Curr Biol, co-auth.: group Fanken

Reindeer in the Arctic reduce sleep need during rumination

Melanie Furrer 1Sara A Meier 2Maxime Jan 3Paul Franken 4Monica A Sundset 5Steven A Brown 2Gabriela C Wagner 6Reto Huber 7

Abstract

Timing and quantity of sleep depend on a circadian (∼24-h) rhythm and a specific sleep requirement.1 Sleep curtailment results in a homeostatic rebound of more and deeper sleep, the latter reflected in increased electroencephalographic (EEG) slow-wave activity (SWA) during non-rapid eye movement (NREM) sleep.2 Circadian rhythms are synchronized by the light-dark cycle but persist under constant conditions.3,4,5 Strikingly, arctic reindeer behavior is arrhythmic during the solstices.6 Moreover, the Arctic’s extreme seasonal environmental changes cause large variations in overall activity and food intake.7 We hypothesized that the maintenance of optimal functioning under these extremely fluctuating conditions would require adaptations not only in daily activity patterns but also in the homeostatic regulation of sleep. We studied sleep using non-invasive EEG in four Eurasian tundra reindeer (Rangifer tarandus tarandus) in Tromsø, Norway (69°N) during the fall equinox and both solstices. As expected, sleep-wake rhythms paralleled daily activity distribution, and sleep deprivation resulted in a homeostatic rebound in all seasons. Yet, these sleep rebounds were smaller in summer and fall than in winter. Surprisingly, SWA decreased not only during NREM sleep but also during rumination. Quantitative modeling revealed that sleep pressure decayed at similar rates during the two behavioral states. Finally, reindeer spent less time in NREM sleep the more they ruminated. These results suggest that they can sleep during rumination. The ability to reduce sleep need during rumination-undisturbed phases for both sleep recovery and digestion-might allow for near-constant feeding in the arctic summer.

Front Mol Biosci, auth.: group Hernandez

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

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

Abstract

MAF1 is a nutrient-sensitive, TORC1-regulated repressor of RNA polymerase III (Pol III). MAF1 downregulation leads to increased lipogenesis in Drosophila melanogasterCaenorhabditis 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.

Int J Obes, co-auth.: I.Lopez-Mejia

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

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

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.

Science, coauth.: Group Gatfield

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

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

Nat Rev Neurosci. Auth: P.Franken

Sleep and circadian rhythmicity as entangled processes serving homeostasis

Paul Franken 1Derk-Jan Dijk 2 3

Affiliations expand

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.

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Nat Metab. co-auth.: group Thorens

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.