bims-ciryme 2023-10-22 papers

PLoS Genet. 2023 Oct 19. 19(10): e1011011

The circadian clock gene bmal1 is necessary for co-ordinated circatidal rhythms in the marine isopod Eurydice pulchra (Leach).

Zhang Lin, Edward W Green, Simon G Webster, Michael H Hastings, David C Wilcockson, Charalambos P Kyriacou.

Circadian clocks in terrestrial animals are encoded by molecular feedback loops involving the negative regulators PERIOD, TIMELESS or CRYPTOCHROME2 and positive transcription factors CLOCK and BMAL1/CYCLE. The molecular basis of circatidal (~12.4 hour) or other lunar-mediated cycles (~15 day, ~29 day), widely expressed in coastal organisms, is unknown. Disrupting circadian clockworks does not appear to affect lunar-based rhythms in several organisms that inhabit the shoreline suggesting a molecular independence of the two cycles. Nevertheless, pharmacological inhibition of casein kinase 1 (CK1) that targets PERIOD stability in mammals and flies, affects both circadian and circatidal phenotypes in Eurydice pulchra (Ep), the speckled sea-louse. Here we show that these drug inhibitors of CK1 also affect the phosphorylation of EpCLK and EpBMAL1 and disrupt EpCLK-BMAL1-mediated transcription in Drosophila S2 cells, revealing a potential link between these two positive circadian regulators and circatidal behaviour. We therefore performed dsRNAi knockdown of Epbmal1 as well as the major negative regulator in Eurydice, Epcry2 in animals taken from the wild. Epcry2 and Epbmal1 knockdown disrupted Eurydice's circadian phenotypes of chromatophore dispersion, tim mRNA cycling and the circadian modulation of circatidal swimming, as expected. However, circatidal behaviour was particularly sensitive to Epbmal1 knockdown with consistent effects on the power, amplitude and rhythmicity of the circatidal swimming cycle. Thus, three Eurydice negative circadian regulators, EpCRY2, in addition to EpPER and EpTIM (from a previous study), do not appear to be required for the expression of robust circatidal behaviour, in contrast to the positive regulator EpBMAL1. We suggest a neurogenetic model whereby the positive circadian regulators EpBMAL1-CLK are shared between circadian and circatidal mechanisms in Eurydice but circatidal rhythms require a novel, as yet unknown negative regulator.

DOI: https://doi.org/10.1371/journal.pgen.1011011

Proc Natl Acad Sci U S A. 2023 Oct 24. 120(43): e2308489120

An intact pituitary vasopressin system is critical for building a robust circadian clock in the suprachiasmatic nucleus.

Yoshiaki Yamaguchi, Yota Maekawa, Kyohei Kabashima, Takanobu Mizuno, Motomi Tainaka, Toru Suzuki, Kumiko Dojo, Takeichiro Tominaga, Sayaka Kuroiwa, Satoru Masubuchi, Masao Doi, Keiko Tominaga, Kazuto Kobayashi, Satoshi Yamagata, Keiichi Itoi, Manabu Abe, William J Schwartz, Kenji Sakimura, Hitoshi Okamura.

The circadian clock is a biological timekeeping system that oscillates with a circa-24-h period, reset by environmental timing cues, especially light, to the 24-h day-night cycle. In mammals, a "central" clock in the hypothalamic suprachiasmatic nucleus (SCN) synchronizes "peripheral" clocks throughout the body to regulate behavior, metabolism, and physiology. A key feature of the clock's oscillation is resistance to abrupt perturbations, but the mechanisms underlying such robustness are not well understood. Here, we probe clock robustness to unexpected photic perturbation by measuring the speed of reentrainment of the murine locomotor rhythm after an abrupt advance of the light-dark cycle. Using an intersectional genetic approach, we implicate a critical role for arginine vasopressin pathways, both central within the SCN and peripheral from the anterior pituitary.

Keywords: circadian clock; pituitary; suprachiasmatic nucleus; vasopressin

DOI: https://doi.org/10.1073/pnas.2308489120

Endocr Connect. 2023 Nov 01. pii: e230064. [Epub ahead of print]12(11):

Daily rhythms of diabetogenic factors in men: role of type 2 diabetes and body weight.

Cheryl M Isherwood, M Denise Robertson, Debra J Skene, Jonathan D Johnston.

Obesity is a major cause of type 2 diabetes. Transition from obesity to type 2 diabetes manifests in the dysregulation of hormones controlling glucose homeostasis and inflammation. As metabolism is a dynamic process that changes across 24 h, we assessed diurnal rhythmicity in a panel of 10 diabetes-related hormones. Plasma hormones were analysed every 2 h over 24 h in a controlled laboratory study with hourly isocaloric drinks during wake. To separate effects of body mass from type 2 diabetes, we recruited three groups of middle-aged men: an overweight (OW) group with type 2 diabetes and two control groups (lean and OW). Average daily concentrations of glucose, triacylglycerol and all the hormones except visfatin were significantly higher in the OW group compared to the lean group (P < 0.001). In type 2 diabetes, glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 increased further (P < 0.05), whereas triacylglycerol, ghrelin and plasminogen activator inhibitor-1 concentrations were significantly lower compared to the OW group (P < 0.001). Insulin, C-peptide, glucose-dependent insulinotropic peptide and leptin exhibited significant diurnal rhythms in all study groups (P < 0.05). Other hormones were only rhythmic in 1 or 2 groups. In every group, hormones associated with glucose regulation (insulin, C-peptide, glucose-dependent insulinotropic peptide, ghrelin and plasminogen activator inhibitor-1), triacylglycerol and glucose peaked in the afternoon, whereas glucagon and hormones associated with appetite and inflammation peaked at night. Thus being OW with or without type 2 diabetes significantly affected hormone concentrations but did not affect the timing of the hormonal rhythms.

Keywords: adipokine; circadian; diurnal rhythms; incretin; obesity

DOI: https://doi.org/10.1530/EC-23-0064

Front Nutr. 2023 ;10 1213661

Effects of reducing free sugars on 24-hour glucose profiles and glycemic variability in subjects without diabetes.

Christina Laeticia Pappe, Beeke Peters, Henrik Dommisch, Johan Peter Woelber, Olga Pivovarova-Ramich.

Background: The Western diet, especially beverages and high processed food products, is high in sugars which are associated with the development of obesity and diabetes. The reduction of refined carbohydrates including free and added sugars improves glycemic control in individuals with diabetes, but the data regarding effects in subjects without diabetes are limited.
Objective: This study aimed to evaluate the effects of reducing free sugar intake on 24-h glucose profiles and glycemic variability using continuous glucose monitoring (CGM).
Methods: In the randomized controlled study, 21 normal weight and overweight/obese subjects (BMI 18-40 kg/m2) without diabetes were assigned to a 4-week reduced-sugar (RS) diet or control diet after a 2-week baseline phase. During the baseline phase, all participants were advised not to change their habitual diet. During the intervention phase, RS participants were asked to avoid added sugar and white flour products, whereas participants of the control group were requested to proceed their habitual diet. Anthropometric parameters and HbA1c were assessed before and at the end of the intervention phase. Interstitial glucose was measured using continuous glucose monitoring (CGM), and the food intake was documented by dietary records for 14 consecutive days during the baseline phase and for the first 14 consecutive days during the intervention phase. Mean 24-h glucose as well as intra- and inter-day indices of glucose variability, i.e., standard deviation (SD) around the sensor glucose level, coefficient of variation in percent (CV), mean amplitude of glucose excursions (MAGE), continuous overlapping net glycemic action (CONGA), and mean absolute glucose (MAG), were calculated for the baseline and intervention phases.
Results: During the intervention, the RS group decreased the daily intake of sugar (i.e., -22.4 ± 20.2 g, -3.28 ± 3.61 EN %), total carbohydrates (-6.22 ± 6.92 EN %), and total energy intake (-216 ± 108 kcal) and increased the protein intake (+2.51 ± 1.56 EN %) compared to the baseline values, whereby this intervention-induced dietary changes differed from the control group. The RS group slightly reduced body weight (-1.58 ± 1.33 kg), BMI, total fat, and visceral fat content and increased muscle mass compared to the baseline phase, but these intervention-induced changes showed no differences in comparison with the control group. The RS diet affected neither the 24-h mean glucose levels nor intra- and inter-day indices of glucose variability, HbA1c, or diurnal glucose pattern in the within- and between-group comparisons.
Conclusion: The dietary reduction of free sugars decreases body weight and body fat which may be associated with reduced total energy intake but does not affect the daily mean glucose and glycemic variability in individuals without diabetes.
Clinical trial registration: German Clinical Trials Register (DRKS); identifier: DRKS00026699.

Keywords: continuous glucose monitoring; free sugar reduction; glucose metabolism; glycemic variability; obesity

DOI: https://doi.org/10.3389/fnut.2023.1213661

Sci Rep. 2023 Oct 16. 13(1): 17597

Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells.

Li-Tzu Cheng, Grace Y T Tan, Fang-Pei Chang, Cheng-Kai Wang, Yu-Chi Chou, Pang-Hung Hsu, Wendy W Hwang-Verslues.

The intestinal epithelium is highly regenerative. Rapidly proliferating LGR5+ crypt base columnar (CBC) cells are responsible for epithelial turnover needed to maintain intestinal homeostasis. Upon tissue damage, loss of LGR5+ CBCs can be compensated by activation of quiescent +4 intestinal stem cells (ISCs) or early progenitor cells to restore intestinal regeneration. LGR5+ CBC self-renewal and ISC conversion to LGR5+ cells are regulated by external signals originating from the ISC niche. In contrast, little is known about intrinsic regulatory mechanisms critical for maintenance of LGR5+ CBC homeostasis. We found that LGR5 expression in intestinal crypt cells is controlled by the circadian core clock gene BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A. BMAL1 directly activated transcription of Mex3a. MEX3A in turn bound to and stabilized Lgr5 mRNA. Bmal1 depletion reduced Mex3a and Lgr5 expression and led to increased ferroptosis, which consequently decreased LGR5+ CBC numbers and increased the number of crypt cells expressing +4 ISC marker BMI1. Together, these findings reveal a BMAL1-centered intrinsic regulatory pathway that maintains LGR5 expression in the crypt cells and suggest a potential mechanism contributing to ISC homeostasis.

DOI: https://doi.org/10.1038/s41598-023-44997-5

F1000Res. 2022 ;11 1556

Circadian clock control of tRNA synthetases in Neurospora crassa.

Kathrina D Castillo, Emily D Chapa, Teresa M Lamb, Madhusree Gangopadhyay, Deborah Bell-Pedersen.

Background: In Neurospora crassa, the circadian clock controls rhythmic mRNA translation initiation through regulation of the eIF2α kinase CPC-3 (the homolog of yeast and mammalian GCN2). Active CPC-3 phosphorylates and inactivates eIF2α, leading to higher phosphorylated eIF2α (P-eIF2α) levels and reduced translation initiation during the subjective day. This daytime activation of CPC-3 is driven by its binding to uncharged tRNA, and uncharged tRNA levels peak during the day under control of the circadian clock. The daily rhythm in uncharged tRNA levels could arise from rhythmic amino acid levels or aminoacyl-tRNA synthetase (aaRSs) levels. Methods: To determine if and how the clock potentially controls rhythms in aspartyl-tRNA synthetase (AspRS) and glutaminyl-tRNA synthetase (GlnRS), both observed to be rhythmic in circadian genomic datasets, transcriptional and translational fusions to luciferase were generated. These luciferase reporter fusions were examined in wild type (WT), clock mutant Δ frq, and clock-controlled transcription factor deletion strains. Results: Translational and transcriptional fusions of AspRS and GlnRS to luciferase confirmed that their protein levels are clock-controlled with peak levels at night. Moreover, clock-controlled transcription factors NCU00275 and ADV-1 drive robust rhythmic protein expression of AspRS and GlnRS, respectively. Conclusions: These data support a model whereby coordinate clock control of select aaRSs drives rhythms in uncharged tRNAs, leading to rhythmic CPC-3 activation, and rhythms in translation of specific mRNAs.

Keywords: Circadian clock; Neurospora cras; tRNA synthetases; translation control

DOI: https://doi.org/10.12688/f1000research.125351.2