bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–07–26
sixteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Ascites-derived lipid barrier at the T cell synapse.
  2. Human body single-cell atlas of three-dimensional genome organization and DNA methylation.
  3. Drug holidays restore exhausted T cell responses to PD1 blockade.
  4. Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
  5. Genome in motion: Mapping the nucleus in health.
  6. Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
  7. Early detection of Alzheimer's disease with circular RNA from blood.
  8. Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.
  9. Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity.
  10. A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.
  11. Localized PD-1 CAR T therapy reprograms neuroinflammation.
  12. GLP-1 Medications May Improve Health in People With PAD and Diabetes.
  13. Dietary environmental impacts and quality differ by socio-demographic characteristics.
  14. Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
  15. Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism.
  16. Three tips to avoid AI image mistakes in science.
  1. Nat Metab. 2026 Jul;8(7): 1455-1456
    Ascites-derived lipid barrier at the T cell synapse.
    Teresa Manzo.
      
    DOI:  https://doi.org/10.1038/s42255-026-01564-2
  2. Science. 2026 Jul 23. 393(6809): eadx0673
    Human body single-cell atlas of three-dimensional genome organization and DNA methylation.
    Jingtian Zhou, Yue Wu, Hanqing Liu, Wei Tian, Rosa G Castanon, Anna Bartlett, Zuolong Zhang, Guocong Yao, Dengxiaoyu Shi, Ben Clock, Samantha Marcotte, Joseph R Nery, Michelle Liem, Naomi Claffey, Lara Boggeman, Cesar Barragan, Rafael Arrojo E Drigo, Annika K Weimer, Minyi Shi, Johnathan Cooper-Knock, Sai Zhang, Michael P Snyder, Sebastian Preissl, Bing Ren, Carolyn O'Connor, Shengbo Chen, Chongyuan Luo, Jesse R Dixon, Joseph R Ecker.
      Higher-order chromatin structure and DNA methylation are critical for gene regulation, but how these vary across the human body remains unclear. We performed multiomic profiling of three-dimensional (3D) genome structure and DNA methylation for 86,689 single nuclei across 16 tissues, identifying 35 major and 206 cell subtypes. We revealed extensive changes in CG and non-CG methylation across cell types and characterized 3D chromatin structure at an unprecedented cellular resolution. Extensive discrepancies exist between cell types delineated by DNA methylation and genome structure, which indicates that the role of distinct epigenomic features in maintaining cell identity may vary by lineage. This study expands our understanding of the diversity of DNA methylation and chromatin structure and offers a reference for exploring gene regulation in human health and disease.
    DOI:  https://doi.org/10.1126/science.adx0673
  3. Nat Rev Immunol. 2026 Jul 21.
    Drug holidays restore exhausted T cell responses to PD1 blockade.
    Chih-Wei Chu, Kenneth Hu.
      
    DOI:  https://doi.org/10.1038/s41577-026-01343-w
  4. Cell Metab. 2026 Jul 21. pii: S1550-4131(26)00274-3. [Epub ahead of print]
    Competitive catabolism drives hyperglycemia and hyperinsulinemia in obesity.
    Daniel R Weilandt, Won Dong Lee, Michael R MacArthur, Lingfan Liang, Corey D Holman, Qingwei Chu, Alexis J Cowan, Joseph A Baur, Ned S Wingreen, Joshua D Rabinowitz.
      Systemic metabolic homeostasis maintains circulating nutrient concentrations within physiological ranges. Insulin is central to this process, lowering circulating levels of glucose, lactate, free fatty acids, and ketones. Yet how the simultaneous homeostasis of these nutrients is achieved remains unclear. Here, we develop a differential equation model of fasting metabolic homeostasis. Grounded in mass action kinetics, this multi-nutrient model reveals how a fixed energy demand naturally leads to competition between major circulating nutrients for oxidation ("competitive catabolism"). Perturbative nutrient infusions confirm this emergent behavior. The multi-nutrient model predicts that insulin promotes fasting glucose homeostasis primarily indirectly by slowing lipolysis. It further identifies a physiological circuit by which obesity causes insulin resistance: increased fat mass promotes lipolysis, releasing fatty acids into circulation that compete with glucose for oxidation, elevating glucose and thus insulin, which acts to restore proper lipid catabolic flux. Thus, quantitative modeling reveals a physiological homeostatic circuit through which obesity causes type 2 diabetes.
    Keywords:  competitive catabolism; differential equation modeling; hyperinsulinemia; insulin regulation; insulin resistance; mass action kinetics; metabolic homeostasis; nutrient competition; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.001
  5. Science. 2026 Jul 23. 393(6809): 364-365
    Genome in motion: Mapping the nucleus in health.
    Di Jiang, Yevgeniya Nusinovich, Sarah Ross.
      
    DOI:  https://doi.org/10.1126/science.aek3868
  6. Nat Aging. 2026 Jul 24.
    Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice.
    Mariah F Calubag, Ismail Ademi, Cara L Green, Dulmalika N H Manchanayake, Hashan S M Jayarathne, Ryan N Marshall, Sandra M Le, Penelope Lialios, Lucia E Breuer, Shoshana Yakar, Reji Babygirija, Michelle M Sonsalla, Isaac Grunow, Chung-Yang Yeh, Yang Liu, Bailey A Knopf, Sarah Yandell, Charles I Opara, William A Ricke, Teresa T Liu, Mark P Keller, Alan D Attie, Marianna Sadagurski, Dudley W Lamming.
      Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
    DOI:  https://doi.org/10.1038/s43587-026-01169-0
  7. Nat Med. 2026 Jul 23.
    Early detection of Alzheimer's disease with circular RNA from blood.
      
    DOI:  https://doi.org/10.1038/s41591-026-04563-8
  8. Nat Metab. 2026 Jul 24.
    Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism.
    Jo Edward Lewis, Mireia Montaner, Danae Nuzzaci, Paula-Peace James-Okoro, Norio Harada, Nobuya Inagaki, W Scott Dodson, Patrick J Knerr, Jonathan D Douros, Fiona Mary Gribble, Frank Reimann.
      The development of dual agonists for the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) has been a landmark moment in the treatment of type 2 diabetes and obesity. However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss1. Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out Gipr in either the area postrema (AP) or hypothalamus of mice (GiprAP-KO and Giprhypo-KO, respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. GiprAP-KO mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in GiprAP-KO and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Giprhypo-KO mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Giprhypo-KO also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide-an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Giprhypo-KO also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.
    DOI:  https://doi.org/10.1038/s42255-026-01575-z
  9. J Clin Invest. 2026 Jul 23. pii: e207089. [Epub ahead of print]
    Palmitic acid coordinates impaired visceral adipose ICOShi Treg-mediated immunosuppression and systemic metabolic disturbance during obesity.
    Weitong Su, Yuxiao Liu, Xi Yan, Mengyao Huang, Linghao Xu, Jing Lin, Xufeng Chen, Puyuan Hu, Chenlin Gao, Jian Wen, Hongdong Wang, Dong Ding, Zengpeng Zheng, Wenjing Li, Lianjia Li, Zhan Liu, Keyu Qian, Jing Gao, Tingting Zhang, Xiaobing Mao, Haibing Zhang, Wei Lu, Bin Li, Hong Li, Aoyuan Cui, Yan Bi, Chunxiang Zhang, Yu Li.
      Regulatory T (Treg) cells in visceral adipose tissue (VAT) play essential roles in systemic metabolic homeostasis under distinct physiological and pathological conditions. However, the metabolic cues that drive Treg cell subset specialization in the obese VAT niche remain elusive. Here, we demonstrated that palmitic acid instigated chronic VAT inflammation and systemic metabolic disturbance by compromising the immunosuppressive function of the ICOShi Treg subset. Palmitic acid, but not oleic acid, activated Crebzf expression in VAT Treg cells from HFHS diet-induced obese and ob/ob mice. Crebzf deficiency significantly attenuated diet-induced obesity and inflammation by upregulating the suppressive function of VAT ICOShi Treg cells. Moreover, adoptive transfer of Crebzf-deficient ICOShi Treg cells into Rag1-/- mice alleviated HFHS diet-induced inflammation and metabolic disorders more effectively than transfer of Crebzf-sufficient ICOShi Treg cells. Mechanistically, CREBZF interacted with c-JUN to inhibit Foxp3 activity, thereby impairing the stability and inhibitory cytokine production of ICOShi Treg cells. In human subjects, CREBZF levels in VAT Treg cells were elevated and negatively correlated with FOXP3 activity. Collectively, these findings uncover a specific ICOShi Treg subset that responds to palmitic acid, thereby coupling obesogenic signals to VAT remodeling and systemic metabolic homeostasis.
    Keywords:  Inflammation; Metabolism; Obesity; T cells
    DOI:  https://doi.org/10.1172/JCI207089
  10. JCI Insight. 2026 Jul 22. pii: e201535. [Epub ahead of print]11(14):
    A loss-of-function polymorphism in the propeptide of lysyl oxidase exacerbates atherosclerosis.
    In-Hyuk Jung, Junedh M Amrute, Sofia E Luna, Ryan E Wagoner, Arturo Alisio, Paul C Lee, Kendall H Burks, Joohee Oh, Hannah C Plunkett Paletta, Chul Joo Kang, Nathan O Stitziel.
      A single-nucleotide missense polymorphism (rs1800449, R158Q) in the propeptide domain of lysyl oxidase (LOX-PP) is associated with increased risk of coronary artery disease (CAD) independent of changes in plasma lipid levels. Although the enzymatic function of LOX has an essential role for the cross-linking of extracellular matrix proteins in connective tissues, whether and how LOX-PP R158Q contributes to the development of atherosclerosis has not been clearly established. Here, hypercholesterolemia was induced in mice that were WT or homozygous for the LOX-PP R158Q polymorphism by adeno-associated virus-8-mediated overexpression of Pcsk9 followed by high-fat diet feeding for 16 weeks. We found that the R158Q polymorphism promoted atherosclerosis and induced proliferation of macrophages and vascular smooth muscle cells without altering LOX enzymatic activity. Using single-cell RNA sequencing, we found the transcriptional program of atherosclerotic plaques from mice harboring R158Q was strongly enriched for proliferation- and calcification-related genes in a regionally distinct manner. Together, these results establish an enzymatically independent proatherogenic role for the LOX-PP and suggest its potential as a novel therapeutic target.
    Keywords:  Atherosclerosis; Cardiology; Vascular biology
    DOI:  https://doi.org/10.1172/jci.insight.201535
  11. Cell. 2026 Jul 21. pii: S0092-8674(26)00756-7. [Epub ahead of print]
    Localized PD-1 CAR T therapy reprograms neuroinflammation.
    Rotem Shalita, Maya Ben Yehuda, Chamutal Gur, Yasmin Frid, Sarah McGrath, Roni Suhler, Lihi Bolokan, Vasyl Eisenberg, Reut Sharet Eshed, Shir Shlomi-Loubaton, Adin Tofield, Karin Vardy, Mor Zada, Anna Kurilovich, Eyal David, Diego Jaitin, Kfir Mazuz, Roberto Avellino, Reut Tzemach, Yuri Kuznetsov, Liat Fellus-Alyagor, Adva Levy-Barda, Sarah Mundt, Rina Rosenzweig, Bettina Schreiner, Anneli Peters, Christine Stadelmann, Pascale Zwicky, Adi Wilf Yarkoni, Florian Ingelfinger, Ido Amit.
      B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.
    Keywords:  CAR T cells; IL-10; PD-1; autoimmunity; deep probabilistic modeling; enhancer-driven regulatory circuits; follicular Th cells; immunotherapy; multiple sclerosis; single-cell genomics
    DOI:  https://doi.org/10.1016/j.cell.2026.06.036
  12. JAMA. 2026 Jul 24.
    GLP-1 Medications May Improve Health in People With PAD and Diabetes.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.9487
  13. Nat Food. 2026 Jul;7(7): 701-710
    Dietary environmental impacts and quality differ by socio-demographic characteristics.
    Oliver Taherzadeh, Arthur Schoorlemmer, Paul Behrens, Martin Bruckner, Hongyi Cai.
      Sustainable food system transitions will likely require targeted dietary strategies, yet most models typically estimate environmental footprints at the aggregate level and overlook variation between individuals and contexts. Here we develop a globally harmonized model integrating individual food intake and supply chain data to estimate diet-related climate, water and land impacts, and dietary quality using the Alternative Healthy Eating Index (AHEI), across 72 socio-demographic subgroups in 165 countries. We find large disparities across groups. Highly educated urban men aged 15-34 years have the greatest emissions (median, 5.66 kgCO2e d-1), with 62% of their diets plant sourced. Low education, rural women aged 35-54 years have the lowest (2.85 kgCO2e d-1), with plant-sourced foods comprising 70% of their diets. Healthier diets are consistently associated with lower environmental impacts, with each 5% increase in AHEI associated with a 7.7% reduction in greenhouse gas emissions, a 4.4% reduction in water footprint and a 7.2% reduction in land footprint. Countries cluster into distinct patterns of diet quality and sustainability, indicating that targeted rather than uniform strategies are needed to accelerate sustainable dietary transitions.
    DOI:  https://doi.org/10.1038/s43016-026-01389-y
  14. Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2600571123
    Peroxisomal ether lipid synthesis regulates cortical neurogenesis and maintains mitochondrial energy homeostasis in radial glial cells.
    Lin Li, Wenzheng Zou, Yuqing Lv, Yingfei Lu, Jiaqi Liang, Shukui Zhang, Baoyang Hu, Jianwei Jiao.
      Neurogenesis is characterized by dynamic structural changes and functional remodeling of multiple organelles, which interact to form an intricate network that precisely modulates processes including neural progenitor cell self-renewal, neurogenesis, and terminal neuronal development. However, the spatiotemporal dynamics of peroxisomes and their functional contributions within this regulatory network remain incompletely defined during mammalian cortical development. Here, we found that radial glial cells (RGCs) exhibit enriched peroxisome abundance, whereas neural differentiation is associated with reduced peroxisome numbers and increased pexophagy, accompanied by the remodeling of lipid metabolic programs. Acute disruption of peroxisomes by PLAAT3-PEX11 impaired neural differentiation in the embryonic mouse cortex, while PEX7 knockout compromised neurogenic progression in human cortical organoids, supporting a conserved requirement for peroxisomal function during cortical development. Lipidomic and imaging analyses revealed that peroxisome-derived ether lipids were essential for driving neural differentiation and were specifically enriched in mitochondria. Consistently, knockdown of Gnpat, which catalyzes the initial step of ether lipid biosynthesis, reduced neural differentiation, and disrupted mitochondrial structure and function, while batyl alcohol supplementation partially restored these defects. Mechanistically, the ether lipids maintain the structural integrity of mitochondrial cristae and thereby support respiratory chain activity, which in turn promotes oxidative phosphorylation and activates the NAD+ associated signaling. Collectively, this work highlights the precise spatiotemporal regulation of neurogenesis through peroxisomal dynamics and interorganelle crosstalk and identifies ether lipids as a potential therapeutic target for neurodevelopmental disorders.
    Keywords:  ether lipids; mitochondria; neurogenesis; peroxisome
    DOI:  https://doi.org/10.1073/pnas.2600571123
  15. Cell Metab. 2026 Jul 20. pii: S1550-4131(26)00284-6. [Epub ahead of print]
    Elevation of JAML Promotes Diabetic Kidney Disease by Modulating Podocyte Lipid Metabolism.
    Yi Fu, Yu Sun, Mei Wang, Yunfeng Hou, Wei Huang, Di Zhou, Ziying Wang, Shuting Yang, Wei Tang, Junhui Zhen, Yujia Li, Xiaojie Wang, Min Liu, Yan Zhang, Baobao Wang, Guangyi Liu, Xiao Yu, Jinpeng Sun, Chun Zhang, Fan Yi.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.011
  16. Nature. 2026 Jul;655(8124): 1093-1094
    Three tips to avoid AI image mistakes in science.
    Sarah Wild.
      
    Keywords:  Machine learning; Publishing; Scientific community; Technology
    DOI:  https://doi.org/10.1038/d41586-026-02233-w
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒26 at 5:51.