bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–10–18
eight papers selected by
Xiong Weng, University of Edinburgh
  1. Artificial intelligence-enabled clinical phenotyping of human brown fat.
  2. Himito: a graph-based toolkit for mitochondrial genome analysis using long reads.
  3. Multi-omics atlas of chronic exercise.
  4. ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
  5. Chromatin modifiers KMT2D, cBAF, and p300 cooperatively facilitate de novo binding of transcription factors on enhancers.
  6. Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease.
  7. Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome.
  8. A phenome-wide structural variant map from 467,152 UK Biobank genomes.
  1. Nature. 2026 Oct 14.
    Artificial intelligence-enabled clinical phenotyping of human brown fat.
    Nicolás Gómez-Banoy, Jorge A Barrero, Luiza Rachel Pinheiro de Carvalho, Caroline S Jiang, Tara Doma Lama, Nakul Karandikar, Mascha Koenen, Tiffany Lam, Kaja Plucińska, Ksenia Morozova, Stephanie Chahwan, Gustavo Barraza, Burcin Agridag Ucpinar, Jennifer E Liu, Rohit Sharma, Daniel Lafontaine, Heiko Schöder, Paul Cohen.
      Adipose tissue has a central role in systemic energy balance and the pathogenesis of obesity and its sequelae1,2. In contrast to white adipose tissue, brown adipose tissue (BAT) uses energy to produce heat3. Detectable BAT in humans is associated with decreased prevalence of cardiometabolic diseases4. However, the complete spectrum of health conditions associated with BAT remains unknown, and high-throughput methods to quantify BAT activity in humans are lacking5,6. Here we leveraged big data and artificial intelligence to systematically define the clinical impact of BAT in a cohort of 101,243 patients from a large cancer centre. Our unbiased analyses revealed that, across all diagnoses, cardiovascular and psychiatric diseases were less prevalent in people with BAT. Using a machine learning approach, we semi-automatically quantified BAT activity in approximately 8,700 patients and demonstrated that higher BAT activity, especially in the axillary depot, is associated with lower odds of cardiometabolic diseases and healthier white fat distribution. People with BAT also exhibited more favourable glycaemic parameters, lipid profiles, inflammatory markers and echocardiographic indices. Analysis of medication usage demonstrated that angiotensin receptor blocker use was positively associated with BAT presence. As proof of concept, we showed that the angiotensin receptor blocker losartan increased brown adipocyte activity and whole-body energy expenditure. Altogether, our studies harnessing artificial intelligence and big data identify new clinical phenotypes linked to BAT and serve as a platform for drug repurposing to activate this tissue in humans.
    DOI:  https://doi.org/10.1038/s41586-026-11162-7
  2. Nat Commun. 2026 Sep 10. pii: 10668. [Epub ahead of print]17(1):
    Himito: a graph-based toolkit for mitochondrial genome analysis using long reads.
    All of Us Research Program Long Read Working Group
      Understanding the genetic and epigenetic regulation of mitochondrial DNA (mtDNA) is essential for elucidating mechanisms of aging and disease. Long-read sequencing can span the mitochondrial genome and capture base-modification signals, yet analytical tools remain limited. We developed Himito, a graph-based toolkit for analyzing mitochondrial genome using long reads. Himito filters reads originating from nuclear mitochondrial insertions (NUMTs), constructs a sequence graph to represent mtDNA diversity, assembles primary haplotypes, calls variants, and analyzes 5-methylcytosine (5mC) modifications within a unified framework. Benchmarking on reference datasets shows Himito achieves superior performance in assembly and variant calling compared with existing tools. Applied to the All of Us (AoU) v8 dataset, Himito identified pathogenic mtDNA variants, revealed population-scale haplogroup diversity, and uncovered age-related genetic and epigenetic patterns. These results demonstrate that long-read sequencing, combined with graph-based analysis, enables integrated characterization of mitochondrial genomic and epigenomic variation. Himito is available at https://github.com/broadinstitute/Himito .
    DOI:  https://doi.org/10.1038/s41467-026-77418-y
  3. Cell. 2026 Oct 15. pii: S0092-8674(26)01185-2. [Epub ahead of print]
    Multi-omics atlas of chronic exercise.
    Geraldine Maier, Manoj Hariharan, Ramesh K Ramasamy, Aidan Glina, Laura van Rosmalen, Suraj J Pathak, Shaunak Deota, Sahil Patel, Terry Lin, Michael Tun Yin Lam, Hiep D Le, Krushali Powale, Takashi Shimomura, Yuta Otobe, Vince Rothenberg, Ming Sun, Takeshi Sakurai, Tiffany Chin, Yue Wu, Rosa Castanon, Anna Bartlett, Huaming Chen, Joseph R Nery, Cesar Barragan, Swetha Devulapalli, Hemal H Patel, Alan Saghatelian, Hikari Yoshitane, Debashis Sahoo, Susan M Keach, Joseph R Ecker, Satchidananda Panda.
      Exercise reduces all-cause mortality, yet its molecular effects across organs, sexes, and circadian phases remain incompletely understood. We subjected mice to 8 weeks of voluntary wheel running and collected 22 tissues and plasma during active and inactive phases for bulk RNA sequencing, metabolomics, proteomics, and single-nucleus RNA and methylation sequencing. Exercise induced canonical fiber-type switching and widespread, tissue-specific remodeling, with the largest transcriptomic changes in skeletal muscle. Except for the hypothalamus, kidney, and lung, most tissues changed more during the active phase. Females showed broader transcriptional responses, with distinct downregulation. Pairing single-nucleus methylomes with transcriptomes resolved the cell types driving exercise-induced epigenetic remodeling-changes undetectable by bulk studies. These included coordinated gene-body demethylation and transcription that tracked with fiber-type switching in specific myonuclei. Cell-type-resolved methylation, including partially methylated domains characterized in muscle, revealed a strong, sex-biased epigenetic response to training. Machine learning identified conserved exercise signatures across mammalian species.
    Keywords:  metabolomics; multi-omics; muscle; proteomics; sex difference; single-nucleus DNA methylation; single-nucleus RNA seqencing; tendon; transcriptomics; voluntary exercise
    DOI:  https://doi.org/10.1016/j.cell.2026.09.044
  4. Nat Commun. 2026 09 10. pii: 10690. [Epub ahead of print]17(1):
    ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.
    Shiqi Xu, Yi Peng, Hengda Zhou, Xuecong Ren, Xin Wang, Zhenguang Ying, Meijiao Li, Yujie Sun, Bing Yang, Mao Zhang, Chonglin Yang, Weirui Ma, Suhong Xu.
      Mitochondrial Ca2+ uptake couples cellular Ca2+ signals to mitochondrial metabolism and stress responses and is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we identify an ATAD-3-dependent mechanism that promotes mitochondrial Ca2+ uptake following plasma membrane injury in C. elegans. Living imaging reveals robust, albeit delayed, mitochondrial Ca2+ influx following injury in mcu-1 mutants, indicating the existence of a compensatory Ca2+ uptake mechanism. RNAi screen identifies the conserved AAA+ ATPase ATAD-3 as an essential regulator of this pathway, whereas MICU-3 acts as a negative regulator. Wounding induces ATAD-3 oligomerization and mitochondrial enrichment, which are enhanced in mcu-1 mutants. Disrupting ATAD-3 oligomerization or expression of disease-associated ATAD-3 variants abolishes wounding-induced mitochondrial Ca2+ uptake. Structure modeling predicts that oligomeric ATAD-3 adopts a channel-like architecture. These findings uncover ATAD-3 as a context-dependent regulator of mitochondrial Ca2+ homeostasis during cellular stress and provide insight into how this process may be disrupted in disease.
    DOI:  https://doi.org/10.1038/s41467-026-77690-y
  5. Nat Commun. 2026 Sep 15. pii: 10816. [Epub ahead of print]17(1):
    Chromatin modifiers KMT2D, cBAF, and p300 cooperatively facilitate de novo binding of transcription factors on enhancers.
    Hieu T Van, Young-Kwon Park, Danyang Wan, Chengyu Liu, Shamima Islam, Stefania Dell'Orso, Weiqun Peng, Vittorio Sartorelli, Ji-Eun Lee, Kai Ge.
      Transcription factors (TFs) bind to enhancers and recruit H3K4me1 methyltransferase KMT2D, chromatin remodeler cBAF, and H3K27 acetyltransferase p300 to activate transcription. However, the role of chromatin modifiers in regulating de novo binding of TFs on enhancers remains unclear. Using a robust nuclear translocation system, we show that the muscle lineage-determining TF MyoD binds to chromatin pervasively within one hour, with half of induced MyoD binding sites co-occupied by KMT2D, cBAF, and p300. On the majority of these MyoD+ enhancers, acute depletion of KMT2D or short-term inhibition of cBAF or p300 enzymatic activity markedly reduces de novo binding of MyoD as well as that of KMT2D, cBAF, and p300. On enhancers with intact MyoD binding despite these perturbations, we observe cooperative recruitment among chromatin modifiers. Similar interdependent relationships are observed between the signal-dependent TF Glucocorticoid Receptor and KMT2D, cBAF, and p300. Together, our findings show that chromatin modifiers are not only downstream effectors but also required for de novo binding of TFs on enhancers, refining a model of enhancer establishment as a process governed by functional cooperation rather than a strict hierarchy.
    DOI:  https://doi.org/10.1038/s41467-026-77757-w
  6. Nat Metab. 2026 Oct 12.
    Systemic proteomic dynamics of acute exercise reveal genetic links to health and disease.
    Nigel Kurgan, Jeppe Kjærgaard, Naja Zenius Jespersen, Virginia Díez-Obrero, Victor Svenstrup, Roger Moreno-Justicia, Sarah Elizabeth Heywood, Cecilie Bergmann Lindqvist, Lisa Ottander, Diana Samodova-Sommer, Alina Malita, Olga Kubrak, Nadja Ahrentløv, Nina Sloth Nielsen, Cody Garett Durrer, Michael Texada, Mathias Ried-Larsen, Simon Rasmussen, Kim Rewitz, Ruth J F Loos, Roelof Adriaan Johan Smit, Bente Klarlund Pedersen, Atul Shahaji Deshmukh.
      Physical activity improves metabolic health, but the molecular responses that mediate its benefits are not fully characterized. Here we present a high-resolution, time-resolved proteomics atlas across plasma, saliva and urine from 25 healthy men in response to acute exercise. We find that exercise regulates more than 3,000 proteins through distinct, fluid-specific temporal dynamics. Network analysis uncovers coordinated remodelling of protein secretion, extracellular matrix and immune activation across body fluids. Replication in an independent cohort shows that many exercise-responsive plasma proteins exhibit consistent responses across age, sex and exercise modalities. Integration with human genome-wide association study data links secreted, exercise-responsive proteins to cardiometabolic diseases. Functional validation of genetically prioritized muscle-specific secreted proteins in Drosophila confirms their role in endurance, behaviour and metabolism. Overall, this open-access atlas ( https://cbmr.ku.dk/research/research-groups/deshmukh-group/shiny-apps/ ) provides a multifluid resource that complements existing exercise-omics efforts for defining molecular adaptations to exercise and for prioritizing candidate exerkines.
    DOI:  https://doi.org/10.1038/s42255-026-01621-w
  7. Cell. 2026 Oct 15. pii: S0092-8674(26)01137-2. [Epub ahead of print]189(21): 6613-6629.e9
    Somatic epimutations cap genetic determinism in the human diploid chromatin epigenome.
    Mitchell R Vollger, Elliott G Swanson, Shane J Neph, Benjamin J Mallory, Danilo Dubocanin, Ching-Huang Ho, Yong-Han Hank Cheng, Jane Ranchalis, Katherine M Munson, Adriana E Sedeno-Cortes, Devaraja G Mudeppa, William E Fondrie, Stephanie C Bohaczuk, Maxwell A Dippel, Yizi Mao, Nancy L Parmalee, William T Harvey, Youngjun Kwon, Gage H Garcia, Kendra Hoekzema, Jeffrey G Meyer, Mine Cicek, Evan E Eichler, William S Noble, Daniela M Witten, James T Bennett, John P Ray, Andrew B Stergachis.
      Diploid human cells contain two non-identical genomes, and differences in their regulation underlie human development and disease. We present Fiber-seq inferred regulatory elements (FIRE) and show that FIRE provides a more comprehensive and quantitative snapshot of the accessible chromatin landscape across the 6 Gbp diploid human genome, overcoming previously unrecognized biases in existing regulatory element catalogs. FIRE enables comprehensive detection of haplotype-selective chromatin accessibility (HSCA), exposing imprinted elements lacking underlying parent-of-origin differences in DNA methylation and gene regulatory modules that permit genes to escape X chromosome inactivation. We uncover that the human leukocyte antigen (HLA) locus harbors the most HSCA in immune cells, where we resolve specific transcription factor (TF) binding events disrupted by disease-associated variants. Finally, we demonstrate that the regulatory landscape of a cell is littered with autosomal somatic chromatin epimutations that are propagated by clonal expansions to create mitotically stable and non-genetically deterministic chromatin alterations.
    Keywords:  FIRE; Fiber-seq; SMaHT; chromatin; diploid; epimutation; haplotype-selective; long-read
    DOI:  https://doi.org/10.1016/j.cell.2026.09.034
  8. Cell. 2026 Oct 15. pii: S0092-8674(26)01138-4. [Epub ahead of print]
    A phenome-wide structural variant map from 467,152 UK Biobank genomes.
    AstraZeneca Genomics Initiative
      Structural variants (SVs) are large (>50 base pairs) genomic rearrangements that can significantly influence human phenotypes, yet their contribution to health and disease remains undercharacterized. We conducted a phenome-wide association study (PheWAS) of 1.6 million SVs identified in whole-genome sequencing data from 467,152 UK Biobank participants, across 13,322 binary, 2,018 quantitative, and 2,923 plasma protein traits. Of these, 82.25% of SVs were outside the detectable range of prior copy-number variant studies. Protein quantitative trait loci analysis linked 3,467 SVs to 1,690 proteins, with effects dependent on SV type and location. In SV-PheWAS, we detected 28,184 associations with human health outcomes. Notably, we uncovered rare SVs with strong phenotypic effects. Furthermore, we show that at known genome-wide association study loci, 32.21% of associated SVs overlapped functional genomic regions. This study underscores the underestimated role of SVs in human genetics and their potential to advance understanding of human biology and drug discovery.
    Keywords:  biomarkers; drug discovery; genomics; human genetics; multi-ancestry meta analysis; non-coding variants; phenome-wide association study; protein quantitative trait loci; structural variants; whole genome sequencing
    DOI:  https://doi.org/10.1016/j.cell.2026.09.035
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