bims-ciryme 2023-09-17 papers

J Clin Invest. 2023 Sep 15. pii: e162515. [Epub ahead of print]133(18):

Gut microbes and the liver circadian clock partition glucose and lipid metabolism.

Katya Frazier, Sumeed Manzoor, Katherine Carroll, Orlando DeLeon, Sawako Miyoshi, Jun Miyoshi, Marissa St George, Alan Tan, Evan A Chrisler, Mariko Izumo, Joseph S Takahashi, Mrinalini C Rao, Vanessa A Leone, Eugene B Chang.

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours.

Keywords: Fatty acid oxidation; Gluconeogenesis; Metabolism; Mouse models

DOI: https://doi.org/10.1172/JCI162515

Cell Chem Biol. 2023 Sep 08. pii: S2451-9456(23)00286-6. [Epub ahead of print]

Metabolic and chemical architecture of the mammalian circadian clock.

Isara Laothamatas, Emil Sjulstok Rasmussen, Carla B Green, Joseph S Takahashi.

Circadian rhythms are endogenous periodic biological processes that occur on a daily timescale. These rhythms are generated by a transcriptional/translational feedback loop that consists of the CLOCK-BMAL1 heterodimeric transcriptional activator complex and the PER1/2-CRY1/2-CK1δ/ε repressive complex. The output pathways of this molecular feedback loop generate circadian rhythmicity in various biological processes. Among these, metabolism is a primary regulatory target of the circadian clock which can also feedback to modulate clock function. This intertwined relationship between circadian rhythms and metabolism makes circadian clock components promising therapeutic targets. Despite this, pharmacological therapeutics that target the circadian clock are relatively rare. In this review, we hope to stimulate interest in chemical chronobiology by providing a comprehensive background on the molecular mechanism of mammalian circadian rhythms and their connection to metabolism, highlighting important studies in the chemical approach to circadian research, and offering our perspectives on future developments in the field.

Keywords: chronobiology; circadian rhythms; drug discovery; high-throughput screening; metabolism

DOI: https://doi.org/10.1016/j.chembiol.2023.08.014

Cell Metab. 2023 Sep 01. pii: S1550-4131(23)00300-5. [Epub ahead of print]

Seasonal light hours modulate peripheral clocks and energy metabolism in mice.

Lewin Small, Leonidas S Lundell, Jo Iversen, Amy M Ehrlich, Morten Dall, Astrid L Basse, Emilie Dalbram, Ann N Hansen, Jonas T Treebak, Romain Barrès, Juleen R Zierath.

Except for latitudes close to the equator, seasonal variation in light hours can change dramatically between summer and winter. Yet investigations into the interplay between energy metabolism and circadian rhythms typically use a 12 h light:12 h dark photoperiod corresponding to the light duration at the equator. We hypothesized that altering the seasonal photoperiod affects both the rhythmicity of peripheral tissue clocks and energy homeostasis. Mice were housed at photoperiods representing either light hours in summer, winter, or the equinox. Mice housed at a winter photoperiod exhibited an increase in the amplitude of rhythmic lipid metabolism and a modest reduction in fat mass and liver triglyceride content. Comparing melatonin-proficient and -deficient mice, the effect of seasonal light on energy metabolism was largely driven by differences in the rhythmicity of food intake and not melatonin. Together, these data indicate that seasonal light impacts energy metabolism by modulating the timing of eating.

Keywords: circadian biology; energy homeostasis; glucose metabolism; hormones; integrative physiology; obesity; transcriptomics

DOI: https://doi.org/10.1016/j.cmet.2023.08.005

bioRxiv. 2023 Aug 29. pii: 2023.08.28.555175. [Epub ahead of print]

Environmental circadian disruption re-programs liver circadian gene expression.

Hao A Duong, Kenkichi Baba, Jason P DeBruyne, Alec J Davidson, Christopher Ehlen, Michael Powell, Gianluca Tosini.

Circadian gene expression is fundamental to the establishment and functions of the circadian clock, a cell-autonomous and evolutionary-conserved timing system. Yet, how it is affected by environmental-circadian disruption (ECD) such as shiftwork and jetlag, which impact millions of people worldwide, are ill-defined. Here, we provided the first comprehensive description of liver circadian gene expression under normal and after ECD conditions. We found that post-transcription and post-translation processes are dominant contributors to whole-cell or nuclear circadian proteome, respectively. Furthermore, rhythmicity of 64% transcriptome, 98% whole-cell proteome and 95% nuclear proteome is re-written by ECD. The re-writing, which is associated with changes of circadian cis-regulatory elements, RNA-processing and protein trafficking, diminishes circadian regulation of fat and carbohydrate metabolism and persists after one week of ECD-recovery.
One-Sentence Summary: Environmental-circadian disruption re-writes the circadian gene expression process which persists after one week of recovery.

DOI: https://doi.org/10.1101/2023.08.28.555175

J Biol Chem. 2023 Sep 13. pii: S0021-9258(23)02279-2. [Epub ahead of print] 105251

Preservation of circadian rhythm in hepatocellular cancer.

Yanyan Yang, Ashraf N Abdo, Hiroaki Kawara, Christopher P Selby, Aziz Sancar.

Circadian rhythms are controlled at the cellular level by a molecular clock consisting of several genes/proteins engaged in a transcription-translation-degradation feedback loop. These core clock proteins regulate thousands of tissue-specific genes. Regarding circadian control in neoplastic tissues, reports to date have demonstrated anomalous circadian function in tumor models and cultured tumor cells. We have extended these studies by analyzing circadian rhythmicity genome-wide in a mouse model of liver cancer, in which mice treated with diethylnitrosamine at 15 days develop liver tumors by 6 months. We injected tumor-bearing and control tumor-free mice with cisplatin every 2 hours over a 24-hour cycle; 2 hours after each injection mice were sacrificed and gene expression was measured by XR-Seq (excision repair sequencing) assay. Rhythmic expression of several core clock genes was observed in both healthy liver and tumor, with clock genes in tumor exhibiting typically robust amplitudes, and a modest phase advance. Interestingly, even though normal hepatic cells and hepatoma cancer cells expressed a comparable number of genes with circadian rhythmicity (clock-controlled genes), there was only about 10% overlap between the rhythmic genes in normal and cancerous cells. "Rhythmic in tumor only" genes exhibited peak expression times mainly in daytime hours, in contrast to the more common pre-dawn and pre-dusk expression times seen in healthy livers. Differential expression of genes in tumors and healthy livers across time may present an opportunity for more efficient anticancer drug treatment as a function of treatment time.

Keywords: Circadian; Rhythmic in tumor; XR-Seq; hepatocellular cancer

DOI: https://doi.org/10.1016/j.jbc.2023.105251