bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–07–12
twenty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Glycosylation in Alzheimer's disease.
  2. Exhausted CD8+ T cell subsets differ a TAD.
  3. Genetic and molecular signatures highlight diverse pathways linking obesity to type 2 diabetes.
  4. CSF1R regulates monocyte subset differentiation and intracellular metabolism.
  5. Psychological stress in mice induces ageing-like HSC dysfunction through intestinal dysbiosis.
  6. Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
  7. Endothelial cannabinoid CB1 receptor deficiency reduces shear stress-induced arterial inflammation and lipid uptake.
  8. Neuropixels harness the light.
  9. Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
  10. Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.
  11. Antibodies sculpt adult brain circuits.
  12. Fate-mapping infiltrating monocytes following experimental myocardial infarction revealsdifferentiation trajectories in the infarcted heart.
  13. FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.
  14. TNF-α induces type I IFN signalling to suppress neurogenesis and recruit T cells.
  15. Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.
  16. Phase separation drives NLRP3 inflammasome activation independently of Golgi localization.
  17. Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity.
  18. Statescope: an integrative deconvolution framework for discovering cell states in tumors.
  19. Dynamic control of nucleotide metabolism in physiology and disease.
  20. Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess.
  1. Nat Neurosci. 2026 Jul;29(7): 1528
    Glycosylation in Alzheimer's disease.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-026-02373-2
  2. Nat Immunol. 2026 Jul 06.
    Exhausted CD8+ T cell subsets differ a TAD.
    Maegan K Murphy, Takeshi Egawa.
      
    DOI:  https://doi.org/10.1038/s41590-026-02583-7
  3. Nat Commun. 2026 Jul 08. pii: 5680. [Epub ahead of print]17(1):
    Genetic and molecular signatures highlight diverse pathways linking obesity to type 2 diabetes.
    Pascal M Mutie, Tijana Stojanovic, Valeria Lo Faro, Torgny Karlsson, Åsa Johansson.
      Obesity is a major risk factor for type 2 diabetes, a disease affecting approximately 10% of the global population. Obesity is a heterogeneous condition, with different components exerting distinct, and sometimes opposing, effects on type 2 diabetes risk. Here, we aim to identify molecular mechanisms through which distinct components of obesity influence risk for type 2 diabetes by integrating multi-omics data. We identify SNPs associated with body mass index in males and females and cluster them based on their Mendelian randomisation estimates on type 2 diabetes risk. This analysis reveals four SNP clusters with distinct effects on type 2 diabetes ranging from strongly harmful to protective. We perform cluster-specific two-sample Mendelian randomisation analyses across over 3000 molecular traits to delineate metabolic, lipid, endocrine and glycaemic pathways mediating the harmful and protective effects of distinct obesity components on type 2 diabetes risk.
    DOI:  https://doi.org/10.1038/s41467-026-74675-9
  4. Nat Commun. 2026 Jul 04.
    CSF1R regulates monocyte subset differentiation and intracellular metabolism.
    Alexandre Gallerand, Johanna Merlin, Zakariya Caillot, Chloé Delaby, Elisa Bord, Jichang Han, Bastien Dolfi, Michael D Chang, Guilhem R Thierry, Alexia Castiglione, Sacha Grenet, Eloïse Goës, Maxime Franceschini, Gisèle Jarretou, Fairouz N Zair, Evy Boré, Florian Tuffin, David Dombrowicz, Giulia Chinetti, Rodolphe R Guinamard, Maxim N Artyomov, Abdelilah Wakkach, Didier F Pisani, Gwendalyn J Randolph, Adeline Bertola, Patrick Auberger, Arnaud Jacquel, David A Hume, Jesse W Williams, Marc Bajénoff, Jaap G Neels, Stoyan Ivanov.
      Monocytes are key circulating effectors of vascular homeostasis, innate immunity and inflammation. Following their generation in mouse bone marrow, classical (Ly6Chigh) monocytes are mobilized into the blood circulation where they mature into non-classical (Ly6Clow) patrolling monocytes or are recruited into peripheral tissues where they differentiate into tissue resident or inflammatory macrophages. Monocytes and macrophages express CSF1R (CD115), the receptor for lineage-specific growth factors CSF1 and IL-34. Here, we report that acute CSF1R blockade or genetic deletion negatively interferes with monocyte intracellular metabolism and reduces blood Ly6Clow monocytes in part by blunting differentiation of Ly6Chigh monocytes. Based upon lineage-specific deletion of Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the hexosamine biosynthetic pathway (HBP) is identified as an important regulator of CSF1R expression and monocyte subsets. Inhibition of receptor tyrosine kinases CSF1R and FLT3 rewires and partially impairs metabolic activity in human monocytes. Our findings provide insights into the link between CSF1R signaling, metabolic regulation, and monocyte survival and differentiation.
    DOI:  https://doi.org/10.1038/s41467-026-75263-7
  5. Nat Rev Immunol. 2026 Jul 10.
    Psychological stress in mice induces ageing-like HSC dysfunction through intestinal dysbiosis.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-026-01336-9
  6. Nat Metab. 2026 Jul 08.
    Oxygen relief for a proteostasis-driven disease associated with mitochondrial complex I dysfunction.
    Anthony S Grillo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01569-x
  7. Nat Commun. 2026 Jul 07. pii: 5939. [Epub ahead of print]17(1):
    Endothelial cannabinoid CB1 receptor deficiency reduces shear stress-induced arterial inflammation and lipid uptake.
    Bingni Chen, Aishvaryaa Prabhu, Guo Li, Anna Kaltenbach, Yong Wang, George Shakir, Lucia Natarelli, Remco Megens, Yvonne Jansen, Srishti Ramanathan, Martina Geiger, Alexander Faussner, Michael Hristov, Daniel Richter, Xinyu Di, Mario van der Stelt, Vasiliki Triantafyllidou, Zhaolong Li, Nadja Sachs, Valentina Paloschi, Lars Maegdefessel, Susanna M Hofmann, Martina Schifferer, Mikael Simons, Christian Weber, Donato Santovito, Stephan Herzig, Raquel Guillamat Prats, Sabine Steffens.
      Peripheral cannabinoid CB1 receptor antagonists that lack central nervous system effects are emerging as promising therapies for metabolic disease, yet the role of endothelial CB1 signaling in atherosclerosis remains unclear. Here, we show that endothelial CB1 is expressed in human atherosclerotic plaques, is induced by oscillatory shear stress in atheroprone flow regions, and promotes vascular inflammation, permeability and lipid uptake. Endothelial-specific Cnr1 deletion or peripheral CB1 antagonism in mice attenuates atherosclerosis, reduces endothelial caveolae-dependent low-density lipoprotein uptake by downregulating caveolin-1 and ALK1 expression, and improves metabolic parameters in brown and white adipose tissue and the liver. The anti-atherogenic and metabolic effects are more pronounced in females, which is possibly linked to estrogen signaling. These findings identify endothelial CB1 as a proatherogenic, sex-biased regulator of vascular lipid transport and plaque development and associated metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-75214-2
  8. Nat Neurosci. 2026 Jul;29(7): 1528
    Neuropixels harness the light.
    Luis A Mejia.
      
    DOI:  https://doi.org/10.1038/s41593-026-02372-3
  9. Cell Calcium. 2026 Jun 18. pii: S0143-4160(26)00054-0. [Epub ahead of print]136 103161
    Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
    Johannes Pfabe, Amanda Cambraia, Prasanna K Dadi, Melanie Cutler, Cristiane Dos Santos, Christopher Acree, Aliyah Habashy, Guy Perkins, Mark H Ellisman, David A Jacobson, Marjan Slak Rupnik, Rafael Arrojo E Drigo.
      Calorie restriction (CR) promotes beta cell longevity by regulating cell identity, organelle and protein homeostasis, and metabolism pathways. CR beta cells have higher cAMP levels and mitochondria with an elevated potential to generate ATP. However, CR beta cells have reduced insulin secretion due to increased peripheral insulin sensitivity. How CR impacts beta cell Ca²⁺ homeostasis to regulate beta cell insulin release remains unknown. We investigated this question using acute pancreatic tissue slices prepared from ad-libitum (AL) or CR mice loaded with a low affinity Ca²⁺ indicator and recorded cytosolic Ca²⁺ gradients with fast confocal imaging. We exposed these slices to increasing glucose concentrations and applied our semi-automatic analysis pipeline to detect thousands of individual beta cells followed by identification of individual Ca²⁺ spiking events. We observed that elevated cAMP in CR beta cells causes fast short-amplitude Ca²⁺ oscillations that potentiate insulin release despite a largely disconnected beta cell network landscape. Using acetylcholine stimulation, we found that faster IP3R-driven Ca²⁺ oscillations linked to higher cytosolic cAMP levels protect beta cells against acute depletion of ER Ca²⁺. Therefore, this study demonstrates that CR promotes beta cell cAMP and ER Ca²⁺ homeostasis to enhance beta cell secretory function.
    Keywords:  Beta cell calcium; Calorie restriction; Endoplasmic reticulum (er)
    DOI:  https://doi.org/10.1016/j.ceca.2026.103161
  10. Nat Commun. 2026 07 04. pii: 5846. [Epub ahead of print]17(1):
    Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.
    Inga Menze, Jose Bernal, Rogier A Kievit, Kumar Parijat Tripathi, Timo Kaleck, Renat Yakupov, Slawek Altenstein, Claudia Bartels, Katharina Buerger, Michaela Butryn, Peter Dechent, Michael Ewers, Klaus Fliessbach, Ingo Frommann, Maria Gemenetzi, Wenzel Glanz, Daria Gref, Julian Hellmann-Regen, Stefan Hetzer, Enise I Incesoy, Daniel Janowitz, Ingo Kiliman, Luca Kleineidam, Marie Theres Kronmüller, Christoph Laske, Debora Melo van Lent, Falk Lüsebrink, Robert Perneczky, Oliver Peters, Lukas Preis, Josef Priller, Boris-Stephan Rauchmann, Ayda Rostamzadeh, Sandra Roeske, Klaus Scheffler, Björn-Hendrik Schott, Anja Schneider, Sebastian Sodenkamp, Annika Spottke, Eike Jakob Spruth, Melina Stark, Stefan Teipel, Michael Wagner, Jens Wiltfang, Frank Jessen, Alfredo Ramirez, Stefanie Schreiber, Emrah Düzel, Gabriel Ziegler.
      Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.
    DOI:  https://doi.org/10.1038/s41467-026-74957-2
  11. Science. 2026 Jul 09. 393(6807): 143-144
    Antibodies sculpt adult brain circuits.
    Lauritz Miarka, Marco Prinz.
      Immune cells target hyperactive neurons to eliminate synaptic connections.
    DOI:  https://doi.org/10.1126/science.aei8076
  12. J Clin Invest. 2026 Jul 07. pii: e189684. [Epub ahead of print]
    Fate-mapping infiltrating monocytes following experimental myocardial infarction revealsdifferentiation trajectories in the infarcted heart.
    Andrew L Koenig, Farid F Kadyrov, Junedh M Amrute, Steven Yang, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Wenjun Li, Gabriella B Smith, Lance Yeh, Daniel Kreisel, Kory J Lavine.
      Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display striking functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisions. We devised a genetic lineage tracing strategy using Ccr2crERT2Rosa26LSL-tdTomato mice in combination with single cell RNA-sequencing to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes were recruited to the heart early after injury and gave rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that were specified prior to extravasation and chronically persisted within the myocardium. Pseudotime analysis predicted two differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we demonstrated that macrophages expressing a type I interferon responsive signature were an intermediate population that gave rise to MHC-IIhi macrophages, were localized within the border zone, induce regulatory T cells, and promote myocardial protection. Collectively, these data uncover complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.
    Keywords:  Cardiology; Cellular immune response; Heart failure; Immunology; Macrophages
    DOI:  https://doi.org/10.1172/JCI189684
  13. Nat Commun. 2026 Jul 09.
    FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.
    Ken Matoba, Takahiro Kochi, Oluwaseun Fatoba, Md Sorwer Alam Parvez, Inssaf Berkiks, Yassin R Mreyoud, Harrison Strong, Jana H Badrani, Hency Patel, Yoshiko Nagaoka-Kamata, Masakazu Kamata, Hiroshi Tsujioka, Toshihide Yamashita, David K Crossman, Minae Niwa, Shin-Ichi Kano.
      Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9hi microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9hi microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9hi microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.
    DOI:  https://doi.org/10.1038/s41467-026-74904-1
  14. Nat Commun. 2026 Jul 07. pii: 5287. [Epub ahead of print]17(1):
    TNF-α induces type I IFN signalling to suppress neurogenesis and recruit T cells.
    Tinne A D Nissen, Arishma Baig, Sahand Farmand, Daniel T Rock, Sandra Shibu, Hyunah Lee, Lauren A O'Neill, Vikki Houghton, Susan John, Linda S Klavinskis, Sandrine Thuret.
      Adult hippocampal neurogenesis is essential for learning, memory, and mood regulation, and its disruption is implicated in ageing, neurodegeneration, and mood disorders. However, the mechanisms linking inflammation to adult hippocampal neurogenesis impairment remain unclear. Here, we identify chronic tumour necrosis factor-alpha signalling as a key driver of neurogenic dysregulation via a previously unrecognised type I interferon autocrine/paracrine loop in human hippocampal progenitor cells. Using a female-derived human in vitro neurogenesis model, single-cell RNA sequencing, and functional T cell migration assays, we show that tumour necrosis factor-alpha induces a robust type I interferon response in hippocampal progenitor cells, promoting chemokine-mediated and CXC motif chemokine receptor 3-dependent T cell recruitment and suppressing neurogenesis. This inflammatory signalling cascade drives a fate switch in hippocampal progenitor cells from a neurogenic trajectory towards an immune-defensive phenotype, with critical implications for infectious and inflammatory disease pathogenesis. These findings uncover a key inflammatory checkpoint regulating human adult hippocampal neurogenesis and highlight potential therapeutic targets to restore neurogenesis in chronic inflammatory states.
    DOI:  https://doi.org/10.1038/s41467-026-74104-x
  15. Nat Immunol. 2026 Jul 06.
    Exhausted CD8+ T cell fate is programmed by dynamic CTCF-mediated enhancer activation and invariant CTCF-imposed barriers.
    Wei Hu, Shaoqi Zhu, Qing Chen, Vladimir P Badovinac, Weiqun Peng, Hai-Hui Xue.
      Exhausted CD8+ T (TEX) cells undergo extensive genome reorganization during differentiation, yet the drivers of this process remain elusive. Here we show that CTCF programmed CD8+ TEX cell fates through two distinct modes of action. CTCF acquired de novo binding sites and concordantly induced open chromatin in early CD8+ TEX cells responding to chronic viral infection. The dynamic CTCF binding activated enhancers and promoted chromatin looping. Consequently, genetic ablation of CTCF diminished chromatin accessibility and interaction strength, impairing CD8+ TEX cell proliferation, effector function and bioenergetic mobilization. Conversely, invariant CTCF binding acted as essential chromatin barriers, and loss of CTCF disrupted insulation and caused aberrant chromatin self-association and undue RNA polymerase II pausing, leading to excessive activation of exhaustion- and stemness-linked genes. Thus, CTCF balanced CD8+ TEX cell differentiation by gaining dynamic binding to induce cytotoxicity and sustain metabolic fitness, while its invariant binding compartmentalized exhaustion and stemness program genes to prevent their overexuberant activation.
    DOI:  https://doi.org/10.1038/s41590-026-02585-5
  16. Cell Death Dis. 2026 Jul 06.
    Phase separation drives NLRP3 inflammasome activation independently of Golgi localization.
    Yuansen Zhu, Chenchao Wei, Xiang Yin, Bolong Lin, Xiaqiong Wang, Hongbin He, Wei Jiang, Rongbin Zhou.
      The NLRP3 inflammasome plays a pivotal role in sterile inflammation and various diseases, yet the mechanisms underlying its activation remain elusive. Previous studies have implicated both NLRP3 Golgi localization and palmitoylation-mediated phase separation in its activation; however, mutations in palmitoylation sites or the FISNA domain's intrinsically disordered region (IDR) concurrently disrupt both processes, hindering delineation of their individual contributions to inflammasome activation. Here, we show that NLRP3 exhibits phase separation and Golgi localization simultaneously during inflammasome activation. The polybasic region and FISNA IDR each mediate both processes, whereas lipid-binding motif deletion abolishes Golgi localization without compromising phase separation or inflammasome activity. Conversely, the C-terminal IDR is essential for phase separation and inflammasome activity but dispensable for Golgi localization. By mechanistically uncoupling these processes, our findings establish that phase separation drives NLRP3 activation independently of Golgi localization, thus redefining the spatial and biophysical paradigm of inflammasome assembly.
    DOI:  https://doi.org/10.1038/s41419-026-09059-4
  17. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00759-X. [Epub ahead of print]45(7): 117681
    Myeloid MMP14 couples extracellular proteolysis to inflammatory and metabolic remodeling during obesity.
    Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun.
      Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring cells. In vivo, myeloid-specific Mmp14 deletion protected mice from HFD-induced insulin resistance, dyslipidemia, hepatic steatosis, adipose inflammation, and fibrosis. These findings identify macrophage MMP14 as a key mediator linking extracellular matrix remodeling with inflammatory and metabolic dysfunction in obesity.
    Keywords:  CP: immunology; CP: metabolism; MMP14; inflammatory signaling; lipid metabolism; macrophages; metabolic adaptation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117681
  18. Nat Commun. 2026 Jul 06.
    Statescope: an integrative deconvolution framework for discovering cell states in tumors.
    Jurriaan Janssen, Mischa F B Steketee, Aryamaan Bose, Saskia van Asten, Paul P Eijk, Frederike Dijk, Arantza Farina Sarasqueta, Febe van Maldegem, David P Noske, Idris Bahce, Jan Koster, Juan J Garcia Vallejo, Richard Schoonhoven, Mark A van de Wiel, Teodora Radonic, Bauke Ylstra, Yongsoo Kim.
      Accurate deconvolution of cell states from bulk tumor RNA-seq is hindered by heterogeneous malignant cells specifically in cancer applications. We present Statescope, a Bayesian framework that incorporates DNA-derived malignant cell purity to overcome this heterogeneity and explicitly models inter-sample variation to accurately identify cell states. Comprehensive benchmarking shows Statescope outperforms existing methods in both cell fraction and state estimation, and is unique in its ability to identify states entirely absent from single-cell references. In real-data applications, Statescope successfully recapitulates established cell states, including multiple states in neutrophils, a cell type often missed by single-cell methods in lung cancer. Critically, in the POPLAR/OAK clinical trials, Statescope identifies a combinatorial signature of effector CD8 + T cells and conventional dendritic cell states that together predict a striking survival benefit from immunotherapy. Collectively, Statescope transforms deconvolution into a versatile discovery platform, enabling deeper biological and clinical insights from widely available bulk multi-omics data.
    DOI:  https://doi.org/10.1038/s41467-026-74997-8
  19. Nat Cell Biol. 2026 Jul 08.
    Dynamic control of nucleotide metabolism in physiology and disease.
    Dohun Kim, Gerta Hoxhaj.
      Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02004-9
  20. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00238-X. [Epub ahead of print]
    Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess.
    Marc Prentki, Christopher J Nolan, David E James, Bernard Thorens, Christopher J Rhodes, Barbara E Corkey, Charlotte Ling, Philippe Froguel, Chantal Mathieu, Jean-François Gautier, Marc Y Donath.
      Obesity-related type 2 diabetes (T2D) is currently defined by insulin resistance and impaired insulin secretion. Sulfonylureas, thiazolinediones, and insulin are effective at lowering glycemia yet have not consistently translated into improved long-term outcomes. In contrast, recent interventions often produce metabolic benefits that exceed expectations based on glucose lowering alone. These contrasting observations suggest that our understanding of T2D pathophysiology is incomplete. We propose that, in obesity-related prediabetes and early T2D, insulin resistance, attenuated glucose-stimulated insulin secretion, modest hyperglycemia, and glucosuria represent beneficial functional changes in response to nutrient excess. These allostatic adaptive responses limit glucose flux into metabolically vulnerable tissues and reduce nutrient stress (nutri-stress). From this perspective, T2D is not simply a failure of glucose regulation but a coordinated systemic allostatic response to chronic energy excess aimed at preserving metabolic homeostasis. Therapeutic success may depend not only on lowering glycemia but also on how interventions alter tissue-specific glucose handling and metabolic stress.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.012
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