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

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

Affiliations expand

• PMID: 38127123
• DOI: 10.1007/s00125-023-06060-w

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.

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

Dorian V Ziegler ¹, Kanishka Parashar ¹, Lluis Fajas ²

• PMID: 38135020
• DOI: 10.1016/j.semcancer.2023.12.002

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.

Reindeer in the Arctic reduce sleep need during rumination

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

• PMID: 38141616
• DOI: 10.1016/j.cub.2023.12.012

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.

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.