bims-stacyt 2024-01-07 papers

Metabolism. 2024 Jan 02. pii: S0026-0495(23)00376-1. [Epub ahead of print] 155772

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

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

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.
OBJECTIVE: To examine how GDF15 regulates AMPK.
METHODS: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used.
RESULTS: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-β1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-β1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice.
CONCLUSIONS: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-β1/SMAD3 pathway.

Keywords: AMPK; Fibrosis; GDF15; Gluconeogenesis; SMAD3; TGF-β

DOI: https://doi.org/10.1016/j.metabol.2023.155772

Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01654-6. [Epub ahead of print]43(1): 113643

Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells.

Julia Hesse, Bodo Steckel, Peter Dieterich, Siyar Aydin, Andreas Deussen, Jürgen Schrader.

CD73-derived adenosine suppresses anti-cancer immunity, and CD73 inhibitors are currently evaluated in several clinical trials. Here, we have assessed enzyme kinetics of all key purinergic ectoenzymes in five cancer cell lines (Hodgkin lymphoma, multiple myeloma, pancreas adenocarcinoma, urinary bladder carcinoma, and glioblastoma) under normoxia and hypoxia. We found that adenosine metabolism varied considerably between individual cancer types. All cell lines investigated exhibited high ecto-adenosine deaminase (ADA) activity, which critically influenced the kinetics of adenosine accumulation. Combining kinetics data with single-cell RNA sequencing data on myeloma and glioblastoma cancerous tissue revealed that purine metabolism is not homogeneously organized, but it differs in a cancer type-specific fashion between malignant cells, stromal cells, and immune cells. Since purine metabolism in cancerous tissue is most likely spatially heterogeneous and differs between the various cell types, diffusion distances in the microenvironment as well as ADA activity may be important variables that influence the level of bioactive adenosine.

Keywords: CP: Cancer; NAD; adenosine; adenosine deaminase; glioblastoma; hypoxia; multiple myeloma

DOI: https://doi.org/10.1016/j.celrep.2023.113643

Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01669-8. [Epub ahead of print]43(1): 113658

Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes.

Yangxiao Hou, Dong Wei, Zhaoqi Zhang, Tong Lei, Sihong Li, Jiaming Bao, Han Guo, Liang Tan, Xubiao Xie, Yuan Zhuang, Zhongbing Lu, Yong Zhao.

Poor skin wound healing, which is common in patients with diabetes, is related to imbalanced macrophage polarization. Here, we find that nutrition sensor GCN2 (general control nonderepressible 2) and its downstream are significantly upregulated in human skin wound tissue and mouse skin wound macrophages, but skin wound-related GCN2 expression and activity are significantly downregulated by diabetes and hyperglycemia. Using wound healing models of GCN2-deleted mice, bone marrow chimeric mice, and monocyte-transferred mice, we show that GCN2 deletion in macrophages significantly delays skin wound healing compared with wild-type mice by altering M1 and M2a/M2c polarization. Mechanistically, GCN2 inhibits M1 macrophages via OXPHOS-ROS-NF-κB pathway and promotes tissue-repairing M2a/M2c macrophages through eukaryotic translation initiation factor 2 (eIF2α)-hypoxia-inducible factor 1α (HIF1α)-glycolysis pathway. Importantly, local supplementation of GCN2 activator halofuginone efficiently restores wound healing in diabetic mice with re-balancing M1 and M2a/2c polarization. Thus, the decreased macrophage GCN2 expression and activity contribute to poor wound healing in diabetes and targeting GCN2 improves wound healing in diabetes.

Keywords: CP: Immunology; GCN2; diabetes; macrophage polarization; macrophages; nutrition sensor; wound healing

DOI: https://doi.org/10.1016/j.celrep.2023.113658