; serves as the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc.; and receives royalties from McGraw Hill, and Philips Respironics for the Actiwatch-2 & Actiwatch Spectrum devices. C.A.C.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. S.W.L. reports the following interests for the last 5 years (2015–2020). S.W.L. has received consulting fees from Atlanta Falcons, Atlanta Hawks, BHP Billiton, Delos Living LLC, EyeJust Inc., McCullough Hill Leary PS, Noble Insights, OpTerra Energy Services Inc., Pegasus Capital Advisors, Phillips Lytle LLP, Plan LED, Rec Room, Serrado Capital, Slingshot Insights, Stantec and Team C Racing. He has current consulting contracts with Akili Interactive, Apex 2100 Ltd, Consumer Sleep Solutions, Headwaters Inc., Hintsa Performance AG, KBR Wyle Services, Light Cognitive, Lighting Science Group Corporation/HealthE, Look Optic, Mental Workout/Timeshifter, Paul Weiss Rifkind Wharton & Garrison LLP, Six Senses, and View Inc. S.W.L. has received unrestricted equipment gifts from Bionetics Corporation and F.LUX Software LLC; a fellowship gift from Stockgrand Ltd; has equity in iSLEEP, Pty; royalties from Oxford University Press; honoraria plus travel, accommodation and/or meals for invited seminars, conference presentations or teaching from Estée Lauder, Ineos, Informa Exhibitions, MIT, Roxbury Latin School, and Teague; travel, accommodation and/or meals only (no honoraria) for invited seminars, conference presentations, teaching or editorial duties from DIN, Emory University, Lightfair, SLTBR, Solemma and Wiley. S.W.L. has an ongoing investigator-initiated grant from F. Lux Software LLC and a Clinical Research Support Agreement from Vanda Pharmaceuticals Inc. SWL holds a process patent for ‘Systems and methods for determining and/or controlling sleep quality’, which is assigned to the Brigham and Women’s Hospital per Hospital policy, and ‘Method and system for generating and providing notifications for a circadian shift protocol’ held by Mental Workout Inc. S.W.L. has served as a paid expert in legal proceedings related to light, health and work patterns. S.W.L. was the Program Leader for ‘Safety and Productivity Improvements’ in the CRC for Alertness, Safety and Productivity from 2015–2019, through a part-time Adjunct Professor appointment at Monash University, Australia. He currently holds the position of Professor (part-time) and VC Fellow at the University of Surrey, UK. S.W.L.’s interests are reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Figures

Fig. 1
Fig. 1. Study protocol.
The schedule for participants (A) 29K6V and (B) 29R8V, plotted in raster format. White and grey bars indicate wake episodes in ambient light of <190 lux or <3 lux, respectively. Black bars indicate scheduled sleep in darkness (0 lux). The hatched bars indicate the 6.5-h light exposure (LE). The open circles indicate the timing of meals and snacks (smaller circle) during the exposure day.
Fig. 2
Fig. 2. Examples of rhythms in CR1 and CR2.
Data collected during CR1 (black filled circles) and CR2 (grey open circles) for (A, E) albumin, (B, F) total cholesterol, (C, G) triglycerides, and (D, H) HDL-C. The x-axis is the time each blood sample was taken and the y-axis is the clinical assay concentration. The solid black line is the fitted cosinor regression for CR1 and the grey solid line is the fitted cosinor regression for CR2. The phase shift (Δϕ) and participant ID for each example is noted in the bottom right corner of the plots. The exposure day schedule is represented in the bar above the plots; grey bars indicate wake episodes in ambient light <3 lux, hatched bars indicate the 6.5-h light exposure (LE), and the open circles indicate the timing of meals and snacks.
Fig. 3
Fig. 3. Phase response curves (PRCs).
Raw phase shifts in (A) melatonin, (B) albumin, (C) total cholesterol, (D) triglycerides, and (E) HDL-C plotted as a function of circadian phase of the stimulus, defined as the onset of LE - CR1 assay-specific acrophase. PRCs are double-plotted. The solid horizontal black line indicates no phase shift. Black squares represent each individual that had statistically significant cosinor regressions in the assay during both CR1 and CR2. The solid sinusoidal black line is the fitted single-harmonic function. The 95% confidence intervals generated from the fit single-harmonic function are shown by the grey dotted lines.
See this image and copyright information in PMC

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