bims-ciryme 2023-01-08 papers

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00545-9. [Epub ahead of print]35(1): 7-9

Timed feeding aligns the adipocyte clock to optimize thermogenesis when eating a high-fat diet.

Paramita Pati, Jennifer S Pollock, Karen L Gamble.

The timing of food intake is vital for metabolic health in obesity. A recent study in mice from Hepler et al. in Science shows the importance of the adipocyte circadian clock in metabolic health, highlighting the creatine pathway and thermogenesis with the alignment of the timing of high-fat feeding.

DOI: https://doi.org/10.1016/j.cmet.2022.12.008

Sci Adv. 2023 Jan 04. 9(1): eabq7032

Network-driven intracellular cAMP coordinates circadian rhythm in the suprachiasmatic nucleus.

Daisuke Ono, Huan Wang, Chi Jung Hung, Hsin-Tzu Wang, Naohiro Kon, Akihiro Yamanaka, Yulong Li, Takashi Sugiyama.

The mammalian central circadian clock, located in the suprachiasmatic nucleus (SCN), coordinates the timing of physiology and behavior to local time cues. In the SCN, second messengers, such as cAMP and Ca2+, are suggested to be involved in the input and/or output of the molecular circadian clock. However, the functional roles of second messengers and their dynamics in the SCN remain largely unclear. In the present study, we visualized the spatiotemporal patterns of circadian rhythms of second messengers and neurotransmitter release in the SCN. Here, we show that neuronal activity regulates the rhythmic release of vasoactive intestinal peptides from the SCN, which drives the circadian rhythms of intracellular cAMP in the SCN. Furthermore, optical manipulation of intracellular cAMP levels in the SCN shifts molecular and behavioral circadian rhythms. Together, our study demonstrates that intracellular cAMP is a key molecule in the organization of the SCN circadian neuronal network.

DOI: https://doi.org/10.1126/sciadv.abq7032

Cell Metab. 2023 Jan 03. pii: S1550-4131(22)00543-5. [Epub ahead of print]35(1): 150-165.e4

Diurnal transcriptome landscape of a multi-tissue response to time-restricted feeding in mammals.

Shaunak Deota, Terry Lin, Amandine Chaix, April Williams, Hiep Le, Hugo Calligaro, Ramesh Ramasamy, Ling Huang, Satchidananda Panda.

Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention that involves a daily cycle of feeding and fasting. In both animals and humans, TRF has pleiotropic health benefits that arise from multiple organ systems, yet the molecular basis of TRF-mediated benefits is not well understood. Here, we subjected mice to isocaloric ad libitum feeding (ALF) or TRF of a western diet and examined gene expression changes in samples taken from 22 organs and brain regions collected every 2 h over a 24-h period. We discovered that TRF profoundly impacts gene expression. Nearly 80% of all genes show differential expression or rhythmicity under TRF in at least one tissue. Functional annotation of these changes revealed tissue- and pathway-specific impacts of TRF. These findings and resources provide a critical foundation for future mechanistic studies and will help to guide human time-restricted eating (TRE) interventions to treat various disease conditions with or without pharmacotherapies.

Keywords: circadian clock; feeding-fasting rhythms; hepatic metabolomics; metabolic flexibility; metabolic syndrome; multi-tissue transcriptomics; time-restricted feeding

DOI: https://doi.org/10.1016/j.cmet.2022.12.006

Proc Natl Acad Sci U S A. 2023 Jan 10. 120(2): e2214829120

Circadian regulator BMAL1::CLOCK promotes cell proliferation in hepatocellular carcinoma by controlling apoptosis and cell cycle.

Meng Qu, Guoxin Zhang, Han Qu, Alexander Vu, Raymond Wu, Hidekazu Tsukamoto, Zhenyu Jia, Wendong Huang, Heinz-Josef Lenz, Jeremy N Rich, Steve A Kay.

Hepatocellular carcinoma (HCC) remains a global health challenge whose incidence is growing worldwide. Previous evidence strongly supported the notion that the circadian clock controls physiological homeostasis of the liver and plays a key role in hepatocarcinogenesis. Despite the progress, cellular and molecular mechanisms underpinning this HCC-clock crosstalk remain unknown. Addressing this knowledge gap, we show here that although the human HCC cells Hep3B, HepG2, and Huh7 displayed variations in circadian rhythm profiles, all cells relied on the master circadian clock transcription factors, BMAL1 and CLOCK, for sustained cell growth. Down-regulating Bmal1 or Clock in the HCC cells induced apoptosis and arrested cell cycle at the G2/M phase. Mechanistically, we found that inhibiting Bmal1/Clock induced dysregulation of the cell cycle regulators Wee1 and p21 which cooperatively contribute to tumor cell death. Bmal1/Clock knockdown caused downregulation of Wee1 that led to apoptosis activation and upregulation of p21 which arrested the cell cycle at the G2/M phase. Collectively, our results suggest that the circadian clock regulators BMAL1 and CLOCK promote HCC cell proliferation by controlling Wee1 and p21 levels, thereby preventing apoptosis and cell cycle arrest. Our findings shed light on cellular impact of the clock proteins for maintaining HCC oncogenesis and provide proof-of-principle for developing cancer therapy based on modulation of the circadian clock.

Keywords: apoptosis; cell cycle; circadian clock; hepatocellular carcinoma

DOI: https://doi.org/10.1073/pnas.2214829120

Cell Mol Life Sci. 2023 Jan 06. 80(1): 28

Brain histone beta-hydroxybutyrylation couples metabolism with gene expression.

Sara Cornuti, Siwei Chen, Leonardo Lupori, Francesco Finamore, Fabrizia Carli, Muntaha Samad, Simona Fenizia, Matteo Caldarelli, Francesca Damiani, Francesco Raimondi, Raffaele Mazziotti, Christophe Magnan, Silvia Rocchiccioli, Amalia Gastaldelli, Pierre Baldi, Paola Tognini.

Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 h fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms''. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgeber times both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-h fasting. Thus, our results suggest that fasting remarkably impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.

Keywords: Beta-hydroxybutyrylation; Cerebral cortex; Epigenome; Fasting; Transcriptome

DOI: https://doi.org/10.1007/s00018-022-04673-9