bims-ciryme 2021-01-31 papers

Nat Commun. 2021 01 25. 12(1): 565

Time-restricted feeding normalizes hyperinsulinemia to inhibit breast cancer in obese postmenopausal mouse models.

Manasi Das, Lesley G Ellies, Deepak Kumar, Consuelo Sauceda, Alexis Oberg, Emilie Gross, Tyler Mandt, Isabel G Newton, Mehak Kaur, Dorothy D Sears, Nicholas J G Webster.

Accumulating evidence indicates that obesity with its associated metabolic dysregulation, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Caloric restriction can ameliorate the harmful metabolic effects of obesity and inhibit cancer progression but is difficult to implement and maintain outside of the clinic. In this study, we aim to test a time-restricted feeding (TRF) approach on mouse models of obesity-driven postmenopausal breast cancer. We show that TRF abrogates the obesity-enhanced mammary tumor growth in two orthotopic models in the absence of calorie restriction or weight loss. TRF also reduces breast cancer metastasis to the lung. Furthermore, TRF delays tumor initiation in a transgenic model of mammary tumorigenesis prior to the onset of obesity. Notably, TRF increases whole-body insulin sensitivity, reduces hyperinsulinemia, restores diurnal gene expression rhythms in the tumor, and attenuates tumor growth and insulin signaling. Importantly, inhibition of insulin secretion with diazoxide mimics TRF whereas artificial elevation of insulin through insulin pumps implantation reverses the effect of TRF, suggesting that TRF acts through modulating hyperinsulinemia. Our data suggest that TRF is likely to be effective in breast cancer prevention and therapy.

DOI: https://doi.org/10.1038/s41467-020-20743-7

Front Neurosci. 2020 ;14 613531

Challenging the Integrity of Rhythmic Maternal Signals Revealed Gene-Specific Responses in the Fetal Suprachiasmatic Nuclei.

Vendula Lužná, Pavel Houdek, Karolína Liška, Alena Sumová.

During fetal stage, maternal circadian system sets the phase of the developing clock in the suprachiasmatic nuclei (SCN) via complex pathways. We addressed the issue of how impaired maternal signaling due to a disturbed environmental light/dark (LD) cycle affects the fetal SCN. We exposed pregnant Wistar rats to two different challenges - a 6-h phase shift in the LD cycle on gestational day 14, or exposure to constant light (LL) throughout pregnancy - and detected the impact on gene expression profiles in 19-day-old fetuses. The LD phase shift, which changed the maternal SCN into a transient state, caused robust downregulation of expression profiles of clock genes (Per1, Per2, and Nr1d1), clock-controlled (Dbp) genes, as well as genes involved in sensing various signals, such as c-fos and Nr3c1. Removal of the rhythmic maternal signals via exposure of pregnant rats to LL abolished the rhythms in expression of c-fos and Nr3c1 in the fetal SCN. We identified c-fos as the gene primarily responsible for sensing rhythmic maternal signals because its expression profile tracked the shifted or arrhythmic maternal SCN clock. Pathways related to the maternal rhythmic behavioral state were likely not involved in driving the c-fos expression rhythm. Instead, introduction of a behavioral rhythm to LL-exposed mothers via restricted feeding regime strengthened rhythm in Vip expression in the fetal SCN. Our results revealed for the first time that the fetal SCN is highly sensitive in a gene-specific manner to various changes in maternal signaling due to disturbances of environmental cycles related to the modern lifestyle in humans.

Keywords: circadian clock; development; fetus; maternal entrainment; suprachiasmatic nucleus

DOI: https://doi.org/10.3389/fnins.2020.613531

Sci Rep. 2021 Jan 28. 11(1): 2573

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains.

Sam-Moon Kim, Chelsea A Vadnie, Vivek M Philip, Leona H Gagnon, Kodavali V Chowdari, Elissa J Chesler, Colleen A McClung, Ryan W Logan.

Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders-80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.

DOI: https://doi.org/10.1038/s41598-021-82069-8

Nutrients. 2021 Jan 24. pii: 346. [Epub ahead of print]13(2):

Pilot Clinical Trial of Time-Restricted Eating in Patients with Metabolic Syndrome.

Iwona Świątkiewicz, Celestyna Mila-Kierzenkowska, Alina Woźniak, Karolina Szewczyk-Golec, Jarosław Nuszkiewicz, Joanna Wróblewska, Paweł Rajewski, Simone J P M Eussen, Kristine Færch, Emily N C Manoogian, Satchidananda Panda, Pam R Taub.

Metabolic syndrome (MetS) and erratic eating patterns are associated with circadian rhythm disruption which contributes to an increased cardiometabolic risks. Restricting eating period (time-restricted eating, TRE) can restore robust circadian rhythms and improve cardiometabolic health. We describe a protocol of the Time-Restricted Eating on Metabolic and Neuroendocrine homeostasis, Inflammation, and Oxidative Stress (TREMNIOS) pilot clinical trial in Polish adult patients with MetS and eating period of ≥14 h/day. The study aims to test the feasibility of TRE intervention and methodology for evaluating its efficacy for improving metabolic, neuroendocrine, inflammatory, oxidative stress and cardiac biomarkers, and daily rhythms of behavior for such population. Participants will apply 10-h TRE over a 12-week monitored intervention followed by a 12-week self-directed intervention. Changes in eating window, body weight and composition, biomarkers, and rhythms of behavior will be evaluated. Dietary intake, sleep, activity and wellbeing will be monitored with the myCircadianClock application and questionnaires. Adherence to TRE defined as the proportion of days recorded with app during the monitored intervention in which participants satisfied 10-h TRE is the primary outcome. TREMNIOS will also provide an exploratory framework to depict post-TRE changes in cardiometabolic outcomes and behavior rhythms. This protocol extends previous TRE-related protocols by targeting European population with diagnosed MetS and including long-term intervention, validated tools for monitoring dietary intake and adherence, and comprehensive range of biomarkers. TREMNIOS trial will lay the groundwork for a large-scale randomized controlled trial to determine TRE efficacy for improving cardiometabolic health in MetS population.

Keywords: body weight; cardiometabolic risks; circadian rhythm; clinical trial; dietary assessment methodologies; eating pattern; health outcomes; m-health applications; metabolic syndrome; time-restricted eating

DOI: https://doi.org/10.3390/nu13020346

EMBO J. 2021 Jan 25. e106745

CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping.

Marrit Putker, David C S Wong, Estere Seinkmane, Nina M Rzechorzek, Aiwei Zeng, Nathaniel P Hoyle, Johanna E Chesham, Mathew D Edwards, Kevin A Feeney, Robin Fischer, Nicolai Peschel, Ko-Fan Chen, Michael Vanden Oever, Rachel S Edgar, Christopher P Selby, Aziz Sancar, John S O'Neill.

Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY-deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have shorter periods than wild-type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY-mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational.

Keywords: cellular clock; circadian rhythm; cryptochrome; daily timekeeping; robustness

DOI: https://doi.org/10.15252/embj.2020106745