Metabolism, co-auth.: W.Wahli

GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis in the liver by attenuating the TGF-β1/SMAD3 pathway

Javier Jurado-Aguilar 1Emma Barroso 1Maribel Bernard 1Meijian Zhang 1Mona Peyman 1Patricia Rada 2Ángela M Valverde 2Walter Wahli 3Xavier Palomer 1Manuel Vázquez-Carrera 4

. 2024 Jan 3:152:155772.

 doi: 10.1016/j.metabol.2023.155772. Online ahead of print.

Abstract

Introduction: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL.

Genome Med, auth.: group Reymond

Rare copy-number variants as modulators of common disease susceptibility

Chiara Auwerx 1 2 3 4Maarja Jõeloo 5 6Marie C Sadler 7 8 9Nicolò Tesio 10Sven Ojavee 7 8Charlie J Clark 10Reedik Mägi 6Estonian Biobank Research TeamAlexandre Reymond # 11Zoltán Kutalik # 12 13 14

Genome Med. 2024 Jan 8;16(1):5. doi: 10.1186/s13073-023-01265-5.

Abstract

Background: Copy-number variations (CNVs) have been associated with rare and debilitating genomic disorders (GDs) but their impact on health later in life in the general population remains poorly described.

Diabetologia co-auth.: B.Thorens

GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion

Nikhil R Gandasi 1 2Rui Gao 3Lakshmi Kothegala 1Abigail Pearce 4Cristiano Santos 1Samuel Acreman 1 3Davide Basco 5Anna Benrick 1Margarita V Chibalina 3Anne Clark 3Claudia Guida 3Matthew Harris 4Paul R V Johnson 6 7Jakob G Knudsen 8Jinfang Ma 3Caroline Miranda 1 3Makoto Shigeto 3Andrei I Tarasov 3 9Ho Yan Yeung 4Bernard Thorens 5Ingrid W Asterholm 1Quan Zhang 3Reshma Ramracheya 3Graham Ladds 4Patrik Rorsman 10 11 12 13

Affiliations expand

Abstract

Aims/hypothesis: Diabetes mellitus is associated with impaired insulin secretion, often aggravated by oversecretion of glucagon. Therapeutic interventions should ideally correct both defects. Glucagon-like peptide 1 (GLP-1) has this capability but exactly how it exerts its glucagonostatic effect remains obscure. Following its release GLP-1 is rapidly degraded from GLP-1(7-36) to GLP-1(9-36). We hypothesised that the metabolite GLP-1(9-36) (previously believed to be biologically inactive) exerts a direct inhibitory effect on glucagon secretion and that this mechanism becomes impaired in diabetes.

ReviewSemin Cancer Biol, auth.: group Fajas

Beyond cell cycle regulation: The pleiotropic function of CDK4 in cancer

Dorian V Ziegler 1Kanishka Parashar 1Lluis Fajas 2

Abstract

CDK4, along with its regulatory subunit, cyclin D, drives the transition from G1 to S phase, during which DNA replication and metabolic activation occur. In this canonical pathway, CDK4 is essentially a transcriptional regulator that acts through phosphorylation of retinoblastoma protein (RB) and subsequent activation of the transcription factor E2F, ultimately triggering the expression of genes involved in DNA synthesis and cell cycle progression to S phase. In this review, we focus on the newly reported functions of CDK4, which go beyond direct regulation of the cell cycle. In particular, we describe the extranuclear roles of CDK4, including its roles in the regulation of metabolism, cell fate, cell dynamics and the tumor microenvironment. We describe direct phosphorylation targets of CDK4 and decipher how CDK4 influences these physiological processes in the context of cancer.

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.