Contrasting effects of whole-body and hepatocyte-specific deletion of the RNA polymerase III repressor Maf1 in the mouse

Gilles Willemin ¹, François Mange ^# 1, Viviane Praz ^# 2, Séverine Lorrain ³, Pascal Cousin ¹, Catherine Roger ¹, Ian M Willis ^4 5, Nouria Hernandez ¹

• PMID: 38143800
• PMCID: PMC10746880
• DOI: 10.3389/fmolb.2023.1297800

Abstract

MAF1 is a nutrient-sensitive, TORC1-regulated repressor of RNA polymerase III (Pol III). MAF1 downregulation leads to increased lipogenesis in Drosophila melanogaster, Caenorhabditis elegans, and mice. However, Maf1 ^-/- mice are lean as increased lipogenesis is counterbalanced by futile pre-tRNA synthesis and degradation, resulting in increased energy expenditure. We compared Chow-fed Maf1 ^-/- mice with Chow- or High Fat (HF)-fed Maf1 ^hep-/- mice that lack MAF1 specifically in hepatocytes. Unlike Maf1 ^-/- mice, Maf1 ^hep-/- mice become heavier and fattier than control mice with old age and much earlier under a HF diet. Liver ChIPseq, RNAseq and proteomics analyses indicate increased Pol III occupancy at Pol III genes, very few differences in mRNA accumulation, and protein accumulation changes consistent with increased lipogenesis. Futile pre-tRNA synthesis and degradation in the liver, as likely occurs in Maf1 ^hep-/- mice, thus seems insufficient to counteract increased lipogenesis. Indeed, RNAseq and metabolite profiling indicate that liver phenotypes of Maf1 ^-/- mice are strongly influenced by systemic inter-organ communication. Among common changes in the three phenotypically distinct cohorts, Angiogenin downregulation is likely linked to increased Pol III occupancy of tRNA genes in the Angiogenin promoter.

SMYD3: a new regulator of adipocyte precursor proliferation at the early steps of differentiation

Tatjana Sajic ^1 2, Chayenne Karine Ferreira Gomes ², Marie Gasser ^1 2, Tiziana Caputo ³, Nasim Bararpour ^4 5, Esther Landaluce-Iturriria ⁶, Marc Augsburger ¹, Nadia Walter ⁷, Alexandre Hainard ⁷, Isabel C Lopez-Mejia ⁶, Tony Fracasso ⁸, Aurélien Thomas ^1 2, Federica Gilardi ^9 10

• PMID: 38148333
• DOI: 10.1038/s41366-023-01450-x

Abstract

Background: In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to a hypertrophic growth that is accompanied by the development of inflammation and metabolic dysfunction. However, the molecular mechanisms underlying the fine-tuned regulation of adipose tissue expansion are far from being understood.

Methods: We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low inflammation (Low-INFL), showed reduced adipose tissue inflammation, as opposed to those developing the expected inflammatory response (Hi-INFL). We identified the discriminants between Low-INFL and Hi-INFL vWAT samples and explored their function in Adipose-Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes.

Results: vWAT proteomics allowed us to quantify 6051 proteins. Among the candidates that most differentiate Low-INFL from Hi-INFL vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in Low-INFL, as compared to Hi-INFL. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was so far unknown, was another top-scored hit. SMYD3 expression was significantly higher in Low-INFL vWAT, as confirmed by western blot analysis. Using AD-hMSCs in culture, we found that SMYD3 mRNA and protein levels decrease rapidly during the adipocyte differentiation. Moreover, SMYD3 knock-down before adipocyte differentiation resulted in reduced H3K4me3 and decreased cell proliferation, thus limiting the number of cells available for adipogenesis.

Conclusions: Our study describes an important role of SMYD3 as a newly discovered regulator of adipocyte precursor proliferation during the early steps of adipogenesis.

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

Goda Snieckute ^# 1 2, Laura Ryder ^# 1 2, Anna Constance Vind ^# 1 2, Zhenzhen Wu ^1 2, Frederic Schrøder Arendrup ³, Mark Stoneley ⁴, Sébastien Chamois ⁵, Ana Martinez-Val ⁶, Marion Leleu ⁷, René Dreos ⁵, Alexander Russell ⁸, David Michael Gay ³, Aitana Victoria Genzor ^1 2, Beatrice So-Yun Choi ⁹, Astrid Linde Basse ¹⁰, Frederike Sass ¹⁰, Morten Dall ¹⁰, Lucile Chantal Marie Dollet ¹⁰, Melanie Blasius ^1 2, Anne E Willis ⁴, Anders H Lund ³, Jonas T Treebak ¹⁰, Jesper Velgaard Olsen ⁶, Steen Seier Poulsen ⁹, Mary Elizabeth Pownall ⁸, Benjamin Anderschou Holbech Jensen ⁹, Christoffer Clemmensen ¹⁰, Zach Gerhart-Hines ¹⁰, David Gatfield ⁵, Simon Bekker-Jensen ^1 2

Science 2023 Dec 8;382(6675):eadf3208. doi: 10.1126/science.adf3208. Epub 2023 Dec 8.

Abstract

The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.

Sleep and circadian rhythmicity as entangled processes serving homeostasis

Paul Franken ¹, Derk-Jan Dijk ^2 3

Affiliations expand

• PMID: 38040815
• DOI: 10.1038/s41583-023-00764-z

• PMID: 38040815
• DOI: 10.1038/s41583-023-00764-z

Abstract

Sleep is considered essential for the brain and body. A predominant concept is that sleep is regulated by circadian rhythmicity and sleep homeostasis, processes that were posited to be functionally and mechanistically separate. Here we review and re-evaluate this concept and its assumptions using findings from recent human and rodent studies. Alterations in genes that are central to circadian rhythmicity affect not only sleep timing but also putative markers of sleep homeostasis such as electroencephalogram slow-wave activity (SWA). Perturbations of sleep change the rhythmicity in the expression of core clock genes in tissues outside the central clock. The dynamics of recovery from sleep loss vary across sleep variables: SWA and immediate early genes show an early response, but the recovery of non-rapid eye movement and rapid eye movement sleep follows slower time courses. Changes in the expression of many genes in response to sleep perturbations outlast the effects on SWA and time spent asleep. These findings are difficult to reconcile with the notion that circadian- and sleep-wake-driven processes are mutually independent and that the dynamics of sleep homeostasis are reflected in a single variable. Further understanding of how both sleep and circadian rhythmicity contribute to the homeostasis of essential physiological variables may benefit from the assessment of multiple sleep and molecular variables over longer time scales.

© 2023. Springer Nature Limited.

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The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing. 

Fu H, Vuononvirta J, Fanti S, Bonacina F, D’Amati A, Wang G, Poobalasingam T, Fankhaenel M, Lucchesi D, Coleby R, Tarussio D, Thorens B, Hearnden RJ, Longhi MP, Grevitt P, Sheikh MH, Solito E, Godinho SA, Bombardieri M, Smith DM, Cooper D, Iqbal AJ, Rathmell JC, Schaefer S, Morales V, Bianchi K, Norata GD, Marelli-Berg FM.

Nat Metab. 2023 Nov;5(11):1969-1985. doi: 10.1038/s42255-023-00913-9. Epub 2023 Oct 26.

PMID: 37884694 Free PMC article.

Remote homolog detection places insect chemoreceptors in a cryptic protein superfamily spanning the tree of life. 

Himmel NJ, Moi D, Benton R.

Curr Biol. 2023 Nov 20;33(22):5023-5033.e4. doi: 10.1016/j.cub.2023.10.008. Epub 2023 Oct 31.

PMID: 37913770