bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–06–15
23 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Senescence-related proteins in blood predict aging traits.
  2. Clonal hematopoiesis driven by microbial metabolite.
  3. How burnout snuck up on me.
  4. How to keep weight off after obesity drugs.
  5. A sweet spot in myeloid cell pro-tumoral functions.
  6. Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC.
  7. GLP-1-mediated synaptic plasticity in feeding regulation is modulated by energy state.
  8. How to speak to a vaccine sceptic: research reveals what works.
  9. No (innate immune) training without lactate.
  10. How you breathe is like a fingerprint that can identify you.
  11. Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming.
  12. Mitochondrial molecule has unexpected role in tissue healing.
  13. Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.
  14. Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice.
  15. The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
  16. A lipid atlas of the human kidney.
  17. Early life high fructose impairs microglial phagocytosis and neurodevelopment.
  18. RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
  19. VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.
  20. Resistance to anti-PD-1 therapy is driven by CD30+ regulatory T cell activity.
  21. Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing.
  22. Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance.
  23. High-resolution lifestyle profiling and metabolic subphenotypes of type 2 diabetes.
  1. Nat Aging. 2025 Jun 10.
    Senescence-related proteins in blood predict aging traits.
      
    DOI:  https://doi.org/10.1038/s43587-025-00891-5
  2. Nat Aging. 2025 Jun 12.
    Clonal hematopoiesis driven by microbial metabolite.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-025-00912-3
  3. Science. 2025 Jun 12. 388(6752): 1234
    How burnout snuck up on me.
    Doulotuzzaman Xames.
      
    DOI:  https://doi.org/10.1126/science.adz5933
  4. Nature. 2025 Jun;642(8067): 286-288
    How to keep weight off after obesity drugs.
    Elie Dolgin.
      
    Keywords:  Health care; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-01770-0
  5. Immunity. 2025 Jun 10. pii: S1074-7613(25)00236-5. [Epub ahead of print]58(6): 1369-1371
    A sweet spot in myeloid cell pro-tumoral functions.
    Gillian Dunphy, David Sancho.
      The regulation of myeloid cell responses can determine tumor outcomes. In this issue of Immunity, Blidner et al. report that galectin-1 triggers both immunoregulatory and pro-angiogenic circuits in myeloid cells, promoting tumor growth via a VEGF-dependent mechanism.
    DOI:  https://doi.org/10.1016/j.immuni.2025.05.015
  6. Nat Commun. 2025 Jun 10. 16(1): 5136
    Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC.
    Songlei Liu, Li Li, Fan Zhang, Mariana Garcia-Corral, Katharina Meyer, Patrick R J Fortuna, Björn van Sambeek, Evan Appleton, Alex H M Ng, Parastoo Khoshakhlagh, Yuancheng Ryan Lu, James Cameron, Ricardo N Ramirez, Yuting Chen, Chun-Ting Wu, Jeremy Y Huang, Yuqi Tan, George Chao, John Aach, Elaine T Lim, Jenny M Tam, Soumya Raychaudhuri, George M Church.
      Differentiation of induced pluripotent stem cells (iPSCs) into specialized cell types is essential for uncovering cell-type specific molecular mechanisms and interrogating cellular function. Transcription factor screens have enabled efficient production of a few cell types; however, engineering cell types that require complex transcription factor combinations remains challenging. Here, we report an iterative, high-throughput single-cell transcription factor screening method that enables the identification of transcription factor combinations for specialized cell differentiation, which we validated by differentiating human microglia-like cells. We found that the expression of six transcription factors, SPI1, CEBPA, FLI1, MEF2C, CEBPB, and IRF8, is sufficient to differentiate human iPSC into cells with transcriptional and functional similarity to primary human microglia within 4 days. Through this screening method, we also describe a novel computational method allowing the exploration of single-cell RNA sequencing data derived from transcription factor perturbation assays to construct causal gene regulatory networks for future cell fate engineering.
    DOI:  https://doi.org/10.1038/s41467-025-59596-3
  7. Nat Metab. 2025 Jun 09.
    GLP-1-mediated synaptic plasticity in feeding regulation is modulated by energy state.
      
    DOI:  https://doi.org/10.1038/s42255-025-01304-y
  8. Nature. 2025 Jun;642(8067): 289-291
    How to speak to a vaccine sceptic: research reveals what works.
    Helen Pearson.
      
    Keywords:  Diseases; Public health; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-01771-z
  9. Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067
    No (innate immune) training without lactate.
    Jan Van den Bossche.
      A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.014
  10. Nature. 2025 Jun 12.
    How you breathe is like a fingerprint that can identify you.
    Humberto Basilio.
      
    Keywords:  Computer science; Human behaviour; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01835-0
  11. Commun Biol. 2025 Jun 12. 8(1): 920
    Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming.
    Wenxue Zhao, Weihong Yuan, Tian Dong, Wei Qi, Zhijie Feng, Cheng Li, Yujie Sun.
      Matrix stiffness has significant effects on cell behavior, however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cells. In this study, we use an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, and integrate multi-omics with imaging and biochemical assays to investigate the molecular mechanisms. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimulus. We also identify activation of p-JUN in response to the stiff matrix and promoting phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness may be responsible for various fibrotic diseases and provide insight into intervening approaches.
    DOI:  https://doi.org/10.1038/s42003-025-08160-2
  12. Nature. 2025 Jun 11.
    Mitochondrial molecule has unexpected role in tissue healing.
    Ram P Chakrabarty, Navdeep S Chandel.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01583-1
  13. EMBO J. 2025 Jun 10.
    Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.
    Linh Thuy Mai, Sharada Swaminathan, Trieu Hai Nguyen, Etienne Collette, Tania Charpentier, Liseth Carmona-Pérez, Hamza Loucif, Alain Lamarre, Krista M Heinonen, David Langlais, Jörg H Fritz, Simona Stäger.
      Exhaustion of CD8+ T-cells leads to their reduced immune functionality and is controlled by numerous transcription factors. Here we show that the transcription factor IRF-5 helps to limit functional exhaustion of murine CD8+ T-cells during the chronic stage of LCMV (CL13) viral infection. Our results suggest that T-cell inhibitory receptors and transcription factor TOX, which are implicated in dampening T-cell activation and promoting exhaustion, are upregulated in infected IRF-5-deficient CD8+ T-cells. In addition, these cells display a reduced capacity to produce cytokines and lower survival rates than wild-type cells. Our findings indicate that these effects are mediated by defective lipid metabolism, increased lipid peroxidation, enhanced mitochondrial ROS production, and reduced levels of oxidative phosphorylation in the absence of IRF-5. These results identify IRF-5 as an important regulator of lipid metabolism and mitochondrial function that protects CD8+ T-cells from functional exhaustion during the chronic stage of viral infection.
    Keywords:  CD8 T Cells; Cell Exhaustion; IRF-5; Lipid Metabolism; Mitochondria
    DOI:  https://doi.org/10.1038/s44318-025-00485-2
  14. Nat Aging. 2025 Jun 09.
    Boosting angiotensin-converting enzyme (ACE) in microglia protects against Alzheimer's disease in 5xFAD mice.
    Andrew R Gomez, Hyae Ran Byun, Shaogen Wu, A K M Ghulam Muhammad, Jasmine Ikbariyeh, Jaelin Chen, Alek Muro, Lin Li, Kenneth E Bernstein, Richard Ainsworth, Warren G Tourtellotte.
      Genome-wide association studies have identified many gene polymorphisms associated with an increased risk of developing late-onset Alzheimer's disease (LOAD). Many of these LOAD risk-associated alleles alter disease pathogenesis by influencing innate immune responses and lipid metabolism of microglia (MG). Here we show that boosting the expression of angiotensin-converting enzyme (ACE), a genome-wide association study LOAD risk-associated gene product, specifically in MG, reduces amyloid-β (Aβ) plaque load, preserves vulnerable neurons and excitatory synapses, and significantly reduces learning and memory abnormalities in the 5xFAD amyloid mouse model of AD. ACE-expressing MG surround plaques more frequently and they have increased Aβ phagocytosis, endolysosomal trafficking and spleen tyrosine kinase activation downstream of the major Aβ receptors, triggering receptor expressed on myeloid cells 2 (Trem2) and C-type lectin domain family 7 member A (Clec7a). These findings establish a role for ACE in enhancing microglial immune function and they identify a potential use for ACE-expressing MG as a cell-based therapy to augment endogenous microglial responses to Aβ in AD.
    DOI:  https://doi.org/10.1038/s43587-025-00879-1
  15. Cell Rep. 2025 Jun 05. pii: S2211-1247(25)00570-4. [Epub ahead of print]44(6): 115799
    The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
    Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.
      Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.
    Keywords:  CP: Immunology; CP: Metabolism; EGCG; PGAM; PGM; T helper 17; central carbon metabolism; epigallocatechin-3-gallate; glycolysis; immune metabolism; immunometabolism; phosphoglycerate mutase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115799
  16. Sci Adv. 2025 Jun 13. 11(24): eadu3730
    A lipid atlas of the human kidney.
    Melissa A Farrow, Léonore E M Tideman, Elizabeth K Neumann, Lukasz G Migas, Nathan Heath Patterson, Madeline E Colley, Jamie L Allen, Ellie L Pingry, Martin Dufresne, Haichun Yang, Maya Brewer, Emilio S Rivera, Carrie E Romer, Katerina Djambazova, Kavya Sharman, Angela R S Kruse, Danielle B Gutierrez, Raymond C Harris, Agnes B Fogo, Mark P de Caestecker, Richard M Caprioli, Raf Van de Plas, Jeffrey M Spraggins.
      Tissue atlases provide foundational knowledge on the cellular organization and molecular distributions across molecular classes and spatial scales. Here, we construct a comprehensive spatiomolecular lipid atlas of the human kidney from 29 donor tissues using integrated multimodal molecular imaging. Our approach leverages high-spatial-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry for untargeted lipid mapping, stained microscopy for histopathological assessment, and tissue segmentation using autofluorescence microscopy. With a combination of unsupervised, supervised, and interpretable machine learning, the atlas provides multivariate lipid profiles of specific multicellular functional tissue units (FTUs) of the nephron, including the glomerulus, proximal tubules, thick ascending limb, distal tubules, and collecting ducts. In total, the atlas consists of tens of thousands of FTUs and millions of mass spectrometry measurements. Detailed patient, clinical, and histopathologic information allowed molecular data to be mined on the basis of these features. As examples, we highlight the discovery of how lipid profiles are altered with sex and differences in body mass index.
    DOI:  https://doi.org/10.1126/sciadv.adu3730
  17. Nature. 2025 Jun 11.
    Early life high fructose impairs microglial phagocytosis and neurodevelopment.
    Zhaoquan Wang, Allie Lipshutz, Celia Martínez de la Torre, Alissa J Trzeciak, Zong-Lin Liu, Isabella C Miranda, Tomi Lazarov, Ana C Codo, Jesús E Romero-Pichardo, Achuth Nair, Tanya Schild, Waleska Saitz Rojas, Pedro H V Saavedra, Ann K Baako, Kelvin Fadojutimi, Michael S Downey, Frederic Geissmann, Giuseppe Faraco, Li Gan, Jon Iker Etchegaray, Christopher D Lucas, Marina Tanasova, Christopher N Parkhurst, Melody Y Zeng, Kayvan R Keshari, Justin S A Perry.
      Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment1-3. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system4. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents-an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.
    DOI:  https://doi.org/10.1038/s41586-025-09098-5
  18. Nature. 2025 Jun 11.
    RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.
    Akihito Sakoguchi, Samuel G Chamberlain, Alexander M Mørch, Marcus Widdess, Thomas E Harrison, Michael L Dustin, Hisashi Arase, Matthew K Higgins, Shiroh Iwanaga.
      Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.
    DOI:  https://doi.org/10.1038/s41586-025-09091-y
  19. Cell Rep. 2025 Jun 11. pii: S2211-1247(25)00605-9. [Epub ahead of print]44(6): 115834
    VDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.
    Gitanjali Roy, Andrea Ordóñez, Derk D Binns, Karina Rodrigues-Dos-Santos, Michael B Kwakye, George C King, Rachel L Kuntz, Noyonika Mukherjee, Andrew T Templin, Zhiyong Tan, Timothy I Richardson, Emma H Doud, Amber L Mosley, Kathryn L Schueler, Christopher H Emfinger, Alan D Attie, Mark P Keller, Travis S Johnson, Michael A Kalwat.
      β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca2+ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However, immunostaining of the T2D human pancreas shows altered distributions of the ratios of the core ERAD components SEL1L, HRD1, and DERL3 in β cells. This work provides a detailed mechanistic characterization of a hypersecretion-specific stress response, revealing potential therapeutic targets, including VDAC1 and ERAD, for modulating β cell function and survival in disease.
    Keywords:  CP: Cell biology; CP: Metabolism; ER stress; ER-associated degradation; congenital hyperinsulinism; diabetes; hypersecretion; insulin secretion; pancreatic islets; target identification; transcriptomics; β cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115834
  20. Nat Immunol. 2025 Jun 10.
    Resistance to anti-PD-1 therapy is driven by CD30+ regulatory T cell activity.
      
    DOI:  https://doi.org/10.1038/s41590-025-02175-x
  21. Nat Neurosci. 2025 Jun 12.
    Protective exercise responses in the dentate gyrus of Alzheimer's disease mouse model revealed with single-nucleus RNA-sequencing.
    Joana F da Rocha, Michelle L Lance, Renhao Luo, Pius Schlachter, Luis Moreira, Mohamed Ariff Iqbal, Paula Kuhn, Robert S Gardner, Sophia Valaris, Mohammad R Islam, Gabriele M Gassner, Sofia Mazuera, Kaela Healy, Sanjana Shastri, Nathaniel B Hibbert, Kristen V Moran-Figueroa, Erin B Haley, Ryan D Pfeiffer, Sema Aygar, Ksenia V Kastanenka, Logan Brase, Oscar Harari, Bruno A Benitez, Nathan R Tucker, Christiane D Wrann.
      Exercise's protective effects in Alzheimer's disease (AD) are well recognized, but cell-specific contributions to this phenomenon remain unclear. Here we used single-nucleus RNA sequencing (snRNA-seq) to dissect the response to exercise (free-wheel running) in the neurogenic stem-cell niche of the hippocampal dentate gyrus in male APP/PS1 transgenic AD model mice. Transcriptomic responses to exercise were distinct between wild-type and AD mice, and most prominent in immature neurons. Exercise restored the transcriptional profiles of a proportion of AD-dysregulated genes in a cell type-specific manner. We identified a neurovascular-associated astrocyte subpopulation, the abundance of which was reduced in AD, whereas its gene expression signature was induced with exercise. Exercise also enhanced the gene expression profile of disease-associated microglia. Oligodendrocyte progenitor cells were the cell type with the highest proportion of dysregulated genes recovered by exercise. Last, we validated our key findings in a human AD snRNA-seq dataset. Together, these data present a comprehensive resource for understanding the molecular mediators of neuroprotection by exercise in AD.
    DOI:  https://doi.org/10.1038/s41593-025-01971-w
  22. Nat Genet. 2025 Jun 12.
    Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance.
    Elizabeth Dorans, Karthik Jagadeesh, Kushal Dey, Alkes L Price.
      Methods that analyze single-cell paired RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) multiome data have shown promise in linking regulatory elements to genes. However, existing methods exhibit low concordance and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on expression quantitative trait locus (eQTL) data to assign a probabilistic score to each candidate single-nucleotide polymorphism-gene link. pgBoost attained higher enrichment than existing methods for evaluation sets derived from eQTL, activity-by-contact, CRISPR and genome-wide association study (GWAS) data. We further determined that restricting pgBoost to features from a focal cell type improved power to identify links relevant to that cell type. We highlight several examples in which pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies improves power to identify target genes underlying GWAS associations.
    DOI:  https://doi.org/10.1038/s41588-025-02220-3
  23. NPJ Digit Med. 2025 Jun 11. 8(1): 352
    High-resolution lifestyle profiling and metabolic subphenotypes of type 2 diabetes.
    Heyjun Park, Ahmed A Metwally, Alireza Delfarah, Yue Wu, Dalia Perelman, Caleb Mayer, Curtis McGinity, Majid Rodgar, Alessandra Celli, Tracey McLaughlin, Emmanuel Mignot, Michael Snyder.
      Distinct metabolic susceptibilities (beta-cell dysfunction, insulin resistance (IR), and impaired incretin response) underlie type 2 diabetes (T2D). However, their relationships with habitual lifestyle behaviors are underexplored. This study integrated high-resolution lifestyle data from wearable devices, continuous glucose monitoring, and smartphone-based food logs with gold-standard physiological tests in 36 individuals at risk for T2D (ClinicalTrials.Gov; NCT03919877; 2019-04-18). Over 6400 timestamped records of diet, sleep, and physical activity were analyzed with in participants with measures of beta-cell function, tissue-specific IR (muscle, hepatic, adipose), and incretin response. We found that lifestyle timing and variability were strongly associated with metabolic subphenotypes: (1) eating timing was associated with muscle IR and incretin function; (2) irregular sleep correlated to IR and incretin function; and (3) Time-of-day effects of physical activity varied by subphenotype. These findings were validated in an independent cohort. Our results highlight novel physiological links between daily behaviors and metabolic risk, informing potential lifestyle modifications for T2D prevention.
    DOI:  https://doi.org/10.1038/s41746-025-01728-6
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