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

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

. 2024 Jan 3:152:155772.

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

• PMID: 38176644
• DOI: 10.1016/j.metabol.2023.155772

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.

Rare copy-number variants as modulators of common disease susceptibility

Chiara Auwerx ^1 2 3 4, Maarja Jõeloo ^5 6, Marie C Sadler ^7 8 9, Nicolò Tesio ¹⁰, Sven Ojavee ^7 8, Charlie J Clark ¹⁰, Reedik Mägi ⁶; Estonian Biobank Research Team; Alexandre Reymond ^# 11, Zoltán 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.

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.