bims-ciryme 2019-06-02 papers

Cell. 2019 May 30. pii: S0092-8674(19)30444-1. [Epub ahead of print]177(6): 1448-1462.e14

Defining the Independence of the Liver Circadian Clock.

Kevin B Koronowski, Kenichiro Kinouchi, Patrick-Simon Welz, Jacob G Smith, Valentina M Zinna, Jiejun Shi, Muntaha Samad, Siwei Chen, Christophe N Magnan, Jason M Kinchen, Wei Li, Pierre Baldi, Salvador Aznar Benitah, Paolo Sassone-Corsi.

Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.

Keywords: autonomous; bmal1; chromatin; circadian; clock; diurnal physiology; epigenetics; light; metabolism; systemic signaling

DOI: https://doi.org/10.1016/j.cell.2019.04.025

Cell. 2019 May 30. pii: S0092-8674(19)30507-0. [Epub ahead of print]177(6): 1436-1447.e12

BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.

Patrick-Simon Welz, Valentina M Zinna, Aikaterini Symeonidi, Kevin B Koronowski, Kenichiro Kinouchi, Jacob G Smith, Inés Marín Guillén, Andrés Castellanos, Georgiana Crainiciuc, Neus Prats, Juan Martín Caballero, Andrés Hidalgo, Paolo Sassone-Corsi, Salvador Aznar Benitah.

Circadian rhythms control organismal physiology throughout the day. At the cellular level, clock regulation is established by a self-sustained Bmal1-dependent transcriptional oscillator network. However, it is still unclear how different tissues achieve a synchronized rhythmic physiology. That is, do they respond independently to environmental signals, or require interactions with each other to do so? We show that unexpectedly, light synchronizes the Bmal1-dependent circadian machinery in single tissues in the absence of Bmal1 in all other tissues. Strikingly, light-driven tissue autonomous clocks occur without rhythmic feeding behavior and are lost in constant darkness. Importantly, tissue-autonomous Bmal1 partially sustains homeostasis in otherwise arrhythmic and prematurely aging animals. Our results therefore support a two-branched model for the daily synchronization of tissues: an autonomous response branch, whereby light entrains circadian clocks without any commitment of other Bmal1-dependent clocks, and a memory branch using other Bmal1-dependent clocks to "remember" time in the absence of external cues.

DOI: https://doi.org/10.1016/j.cell.2019.05.009

Sci Rep. 2019 May 27. 9(1): 7874

Time-restricted feeding improves adaptation to chronically alternating light-dark cycles.

Maaike Schilperoort, Rosa van den Berg, Martijn E T Dollé, Conny T M van Oostrom, Karina Wagner, Lauren L Tambyrajah, Paul Wackers, Tom Deboer, Gerben Hulsegge, Karin I Proper, Harry van Steeg, Till Roenneberg, Nienke R Biermasz, Patrick C N Rensen, Sander Kooijman, Linda W M van Kerkhof.

Disturbance of the circadian clock has been associated with increased risk of cardio-metabolic disorders. Previous studies showed that optimal timing of food intake can improve metabolic health. We hypothesized that time-restricted feeding could be a strategy to minimize long term adverse metabolic health effects of shift work and jetlag. In this study, we exposed female FVB mice to weekly alternating light-dark cycles (i.e. 12 h shifts) combined with ad libitum feeding, dark phase feeding or feeding at a fixed clock time, in the original dark phase. In contrast to our expectations, long-term disturbance of the circadian clock had only modest effects on metabolic parameters. Mice fed at a fixed time showed a delayed adaptation compared to ad libitum fed animals, in terms of the similarity in 24 h rhythm of core body temperature, in weeks when food was only available in the light phase. This was accompanied by increased plasma triglyceride levels and decreased energy expenditure, indicating a less favorable metabolic state. On the other hand, dark phase feeding accelerated adaptation of core body temperature and activity rhythms, however, did not improve the metabolic state of animals compared to ad libitum feeding. Taken together, restricting food intake to the active dark phase enhanced adaptation to shifts in the light-dark schedule, without significantly affecting metabolic parameters.

DOI: https://doi.org/10.1038/s41598-019-44398-7

Diabetologia. 2019 May 27.

Cellular circadian period length inversely correlates with HbA1c levels in individuals with type 2 diabetes.

Flore Sinturel, Anne-Marie Makhlouf, Patrick Meyer, Christel Tran, Zoltan Pataky, Alain Golay, Guillaume Rey, Cédric Howald, Emmanouil T Dermitzakis, Claude Pichard, Jacques Philippe, Steven A Brown, Charna Dibner.

AIMS/HYPOTHESIS: The circadian system plays an essential role in regulating the timing of human metabolism. Indeed, circadian misalignment is strongly associated with high rates of metabolic disorders. The properties of the circadian oscillator can be measured in cells cultured in vitro and these cellular rhythms are highly informative of the physiological circadian rhythm in vivo. We aimed to discover whether molecular properties of the circadian oscillator are altered as a result of type 2 diabetes.
METHODS: We assessed molecular clock properties in dermal fibroblasts established from skin biopsies taken from nine obese and eight non-obese individuals with type 2 diabetes and 11 non-diabetic control individuals. Following in vitro synchronisation, primary fibroblast cultures were subjected to continuous assessment of circadian bioluminescence profiles based on lentiviral luciferase reporters.
RESULTS: We observed a significant inverse correlation (ρ = -0.592; p < 0.05) between HbA1c values and circadian period length within cells from the type 2 diabetes group. RNA sequencing analysis conducted on samples from this group revealed that ICAM1, encoding the endothelial adhesion protein, was differentially expressed in fibroblasts from individuals with poorly controlled vs well-controlled type 2 diabetes and its levels correlated with cellular period length. Consistent with this circadian link, the ICAM1 gene also displayed rhythmic binding of the circadian locomotor output cycles kaput (CLOCK) protein that correlated with gene expression.
CONCLUSIONS/INTERPRETATION: We provide for the first time a potential molecular link between glycaemic control in individuals with type 2 diabetes and circadian clock machinery. This paves the way for further mechanistic understanding of circadian oscillator changes upon type 2 diabetes development in humans.
DATA AVAILABILITY: RNA sequencing data and clinical phenotypic data have been deposited at the European Genome-phenome Archive (EGA), which is hosted by the European Bioinformatics Institute (EBI) and the Centre for Genomic Regulation (CRG), ega-box-1210, under accession no. EGAS00001003622.

Keywords: Circadian bioluminescence recording; Circadian clock; HbA1c; Humans; ICAM1; Type 2 diabetes

DOI: https://doi.org/10.1007/s00125-019-4907-0

Proc Natl Acad Sci U S A. 2019 May 28. pii: 201901824. [Epub ahead of print]

High sensitivity and interindividual variability in the response of the human circadian system to evening light.

Andrew J K Phillips, Parisa Vidafar, Angus C Burns, Elise M McGlashan, Clare Anderson, Shantha M W Rajaratnam, Steven W Lockley, Sean W Cain.

Before the invention of electric lighting, humans were primarily exposed to intense (>300 lux) or dim (<30 lux) environmental light-stimuli at extreme ends of the circadian system's dose-response curve to light. Today, humans spend hours per day exposed to intermediate light intensities (30-300 lux), particularly in the evening. Interindividual differences in sensitivity to evening light in this intensity range could therefore represent a source of vulnerability to circadian disruption by modern lighting. We characterized individual-level dose-response curves to light-induced melatonin suppression using a within-subjects protocol. Fifty-five participants (aged 18-30) were exposed to a dim control (<1 lux) and a range of experimental light levels (10-2,000 lux for 5 h) in the evening. Melatonin suppression was determined for each light level, and the effective dose for 50% suppression (ED50) was computed at individual and group levels. The group-level fitted ED50 was 24.60 lux, indicating that the circadian system is highly sensitive to evening light at typical indoor levels. Light intensities of 10, 30, and 50 lux resulted in later apparent melatonin onsets by 22, 77, and 109 min, respectively. Individual-level ED50 values ranged by over an order of magnitude (6 lux in the most sensitive individual, 350 lux in the least sensitive individual), with a 26% coefficient of variation. These findings demonstrate that the same evening-light environment is registered by the circadian system very differently between individuals. This interindividual variability may be an important factor for determining the circadian clock's role in human health and disease.

Keywords: circadian disruption; circadian rhythms; evening light; light sensitivity; melatonin suppression

DOI: https://doi.org/10.1073/pnas.1901824116