bims-stacyt 2025-04-27 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–04–27
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The association between serum growth differentiation factor 15 and insulin resistance in women diagnosed with polycystic ovary syndrome.
Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.
Glucose sensing and the unfolded protein response.
Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.
Prolonged fasting promotes systemic inflammation and platelet activation in humans: a medically supervised, water-only fasting and refeeding study.
Snf1 and yeast GSK3-β activates Tda1 to suppress glucose starvation signaling.

Sci Rep. 2025 Apr 22. 15(1): 13824

The association between serum growth differentiation factor 15 and insulin resistance in women diagnosed with polycystic ovary syndrome.

Yufeng Mei, Wanzhen Li, Zhenni Chen, Min Wang.

  Polycystic ovary syndrome (PCOS) is strongly associated with metabolic abnormalities, with 50-70% of patients exhibiting insulin resistance (IR), which significantly impacts the reproductive health of women in their reproductive years. Growth differentiation factor 15 (GDF15), a hormone responsive to nutritional stress, has been implicated in several diseases. This study sought to clarify the relationship between GDF15 levels and IR condition in PCOS patients. Based on the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), patients were categorized into an IR-PCOS group (n = 124) and a non-insulin-resistant group (non-IR-PCOS group, n = 109). Fasting blood samples were collected to measure GDF15 concentrations. To assess metabolic complications in relation to GDF15 levels, patients were also classified into high and normal GDF15 groups. Serum GDF15 levels were significantly higher in IR-PCOS patients (median 772.94 pg/ml) compared to non-IR-PCOS patients (median 575.80 pg/ml, P < 0.05). The high GDF15 group showed more severe metabolic and lipid abnormalities than the normal GDF15 group. Spearman correlation analysis revealed a correlation between increased GDF15 levels and impaired glucose metabolism. Logistic regression analysis identified GDF15, HDL-C, and prolactin as risk factors for IR in PCOS, and the fully adjusted regression coefficient for GDF15 levels and IR prevalence was 4.490 (95% CI 1.541 to 13.088). Restricted cubic spline analysis confirmed a positive association between GDF15 levels and IR within a specific range. The combined predictive probability of GDF15, prolactin, and HDL-C for IR was 0.763 (95% CI 0.701 to 0.826) according to ROC analysis. Elevated GDF15 levels may be associated with IR in PCOS patients, suggesting a potential role for GDF15 in the pathophysiology of IR in this condition.

Keywords:  Growth differentiation factor 15; Insulin resistance; Polycystic ovarian syndrome

DOI:  https://doi.org/10.1038/s41598-025-98028-6
Nat Metab. 2025 Apr;7(4): 823-841

Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.

Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.

Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.

DOI: https://doi.org/10.1038/s42255-025-01265-2
Front Immunol. 2025 ;16 1548509

Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.

Agathe Dubuisson, Adèle Mangelinck, Samantha Knockaert, Adrien Zichi, Etienne Becht, Wendy Philippon, Sandra Dromaint-Catesson, Manon Fasquel, Fabien Melchiore, Nicolas Provost, Dawid Walas, Hélène Darville, Jean-Pierre Galizzi, Céline Lefebvre, Véronique Blanc, Vincent Lombardi.

   Background: The ability of immune cells to rapidly respond to pathogens or malignant cells is tightly linked to metabolic pathways. In cancer, the tumor microenvironment (TME) represents a complex system with a strong metabolism stress, in part due to glucose shortage, which limits proper T cell activation, differentiation and functions preventing anti-tumor immunity.
Methods: In this study, we evaluated T cell immune reactivity in glucose-restricted mixed lymphocyte reaction (MLR), using a comprehensive profiling of soluble factors, multiparametric flow cytometry and single cell RNA sequencing (scRNA-seq).
Results: We determined that glucose restriction potentiates anti-PD-1 immune responses and identified thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake, as a potential immunometabolic modulator of T cell activation. We confirmed TXNIP downregulation in tumor infiltrating T cells in cancer patients. We next investigated the implication of TXNIP in modulating immune effector functions in primary human T cells and showed that TXNIP depletion increased IFN-γ secretion and tumor cell killing.
Conclusions: TXNIP is at the interface between immunometabolism and T cell activation and could represent a potential target for immuno-oncology treatments.

Keywords:  T cells activation; TXNIP; cancer immunotherapy; glucose deprivation; mixed lymphocyte reaction; single-cell RNA-sequencing; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1548509
FEBS J. 2025 Apr 24.

Glucose sensing and the unfolded protein response.

Mabel Cruz-Rodríguez, Eric Chevet, Cristina Muñoz-Pinedo.

  The unfolded protein response (UPR) is activated primarily upon alteration of protein folding in the endoplasmic reticulum (ER). This occurs under physiological situations that cause an abrupt increase in protein synthesis, or under redox and metabolic stresses. Among the latter, hyperglycemia and glucose scarcity have been identified as major modulators of UPR signaling. Indeed, the first mammalian UPR effector, the glucose-regulated protein 78, also known as BiP, was identified in response to glucose deprivation. Tunicamycin, arguably the most commonly used drug to induce ER stress responses in vitro and in vivo, is an inhibitor of N-glycosylation. We compile here evidence that the UPR is activated upon physiological and pathological conditions that alter glucose levels and that this is mostly mediated by alterations of protein N-glycosylation, ATP levels, or redox balance. The three branches of the UPR transduced by PERK/ATF4, IRE1/XBP1s, and ATF6, as well as non-canonical ER sensors such as SCAP/SREBP, sense ER protein glycosylation status driven by glucose and other glucose-derived metabolites. The outcomes of UPR activation range from restoring protein N-glycosylation and protein folding flux to stimulating autophagy, organelle recycling, and mitochondrial respiration, and in some cases, cell death. Anabolic responses to glucose levels are also stimulated by glucose through components of the UPR. Therefore, the UPR should be further studied as a potential biomarker and mediator of glucose-associated diseases.

Keywords:  ATF6; IRE1; PERK; glucose; glycosylation; nutrient sensing; starvation; unfolded protein response

DOI:  https://doi.org/10.1111/febs.70113
Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00396-1. [Epub ahead of print]44(5): 115625

Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation.

Yusra Zaidi, Rebekah Tritz, Nida Zaidi, Faisal Nabi, Syed Adeel H Zaidi, Abdelhakim Morsy, Valerie Harris, Rilee Racine, Farlyn Z Hudson, Zsuzsanna Bordan, Simone Kennard, Robert Batori, Yuqing Huo, Gabor Csanyi, Eric J Belin de Chantemèle, Kecheng Lei, Nicholas M Boulis, David J Fulton, Rizwan Hasan Khan, Ruth B Caldwell, Brian K Stansfield.

  Persons with neurofibromatosis type 1 (NF1) exhibit enhanced glucose metabolism, which is replicated in Nf1-mutant mice. Inflammatory macrophages invest NF1-associated tumors, and targeting macrophages appears efficacious in NF1 models. Inflammatory macrophages rely on glycolysis to generate ATP; thus, identifying whether neurofibromin, the protein encoded by NF1, controls glucose metabolism in macrophages is therapeutically compelling. Using neurofibromin-deficient macrophages and macrophage-specific Nf1-knockout mice, we demonstrate that neurofibromin complexes with glucose transporter-1 (GLUT1) to restrain its activity and that loss of neurofibromin permits Akt2 to facilitate GLUT1 translocation to the membrane. In turn, glucose internalization and glycolysis are upregulated and provoke reparative (MIL4) macrophages to undergo an inflammatory phenotypic switch. Inflammatory MLPSIFNγ macrophages and inflammatory-like MIL4 macrophages invest the perivascular stroma of tumors and induce pathologic angiogenesis in macrophage-specific Nf1-knockout mice. These studies identify a mechanism for the enhanced glycolysis associated with NF1 and provide a novel therapeutic target for NF1.

Keywords:  Akt2; CP: Immunology; CP: Metabolism; glucose transporter-1; glucose uptake; glycolysis; inflammation; macrophages; neurofibromin; pathological neovascularization

DOI:  https://doi.org/10.1016/j.celrep.2025.115625
Mol Metab. 2025 Apr 21. pii: S2212-8778(25)00059-6. [Epub ahead of print] 102152

Prolonged fasting promotes systemic inflammation and platelet activation in humans: a medically supervised, water-only fasting and refeeding study.

Serena Commissati, Maria Lastra Cagigas, Andrius Masedunskas, Giovanna Petrucci, Valeria Tosti, Isabella De Ciutiis, Gayathiri Rajakumar, Kristopher M Kirmess, Matthew R Meyer, Alan Goldhamer, Brian K Kennedy, Duaa Hatem, Bianca Rocca, Giovanni Fiorito, Luigi Fontana.

  Prolonged fasting (PF), defined as abstaining from energy intake for ≥4 consecutive days, has gained interest as a potential health intervention. However, the biological effects of PF on the plasma proteome are not well understood. In this study, we investigated the effects of a medically supervised water-only fast (mean duration: 9.8 ± 3.1 days), followed by 5.3 ± 2.4 days of guided refeeding, in 20 middle-aged volunteers (mean age: 52.2 ± 11.8 years; BMI: 28.8 ± 6.4 kg/m2). Fasting resulted in a 7.7% mean weight loss and significant increases in serum beta-hydroxybutyrate (BHB), confirming adherence. Untargeted high-dimensional plasma proteomics (SOMAScan, 1,317 proteins) revealed multiple adaptations to PF, including preservation of skeletal muscle and bone, enhanced lysosomal biogenesis, increased lipid metabolism via PPARα signaling, and reduced amyloid fiber formation. Notably, PF significantly reduced circulating amyloid beta proteins Aβ40 and Aβ42, key components of brain amyloid plaques. In addition, PF induced an acute inflammatory response, characterized by elevated plasma C-reactive protein (CRP), hepcidin, midkine, and interleukin 8 (IL-8), among others. A retrospective cohort analysis of 1,422 individuals undergoing modified fasting confirmed increased CRP levels (from 2.8 ± 0.1 to 4.3 ± 0.2 mg/L). The acute phase response, associated with transforming growth factor (TGF)-β signaling, was accompanied by increased platelet degranulation and upregulation of the complement and coagulation cascade, validated by ELISAs in blood and urine. While the acute inflammatory response during PF may serve as a transient adaptive mechanism, it raises concerns regarding potential cardiometabolic effects that could persist after refeeding. Further investigation is warranted to elucidate the long-term molecular and clinical implications of PF across diverse populations.

Keywords:  SUMMARY; cardiometabolic; inflammation; prolonged fasting; proteomics

DOI:  https://doi.org/10.1016/j.molmet.2025.102152
EMBO Rep. 2025 Apr 24.

Snf1 and yeast GSK3-β activates Tda1 to suppress glucose starvation signaling.

Kazuki Nonaka, Kohei Nishimura, Kazuma Uesaka, Emi Mishiro-Sato, Minako Fukase, Rei Kato, Fumihiko Okumura, Kunio Nakatsukasa, Keisuke Obara, Takumi Kamura.

  In budding yeast, the presence of glucose, a preferred energy source, suppresses the expression of respiration-related genes through a process known as glucose repression. Conversely, under glucose starvation conditions, Snf1 phosphorylates and activates downstream factors, relieving this repression and allowing cells to adapt. Recently, the Tda1 protein kinase has been implicated in these glucose starvation responses, although its function remains largely uncharacterized. In this study, we demonstrate that Snf1 and yeast glycogen synthase kinase 3-beta (GSK3-β) independently phosphorylate and activate Tda1, which in turn phosphorylates Hxk2 at Ser15. The Ser483 and Thr484 residues of Tda1 are critical for its activation by Snf1, while the Ser509 residue is crucial for its activation by yeast GSK3-β. Importantly, under glucose starvation conditions, the TDA1 deletion mutant shows increased expression of respiration-related genes and a faster growth rate compared to wild-type cells, which is opposite to what is observed in SNF1 and yeast GSK3-β deletion mutants. These findings suggest that Tda1 is activated by Snf1 and yeast GSK3-β, and functions as a suppressor of the glucose starvation signaling.

Keywords:  Glucose Starvation; Glycogen Synthase Kinase 3-beta; Hxk2; Snf1; Tda1

DOI:  https://doi.org/10.1038/s44319-025-00456-y