bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–05–24
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A mitochondrial ROS-dependent antiviral response promotes β cell resilience and is diminished in donors with type 1 diabetes.
  2. Western diet-induced MASH in PWK/PhJ mice identifies disruptions in amino acid and sphingolipid metabolism contributing to cardiac dysfunction.
  3. Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons.
  4. From whole-body to organ-specific biological age clocks.
  5. Too little or too much sleep is linked to faster ageing throughout the body.
  6. Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
  7. Interleukin-4-producing type 2 innate lymphoid cells in the lymph node promote proallergic Tfh13 cell differentiation.
  8. Genetic variants affect diurnal glucose levels throughout the day.
  9. Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
  10. Does Weight Loss Prevent Atrial Fibrillation?
  11. In situ cryo-ET defines the ultrastructure of ER exit sites in human cells.
  12. Genome instability triggers intercellular DNA transfer between human cells.
  13. TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease.
  14. An AI framework for multi-disease detection via retinal imaging.
  15. Glucosamine links hyperglycemia to mTORC1 activation and glucose toxicity in diabetes.
  16. Genetic analysis of circulating metabolic traits in 619,372 individuals.
  17. C2orf74 orchestrates germ-Leydig crosstalk to inhibit white adipose tissue browning in male mice.
  18. Chaperone-mediated autophagy is required for regulatory T cell function.
  19. Maternal age and pregnancy-related cardiovascular complications.
  1. Sci Transl Med. 2026 May 20. 18(850): eadx7770
    A mitochondrial ROS-dependent antiviral response promotes β cell resilience and is diminished in donors with type 1 diabetes.
    Leslie E Wagner, Olha Melnyk, Alissa N Muncy, Abigail Turner, Bryce E Duffett, Charanya Muralidharan, Michelle M Martinez-Irizarry, Matthew C Arvin, Kara S Orr, Wenting Wu, Elisabetta Manduchi, Estefania Quesada-Masachs, Jon D Piganelli, Klaus H Kaestner, Joseph T Brozinick, Amelia K Linnemann.
      Type 1 diabetes (T1D) is a multifactorial disease driven by genetic and environmental factors, including, potentially, viral infection. However, the mechanisms linking infection-associated cytokines to human β cell loss are poorly understood. Here, we coupled in vivo and in vitro imaging with genetic analysis to investigate the impact of interferon α (IFN-α), a cytokine produced during the immune response to viral infection or detection of unedited endogenous double-stranded RNAs, on human β cell physiology. We identified a subset of human β cells that acutely produce reactive oxygen species (ROS) in response to IFN-α and were more prevalent in islets from donors with lower body mass index and HbA1c. RNA sequencing of flow-sorted ROS+ and ROS- populations identified a gene signature predisposing some cells to IFN-α-stimulated ROS production, including genes involved in inflammatory and immune response. IFN-α treatment of human islets in vitro similarly elicited a heterogeneous increase in superoxide production. Parallel analysis of a human β cell line demonstrated that this ROS originated in the mitochondria. Rapid stimulation of key antiviral response genes by IFN-α in human islets was dependent on mitochondrial ROS elevation. Comparison with single-cell RNA sequencing datasets showed that genes up-regulated in ROS-producing cells were enriched in β cells from nondiabetic and autoantibody-positive donors rather than donors with T1D. Overall, our data demonstrate that IFN-α-induced mitochondrial ROS production in healthy human β cells is critical for the acute antiviral response, and impairment of this heterogeneous adaptive response may predict β cell loss during T1D pathogenesis.
    DOI:  https://doi.org/10.1126/scitranslmed.adx7770
  2. Nat Commun. 2026 May 20.
    Western diet-induced MASH in PWK/PhJ mice identifies disruptions in amino acid and sphingolipid metabolism contributing to cardiac dysfunction.
    Sandra Rodríguez-López, Miguel Pérez-Rodríguez, Alaa Badreddine, Rafael Calais Gaspar, Henrique J Novaes Morgan, Ikki Sakuma, Giacomo V G von Alvensleben, Alejandro Alonso-Calleja, Stacia P A Everts, Nicolas-Enzo Suter, Giorgia Benegiamo, Christine Goepfert, Simone de Brot, José Manuel Villalba, Gerald I Shulman, Kristina Schoonjans, Johan Auwerx.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are liver disorders strongly associated with cardiovascular disease (CVD). The PWK/PhJ mouse strain is an emerging model for severe MASH, highly susceptible to Western diet (WD) and closely mimicking the clinical and molecular profile of human MASH. Here, we demonstrate that male and female PWK/PhJ mice develop hepatic fibrosis and cardiac dysfunction after 17 weeks of WD challenge. Elevated cholesterol levels and altered transcript profiles associated with translation and lipid metabolism characterize the early metabolic changes induced by WD. Chronic exposure to WD exacerbates hepatic lipid accumulation, inflammation, and fibrosis, while disrupting amino acid and mitochondrial metabolism. These alterations increase hepatic synthesis of ceramides and deoxy-ceramides, contributing to elevated sphingolipid levels in plasma and heart tissue. Collectively, these metabolic changes drive the development of MASH and significantly increase CVD risk. Our findings establish the PWK/PhJ strain as a robust model to study cardio-metabolic cross talk and identifying therapeutic targets for cardio-metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-73449-7
  3. Nat Metab. 2026 May 22.
    Semaglutide drives weight loss through cAMP-dependent mechanisms in GLP1R-expressing hindbrain neurons.
    Claire Gao, Isabelle C Geneve, Shakira Rodriguez-Gonzalez, Chia Li, Kaitlyn McElhern, Marc L Reitman, Andrew Lutas, Michael J Krashes.
      Glucagon-like peptide 1 receptor (GLP1R) agonists, such as semaglutide, drive weight loss by binding to GLP1Rs-classically described as Gs-coupled G-protein-coupled receptors-in the brain; however, the intracellular signalling mechanisms underlying these effects remain poorly defined. Here, we find that semaglutide engages both Gs- and Gq-dependent signalling pathways in Glp1r-expressing neurons in the area postrema (APGlp1r), the primary site of semaglutide action in the brain, and differentially regulates neuronal activation across distinct neuronal clusters. Semaglutide also drives graded increases of the essential secondary messenger cyclic adenosine monophosphate (cAMP) in APGlp1r neurons through the Gs pathway. Inhibition of the cAMP-degrading enzyme phosphodiesterase 4 (PDE4) enhances and sustains these cAMP responses, and disruption of Gs or cAMP signalling in APGlp1r neurons abolishes semaglutide-induced weight loss and downstream brain-wide activation. Our systematic characterization of semaglutide's signalling mechanisms in the hindbrain reveals the intracellular signalling architecture through which semaglutide engages cAMP and calcium to regulate body weight, providing avenues for improving obesity therapeutics.
    DOI:  https://doi.org/10.1038/s42255-026-01534-8
  4. Nat Aging. 2026 May;6(5): 961-969
    From whole-body to organ-specific biological age clocks.
    Andrew Zalesky, Junhao Wen, Ye Ella Tian.
      Recent work leveraging omics and imaging data now enables the estimation of aging at the level of individual organs. Emerging findings suggest that organs age at different rates, which may be linked to environmental exposures and genetic factors. However, premature aging in one organ may also drive aging in connected organs within multi-organ aging networks. Here, we outline methods for measuring organ-specific biological age and discuss insights derived from recent progress in multi-organ aging research. We put forward recommendations, best practices and research priorities, including the importance of longitudinal tracking, biomarkers with high organ specificity and reference ranges for organ age gaps. We envision routine organ-specific biological age assessments as tools for developing personalized organ aging maps and tracking organ aging across the life course, thereby facilitating early, targeted interventions to delay organ-specific decline and interorgan consequences.
    DOI:  https://doi.org/10.1038/s43587-026-01113-2
  5. Nature. 2026 May 20.
    Too little or too much sleep is linked to faster ageing throughout the body.
      
    Keywords:  Ageing; Diseases
    DOI:  https://doi.org/10.1038/d41586-026-01564-y
  6. Sci Immunol. 2026 May 29. 11(119): eaef0098
    Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
    Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.
      Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.
    DOI:  https://doi.org/10.1126/sciimmunol.aef0098
  7. Immunity. 2026 May 19. pii: S1074-7613(26)00177-9. [Epub ahead of print]
    Interleukin-4-producing type 2 innate lymphoid cells in the lymph node promote proallergic Tfh13 cell differentiation.
    DongUk Lee, Meng-Ping Lu, Priya Rajamanimuthu, Mrinmoy Das, Enxhi Ferraj, Courtney Fisher, Peri Matatia, Chun-Wei Chen, Raif S Geha, Caroline L Sokol, Uthaman Gowthaman.
      Proallergic T follicular helper 13 (Tfh13) cells are obligatory for generating high-affinity, anaphylactic immunoglobulin E (IgE) responses to allergens. Unlike Tfh2 cells, which are induced by vaccination and most type 2 immune responses, Tfh13 cells are primarily elicited during allergic disease states. However, the cellular and molecular determinants governing Tfh13 cell differentiation remain unclear. Using orthogonal genetic and bone marrow chimera approaches, we identified a critical role for group 2 innate lymphoid cells (ILC2s) within draining lymph nodes (dLNs) in promoting Tfh13 cell differentiation. During allergen sensitization, ILC2s trafficked into dLNs in a chemokine receptor CCR8-dependent manner and produced interleukin (IL)-4, a factor necessary for Tfh13-but not for Tfh2-cell induction. These findings uncover a mechanism by which ILC2s selectively drive pathogenic Tfh13 responses, underscoring the distinct regulatory requirements for Tfh2 and Tfh13 cell differentiation in allergic immunity.
    Keywords:  CCR8; IL-4; ILC2s; IgE; Tfh cells; Tfh13 cells; allergy; anaphylaxis; group 2 innate lymphoid cells
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.015
  8. Nat Commun. 2026 May 22.
    Genetic variants affect diurnal glucose levels throughout the day.
    FinnGen
      Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. The genetic variants that contribute to the temporal control of glucose levels have not been previously examined. Using genome-wide data from ~420,000 individuals from the UK Biobank and replication in ~100,000 individuals from the Estonian Biobank, ~500,000 from FinnGen, ~160,000 from the VA Million Veteran Program, and ~52,000 from the MGB Biobank, we show that glucose levels are under diurnal genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B, rs10830963, P = 1×10-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1×10-16). Furthermore, we show that sleep modulates glucose levels, and the genetic variants have an independent role in diurnal glucose control. Finally, we show that these variants independently modulate risk of type 2 diabetes and that sleep medications including melatonin associate with type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight genetic variation at MTNR1B and CRY2 in the control of diurnal glucose levels.
    DOI:  https://doi.org/10.1038/s41467-026-72432-6
  9. Nat Metab. 2026 May 18.
    Cardiolipin preserves Treg metabolic fitness and immune homeostasis in the gut.
    Annamaria Regina, Francesca Solagna, Malkon Sanchez Estrada, Maaike M E Jacobs, Daniel Martinez-Martinez, Theodoros Georgomanolis, Irma Alibashikj, Sara Gjurgji, Claire Pearson, Dehui Chang, Chrysanthi Moschandrea, Ana Sagrera Aparisi, Elena Crespo, Jessica Buechel, Farina Schneider, Lea Trojahn, Paulina Pfelzer, Milica Popovic, Elena Potenza, Agnieszka M Kabat, Carien Niessen, Borko Amulic, Niloufar Safinia, Sara Cogliati, David E Sanin, Matteo Villa, Edward J Pearce, Christian Frezza, Erika L Pearce, Filipe Cabreiro, Fiona Powrie, Mauro Corrado.
      Loss of host-microbiota balance promotes gut inflammation, colitis and inflammatory bowel disease. Yet, whether host or microbial factors are the critical driver of the pathology remains unclear. Here, we investigate how cardiolipin maintains metabolic fitness of regulatory T (Treg) cells to preserve gut-immune homeostasis. We discover that deleting the cardiolipin-synthesizing enzyme protein tyrosine phosphatase mitochondrial 1 (PTPMT1) in T cells predisposes mice to colitis due to impaired Treg cell function in the absence of dysbiosis. Subsequent pathobiont infections accelerate the progression and severity of gut inflammation. Mechanistically, the absence of cardiolipin impairs Treg cell metabolic fitness and triggers a maladaptive integrated stress response, which can be reversed pharmacologically or genetically, restoring gut homeostasis and extending lifespan in PTPMT1 ΔT mice. Barth syndrome, a genetic disorder marked by severe cardiolipin deficiency, also exhibits gastrointestinal symptoms and inflammation associated with helper T cell imbalance and an active integrated stress response signature. Overall, these results suggest that a cardiolipin-mediated mitonuclear axis in T cells preserves gut-immune homeostasis and dictates outcome in pathobiont infections.
    DOI:  https://doi.org/10.1038/s42255-026-01533-9
  10. JAMA. 2026 May 20.
    Does Weight Loss Prevent Atrial Fibrillation?
    Gregory M Marcus.
      
    DOI:  https://doi.org/10.1001/jama.2026.6094
  11. Nat Cell Biol. 2026 May 20.
    In situ cryo-ET defines the ultrastructure of ER exit sites in human cells.
    Katie W Downes, Julia R Flood, Andrea Nans, Sander E Van der Verren, Anjon Audhya, Giulia Zanetti.
      Trafficking of secretory proteins from the endoplasmic reticulum (ER) to the Golgi apparatus comprises the first, essential steps towards the appropriate localization of 30% of eukaryotic proteins. Coat protein complexes COPII and COPI are involved in the forward and retrograde transport of cargo and cargo receptors between the ER and the Golgi, respectively. Although COPII forms coated vesicles in vitro, the biogenesis, morphology and organization of transport carriers in mammalian cells is subject to debate. Here we use in situ cryo-electron tomography and super-resolution fluorescence microscopy to reveal the molecular architecture of ER exit sites in human cells that were not perturbed with drugs, temperature blocks or overexpression systems. We visualize ribosome-exclusion zones enriched with COPII- and COPI-coated vesicles and thus resolve the debate regarding the existence of COPII-coated vesicles. COPII vesicles derive from ER membranes, whereas COPI vesicles originate from vesicular-tubular clusters that constitute the ER-Golgi intermediate compartment (ERGIC). We quantify coated vesicle morphology and positioning with respect to other ER exit site components, providing a molecular description of the organization of the mammalian early secretory pathway.
    DOI:  https://doi.org/10.1038/s41556-026-01964-2
  12. Cell. 2026 May 19. pii: S0092-8674(26)00508-8. [Epub ahead of print]
    Genome instability triggers intercellular DNA transfer between human cells.
    Elizabeth G Maurais, Alice Mazzagatti, Yu-Fen Lin, Maria Narozna, Qing Hu, Rashmi Dahiya, Derek Santiago-Ferrer, Conor P Herlihy, Mary Krebs, Nikoleta Pateraki, Evlampia Parcharidou, Stamatis Papathanasiou, Brian J Beliveau, Gary J Gorbsky, Isidro Cortés-Ciriano, Peter Ly.
      The mammalian genome is safeguarded within the confines of the interphase nucleus. However, genomic instability can trigger the mislocalization of nuclear DNA to the cytoplasm within micronuclei or as fragmented chromosomes. Beyond activating cell-autonomous signaling programs, whether such cytoplasmic DNA can elicit non-cell-autonomous consequences to nearby cells remains unclear. Here, we show that cytoplasmic DNAs undergo intercellular transfer through contact-dependent, cytoskeleton-based nanotube structures connecting adjacent human cells. Diverse sources of genomic instability-including exposure to mitotic spindle poisons, ionizing radiation, and Cas9-induced chromosome breakage-promote nanotube-mediated DNA transfer in both cancerous and non-cancerous cells. Transferred DNA fragments are stably inherited as functional extrachromosomal genetic elements in the recipient host genome, thereby conferring heritable phenotypic traits to the recipient cell. Our findings uncover a horizontal gene transfer-like mechanism through which direct cell-cell contact can propagate genomic instability and reshape mammalian genomes.
    Keywords:  DNA damage; chromothripsis; cytoplasmic DNA; ecDNA; genomic instability; horizontal gene transfer; intercellular transfer; micronuclei; mitosis; tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.cell.2026.04.041
  13. Nat Commun. 2026 May 22.
    TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease.
    Jessica Carriere, Chawon Yun, Sonal Khare, Sana Ismaeel, Elisabeth Jäger, Vinicius Dantas Martins, Kaiden A Sims, Lan H Chu, Huyen Nguyen, Lucia de Almeida, Janset Onyuru, Justin Ruiz, Hemisha Khatri, Savita Devi, Jae Jin Chae, Daniel L Kastner, Lori Broderick, Hal M Hoffman, Andrea Dorfleutner, Christian Stehlik.
      Inflammasomes are cytosolic multiprotein complexes facilitating the maturation and release of the inflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. ASC (apoptosis-associated-speck-like protein containing a CARD) is the central inflammasome adaptor. ASC polymerization is crucial for inflammasome assembly, and ASC particle release propagates inflammasome responses to bystander cells. However, control of inflammasome and ASC particle assembly to limit chronic inflammation and the emergence of autoinflammatory diseases is still incompletely understood. Here, we show that the E3 ubiquitin ligase TRIM (tripartite-motif-containing protein) 21, a common autoantigen in autoimmune diseases, is involved in inflammasome assembly. Specifically, TRIM21 binds to and ubiquitinates ASC to facilitate ASC/NLRP3 interactions, ASC polymerization and the release of ASC/TRIM21-containing particles during pyroptosis in human and mouse macrophages. Furthermore, we detect systemic ASC/TRIM21 particles and autoantibodies in human and mouse autoinflammatory disease. Thus, our findings highlight a previously unrecognized role of TRIM21 as an inflammasome component and driver of autoinflammation.
    DOI:  https://doi.org/10.1038/s41467-026-73350-3
  14. Nat Med. 2026 May 20.
    An AI framework for multi-disease detection via retinal imaging.
      
    DOI:  https://doi.org/10.1038/s41591-026-04424-4
  15. JCI Insight. 2026 May 22. pii: e197331. [Epub ahead of print]11(10):
    Glucosamine links hyperglycemia to mTORC1 activation and glucose toxicity in diabetes.
    Yael Riahi, Aviram Kogot-Levin, Ziv Teselpapa, Elisheva Zemelman, Fatema Gamal, Tamar Cohen, Abed Nasereddin, Idit Shiff, Ifat Abramovich, Bella Agranovich, Dana Avrahami, Liad Hinden, Erol Cerasi, Daljeet Kaur, Lihi Grinberg, Ron Piran, Joseph Tam, Ernesto Bernal-Mizrachi, Erez Dror, Gil Leibowitz.
      Hyperglycemia is a principal driver of β cell failure and multiple-organ complications in diabetes. Chronic exposure to hyperglycemia overstimulates mTORC1, disrupting glucose metabolism and promoting ER stress, oxidative stress, and inflammation; however, the upstream metabolic signal(s) linking glucose to mTORC1 activation remains unclear. Here, we identified glucosamine as a key metabolite connecting elevated glucose to mTORC1 signaling in pancreatic islets and kidney, both major targets of hyperglycemic damage. Using 13C6-glucose metabolic labeling in diabetic rodents treated with or without the SGLT2 inhibitor dapagliflozin or insulin, combined with targeted metabolomics and metabolic flux analysis, we found that tissue glucose concentrations strongly correlated with glucosamine. A similar correlation with plasma glucose was conserved in humans with or without type 2 diabetes, and inversely associated with β cell function. In vitro, low-dose glucosamine stimulated mTORC1 in islets and kidney proximal tubule cells in an O-GlcNAcylation-dependent manner. Broad phosphoproteomics and transcriptomics analyses in β cells showed that glucosamine activated mTORC1-regulating pathways, induced oxidative stress, ER stress, and dedifferentiation. Genetic inhibition of β cell mTORC1 via heterozygous Raptor knockout, as well as pharmacologic inhibition of the glucosamine/mTORC1 axis through SGLT2 inhibition, alleviated β cell stress, improved glycemic control, and restored β cell function. These findings identified the glucosamine/mTORC1 pathway as an important mediator of β cell and kidney dysfunction in diabetes.
    Keywords:  Beta cells; Cell biology; Diabetes; Endocrinology; Metabolism; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.197331
  16. Nature. 2026 May 20.
    Genetic analysis of circulating metabolic traits in 619,372 individuals.
    Estonian Biobank Research Team
      Interpreting the association of genetic variants with complex traits can be improved by gaining a greater understanding of the molecular consequences of these variants. Although genome-wide association studies (GWAS) for complex diseases routinely profile over one million individuals1-5, studies of molecular traits have lagged behind. Here we performed a GWAS meta-analysis for 249 circulating metabolic traits in the Estonian Biobank and the UK Biobank in up to 619,372 individuals. We identified 88,127 common and low-frequency locus-trait associations from 8,398 loci that converged on shared genes and pathways. Using statistical fine mapping, systematic phenome-wide colocalization and cis-Mendelian randomization, we explored putative causal links between metabolic traits and disease outcomes. We predict that although plasma branched-chain amino acids (BCAAs) have been associated with type 2 diabetes in observational studies6,7, lowering BCAA levels by targeting the BCAA catabolism pathway is unlikely to reduce type 2 diabetes risk. Leveraging our large sample size and high-quality genotype imputation, we found that 19.4% of the confidently fine-mapped variants had minor allele frequencies between 0.1 and 1%, and these variants were twofold enriched for predicted missense and splice-altering variants. Our results highlight the value of integrating low-frequency variants into genetic association studies.
    DOI:  https://doi.org/10.1038/s41586-026-10532-5
  17. Nat Commun. 2026 May 21.
    C2orf74 orchestrates germ-Leydig crosstalk to inhibit white adipose tissue browning in male mice.
    Li Zhao, Jialuo Han, Xinxin Wang, Qin Li, Qinghua Shi, Fangbiao Tao, Pilong Li, Chengxin Zhang, Qiang Liu, Juan Zhang.
      Sex differences in obesity are well recognized; however, the identification of sex-specific obesity genes and the mechanisms through which they affect obesity development remain elusive. Here, we identify a germ-cell-specific gene C2orf74, whose expression is responsive to high-fat diet (HFD) and promotes HFD-induced obesity in male mice by restraining lipolysis and limiting the browning of white adipocytes through suppression of androgen receptor signaling, but not in females. Additionally, C2orf74's expression increases with aging, contributing to aging-related obesity and metabolic comorbidities in chow-fed male mice. We demonstrate that C2orf74 is an ER-residing transmembrane protein that anchors and stabilizes dolichol phosphate mannose synthase 1 (Dpm1) on the ER membrane, facilitating Dpm1-mediated glycosylation and secretion of Bpifa3 from germ cells. As a paracrine regulator, Bpifa3 transcriptionally suppresses the expression of testosterone biosynthesis enzymes in Leydig cells. Therapeutically, we demonstrate that antisense oligonucleotide (ASO) targeting C2orf74 protects male mice from HFD-induced obesity. Thus, our study defines a role for germ-Leydig cell crosstalk, mediated by C2orf74, in the white adipocytes browning in both age-associated and diet-induced obesity.
    DOI:  https://doi.org/10.1038/s41467-026-73368-7
  18. Nat Commun. 2026 May 22.
    Chaperone-mediated autophagy is required for regulatory T cell function.
    Ranee Harrison, Floralba Gjergjova, Sandra Pelka, Adrian Macho-Gonzalez, Bhakti Chavda, Kristen Lindenau, Aiara Gazteluiturri Garcia, Rabia R Khawaja, Jennifer T Aguilan, Simone Sidoli, Susmita Kaushik, Yair Botbol, Ana Maria Cuervo, Fernando Macian.
      Chaperone-mediated autophagy (CMA) is a selective form of protein degradation in lysosomes that declines with age. Besides protein quality control, CMA also regulates several cellular processes through timely proteome remodeling. We previously demonstrated the importance of CMA in the activation of helper T cells. In this work, we analyzed the role of CMA in the generation and function of regulatory T cells (Tregs), a specialized type of T cells that suppress immune responses. We found that the basal CMA activity of Tregs further increases upon their activation. Using a Treg-specific CMA-deficient mouse model, we show that CMA is crucial for maintenance of peripheral tolerance by Tregs. Mice with CMA-defective Tregs display signs of chronic inflammation, which results in reduced survival as they age. We demonstrate that CMA-deficient Tregs have reduced suppressive activity in vivo using an experimental model of inflammatory bowel disease and a second model of tumor-induced immune response. Comparative quantitative proteomic analysis enabled us to identify the subproteome degraded by CMA and, consequently, the cellular pathways modulated by this type of autophagy to sustain Treg homeostasis and function. Collectively, our findings uncover a previously unknown role for CMA in regulating Treg function.
    DOI:  https://doi.org/10.1038/s41467-026-73417-1
  19. Nat Commun. 2026 05 18. pii: 4066. [Epub ahead of print]17(1):
    Maternal age and pregnancy-related cardiovascular complications.
    Hooman Kamel, Laura E Riley, Moeun Son, Maria G Karas, Mary J Roman, Maria T De Sancho, Matthew E Fink, Ava L Liberman, Babak B Navi.
      Pregnancy-related cardiovascular complications cause substantial morbidity and account for a large proportion of maternal deaths. The relationship between maternal age and pregnancy-related cardiovascular complications remains unclear. Most prior studies categorized patients using an age threshold, and previous studies did not delineate patients' baseline cardiovascular risk versus pregnancy-specific risk. Here we show that pregnancy and the postpartum period are associated with a 7-fold higher risk of major adverse cardiovascular events compared to patients' baseline risk. This relative risk increase does not vary with maternal age. Absolute risk increases are stable at approximately 3 excess events per 1000 pregnancies until 31 years of age, then steadily increase, reaching 10 excess events per 1000 pregnancies by 44 years of age. These findings suggest that aging does not drive pregnancy-specific mechanisms of cardiovascular events. Rather, our findings suggest that pregnancy uniformly amplifies existing cardiovascular risk, resulting in increasing complications as patients accrue more baseline risk with age.
    DOI:  https://doi.org/10.1038/s41467-026-72580-9
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