bims-ciryme 2019-05-05 papers

Cell. 2019 May 02. pii: S0092-8674(19)30166-7. [Epub ahead of print]177(4): 896-909.e20

Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

Priya Crosby, Ryan Hamnett, Marrit Putker, Nathaniel P Hoyle, Martin Reed, Carolyn J Karam, Elizabeth S Maywood, Alessandra Stangherlin, Johanna E Chesham, Edward A Hayter, Lyn Rosenbrier-Ribeiro, Peter Newham, Hans Clevers, David A Bechtold, John S O'Neill.

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

Keywords: IGF-1; PERIOD; circadian; food entrainment; insulin; mTORC1; miRNA

DOI: https://doi.org/10.1016/j.cell.2019.02.017

Proc Natl Acad Sci U S A. 2019 May 02. pii: 201815360. [Epub ahead of print]

Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism in Neurospora crassa.

Mokryun Baek, Stela Virgilio, Teresa M Lamb, Oneida Ibarra, Juvana Moreira Andrade, Rodrigo Duarte Gonçalves, Andrey Dovzhenok, Sookkyung Lim, Deborah Bell-Pedersen, Maria Celia Bertolini, Christian I Hong.

Circadian clocks generate rhythms in cellular functions, including metabolism, to align biological processes with the 24-hour environment. Disruption of this alignment by shift work alters glucose homeostasis. Glucose homeostasis depends on signaling and allosteric control; however, the molecular mechanisms linking the clock to glucose homeostasis remain largely unknown. We investigated the molecular links between the clock and glycogen metabolism, a conserved glucose homeostatic process, in Neurospora crassa We find that glycogen synthase (gsn) mRNA, glycogen phosphorylase (gpn) mRNA, and glycogen levels, accumulate with a daily rhythm controlled by the circadian clock. Because the synthase and phosphorylase are critical to homeostasis, their roles in generating glycogen rhythms were investigated. We demonstrate that while gsn was necessary for glycogen production, constitutive gsn expression resulted in high and arrhythmic glycogen levels, and deletion of gpn abolished gsn mRNA rhythms and rhythmic glycogen accumulation. Furthermore, we show that gsn promoter activity is rhythmic and is directly controlled by core clock component white collar complex (WCC). We also discovered that WCC-regulated transcription factors, VOS-1 and CSP-1, modulate the phase and amplitude of rhythmic gsn mRNA, and these changes are similarly reflected in glycogen oscillations. Together, these data indicate the importance of clock-regulated gsn transcription over signaling or allosteric control of glycogen rhythms, a mechanism that is potentially conserved in mammals and critical to metabolic homeostasis.

Keywords: Neurospora crassa; circadian rhythms; glycogen metabolism; glycogen phosphorylase; glycogen synthase

DOI: https://doi.org/10.1073/pnas.1815360116

Cell Metab. 2019 Apr 25. pii: S1550-4131(19)30185-8. [Epub ahead of print]

Amygdala NPY Circuits Promote the Development of Accelerated Obesity under Chronic Stress Conditions.

Chi Kin Ip, Lei Zhang, Aitak Farzi, Yue Qi, Ireni Clarke, Felicia Reed, Yan-Chuan Shi, Ronaldo Enriquez, Chris Dayas, Bret Graham, Denovan Begg, Jens C Brüning, Nicola J Lee, Diana Hernandez-Sanchez, Gopana Gopalasingam, Julia Koller, Ramon Tasan, Günther Sperk, Herbert Herzog.

Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that leads to the exaggerated development of obesity.

Keywords: NPY; central amygdala; feeding; insulin; obesity; stress

DOI: https://doi.org/10.1016/j.cmet.2019.04.001

F1000Res. 2019 ;pii: F1000 Faculty Rev-499. [Epub ahead of print]8

A period without PER: understanding 24-hour rhythms without classic transcription and translation feedback loops.

Arthur Millius, Koji L Ode, Hiroki R Ueda.

Since Ronald Konopka and Seymour Benzer's discovery of the gene Period in the 1970s, the circadian rhythm field has diligently investigated regulatory mechanisms and intracellular transcriptional and translation feedback loops involving Period, and these investigations culminated in a 2017 Nobel Prize in Physiology or Medicine for Michael W. Young, Michael Rosbash, and Jeffrey C. Hall. Although research on 24-hour behavior rhythms started with Period, a series of discoveries in the past decade have shown us that post-transcriptional regulation and protein modification, such as phosphorylation and oxidation, are alternatives ways to building a ticking clock.

Keywords: circadian rhythms; dopaminergic ultradian oscillator; peroxiredoxin; phosphorylation; post-transcriptional oscillator; red blood cells; transcriptional-translation feedback loop

DOI: https://doi.org/10.12688/f1000research.18158.1

Front Genet. 2019 ;10 329

DNA Methylation of Five Core Circadian Genes Jointly Contributes to Glucose Metabolism: A Gene-Set Analysis in Monozygotic Twins.

Hao Peng, Yun Zhu, Jack Goldberg, Viola Vaccarino, Jinying Zhao.

The timing of daily fluctuations in blood glucose is tightly controlled by the circadian rhythm. DNA methylation accompanies the circadian clock, and aberrant DNA methylation has been associated with circadian disruption and hyperglycemia. However, the precise role of circadian genes methylation in glucose metabolism is unknown. Using a gene-set approach in monozygotic (MZ) twin pairs, we examined the joint effect of 77 CpGs in five core circadian genes (CLOCK, BMAL1, PER1, PER2, PER3) on glucose-related traits in 138 middle-aged, male-male MZ twins (69 pairs). DNA methylation was quantified by bisulfite pyrosequencing. We first conducted matched twin pair analysis to examine the association of single CpG methylation with glucose metabolism. We then performed gene-based and gene-set analyses by the truncated product method to examine the combined effect of DNA methylation at multiple CpGs in a gene or all five circadian genes as a pathway on glucose metabolism. Of the 77 assayed CpGs, only one site was individually associated with insulin resistance at FDR < 0.05. However, the joint effect of DNA methylation in all five circadian genes together showed a significant association with glucose metabolism. Our results may unravel a biological mechanism through which circadian rhythm regulates blood glucose, and highlight the importance of testing the joint effect of multiple CpGs in epigenetic analysis.

Keywords: DNA methylation; circadian rhythm; epigenetics; glucose metabolism; monozygotic twins

DOI: https://doi.org/10.3389/fgene.2019.00329