bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–10–25
ten papers selected by
Xiong Weng, University of Edinburgh
  1. Attractin-like protein 1 is an essential partner of MC4R to regulate body weight.
  2. Miro1 mediates skeletal muscle insulin resistance in type 2 diabetes.
  3. A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
  4. Mammalian DNA maintenance methylation depends on histone but not PAF15 ubiquitination.
  5. Genome-wide analyses identify 60 loci associated with liver triglyceride content.
  6. MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
  7. The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality.
  8. Inducible chronic NAD deficiency in mice reveals multi-systemic phenotypical, metabolic, and transcriptional changes.
  9. Establishing Polycomb regulatory landscapes in human early development.
  10. Leveraging genomic deep learning models for the prediction of noncoding variant effects.
  1. Nat Commun. 2026 Sep 22. pii: 11041. [Epub ahead of print]17(1):
    Attractin-like protein 1 is an essential partner of MC4R to regulate body weight.
    Paul Buscaglia, Kate R Bowman, Katherine Lawler, Ciria C Hernandez, Jacopo Scotucci, Rebecca Bounds, Julia M Keogh, Elana Henning, Roger D Cone, I Sadaf Farooqi, Julien A Sebag.
      The melanocortin 4 receptor (MC4R) plays a critical role in the central control of energy homeostasis, and its disruption causes severe early-onset obesity. MC4R signaling is tightly regulated by endogenous agonists and antagonists, as well as the accessory protein MRAP2. The single transmembrane protein attractin-like protein 1 (ATRNL1) is a known interactor of MC4R, however, its effect on MC4R signaling and physiological function is not well understood. Here we show that ATRNL1 interacts with MC4R to amplify its signaling in cells and that expression of ATRNL1 potentiates agonist-induced activation of MC4R neurons. Deletion of Atrnl1 in MC4R neurons increased food intake and body weight in rodents. In exomes from 1,623 children with severe early-onset obesity, we identified multiple rare ATRNL1 variants that impair ATRNL1-mediated regulation of MC4R signaling. Cumulatively, these findings establish ATRNL1 as an important regulator of mammalian energy homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-77897-z
  2. Nat Commun. 2026 10 19. pii: 10702. [Epub ahead of print]17(1):
    Miro1 mediates skeletal muscle insulin resistance in type 2 diabetes.
    Elizabeth C Heintz, Wagner S Dantas, Analisa L Taylor, Elizabeth R M Zunica, Kathryn P Belmont, Jackson M Slone, Jacob T Mey, Robbie Beyl, Bolormaa Vandanmagsar, Hailey A Parry, Peter Ajayi, Brian Glancy, Christopher L Axelrod, John P Kirwan.
      Imbalanced skeletal muscle mitochondrial dynamics contribute to the onset and progression of type 2 diabetes (T2D) by mechanisms that remain incompletely understood. Here, we examined the role of Mitochondrial Rho GTPase 1 (Miro1), an outer mitochondrial membrane enzyme, in regulating skeletal muscle insulin action and glucose homeostasis in type 2 diabetes (T2D). In a cross-sectional clinical study, we show that Miro1 accumulates in the skeletal muscle of patients with obesity and T2D, which was further replicated in mouse models of T2D. This accumulation is explained by inadequate insulin-mediated interaction between AKT and Miro1 at the outer mitochondrial membrane. In a randomized controlled trial (NCT02977442), we show that exercise training relieves skeletal muscle Miro1 accumulation while improving insulin sensitivity in patients with T2D. Muscle-specific Miro1 deletion improves oxidative capacity and insulin sensitivity in mice and cells. Taken together, these data support a key regulatory role for skeletal muscle Miro1 in the pathophysiology of T2D. ClinicalTrials.gov Identifier: NCT02977442.
    DOI:  https://doi.org/10.1038/s41467-026-77278-6
  3. Nat Metab. 2026 Oct 21.
    A futile Na+ K+ transport cycle augments energy expenditure in beige adipocytes.
    Qing Liu, Ying Cheng, Dandan Yan, Wenjie Wu, Zhenchuan Lei, Qiaoyun Long, Ziyu Zhao, Yuan Gao, Baile Wang, Tianshi Feng, Jihoon Shin, Jiayu Zhao, Shiting Zhao, Kang Chen, Kingyip Cheng, Xiaoqiang Yao, Ping Gu, Xuefei Gao, Ching-Lung Cheung, Shingo Kajimura, Pengtao Liu, Donghai Wu, Wei Sun, Jinfeng Xiao, Zexin Lin, Yi Wang, Maxwell Kwok, Ngar Yun Ellen Poon, Cheng Hu, Aimin Xu, Hannah Xiaoyan Hui.
      Uncoupling protein 1 (UCP1)-independent energy dissipation has been proven to serve physiological functions in beige adipocytes. Here we show that a futile sodium/potassium (Na+/K+) transport cycle is preferentially amplified in mouse and human beige adipocytes and contributes to UCP1-independent energy expenditure. In mice, cold exposure activates a sympathetic-thyroid hormone signaling axis that coordinatedly induces the Na+/K+-ATPase subunit ATP1A2 together with Na+ and K+ channels, increasing bidirectional ion flux across the plasma membrane while maintaining ionic balance. Atp1a2+Kcnk3+ adipocytes are detected in mouse inguinal white adipose tissue after cold exposure. Acute inhibition of Na+/K+-ATPase reduces energy expenditure in mouse and human beige adipocytes, whereas overexpressing Atp1a2 in murine adipocytes potentiates energy expenditure, independent of UCP1. Adipocyte-specific Atp1a2 deletion impairs thermogenic capacity and exacerbates diet-induced obesity in mice. Expression of a human ATP1A2 missense variant reduces ATP1A2-dependent respiration in mouse adipocytes. Together, these identify ion transport as a tunable ATP-consuming mechanism that expands the thermogenic repertoire of beige adipocytes.
    DOI:  https://doi.org/10.1038/s42255-026-01630-9
  4. Nat Commun. 2026 09 17. pii: 10925. [Epub ahead of print]17(1):
    Mammalian DNA maintenance methylation depends on histone but not PAF15 ubiquitination.
    Jialun Li, Yuanyong Huang, Meilin Sun, Shaoqi Zheng, Fenghua Chen, Xingrui Song, Weiyi Lai, Yanling Yao, Zhaosu Chen, Hailin Wang, Jiwen Li, Matthias Bochtler, Jiemin Wong.
      In mammals, DNA methylation is an essential inheritable epigenetic modification maintained by the DNMT1-UHRF1 machinery in a UHRF1 E3 ubiquitin ligase-activity-dependent manner. UHRF1-catalyzed histone ubiquitination and PAF15 ubiquitination have been proposed to recruit DNMT1 to hemi-methylated CpGs. Here, we confirm that both PAF15 and histone H3 are robustly ubiquitinated by UHRF1 in a replication-dependent manner during S phase. However, loss of PAF15 or its ubiquitination, or overexpression of ubiquitination-deficient PAF15, does not alter DNMT1 recruitment to replicating DNA or global DNA methylation. Notably, the DNMT1 inhibitor GSK-3685032 strongly enhances histone ubiquitination, likely via UHRF1 activation driven by accumulated hemi-methylated CpGs, but markedly reduces PAF15 ubiquitination. We show that UHRF1-mediated PAF15 ubiquitination requires DNMT1, is strictly replication-coupled, and that PAF15 and histone ubiquitination are mediated by distinct UHRF1 pools. Taken together, our study demonstrates that hemi-methylated-DNA-stimulated local histone ubiquitination, rather than replication-coupled PAF15 ubiquitination, drives DNMT1 targeting for maintenance methylation.
    DOI:  https://doi.org/10.1038/s41467-026-77759-8
  5. Nat Genet. 2026 Oct 21.
    Genome-wide analyses identify 60 loci associated with liver triglyceride content.
    Oveis Jamialahmadi, Shahir Mowlaei, Kyla Z Gelev, Rosellina M Mancina, Valentina Flagiello, Julia Kozlitina, Päivi Pajukanta, Luca Valenti, Stefano Romeo.
      We performed a large-scale genome-wide association study meta-analysis of magnetic resonance imaging-derived liver triglyceride content across 71,488 European-ancestry participants from the UK Biobank, approximately doubling the sample size of previous genome-wide association studies1. We identified 60 independent loci, including 31 not previously reported, and estimated the single nucleotide polymorphism-based heritability of liver triglyceride content at 25%. Integrative fine-mapping and gene-prioritization analyses nominated candidate effector genes for 48 loci. Of the 31 newly identified variants, 14 were validated in meta-analyses of clinically diagnosed metabolic dysfunction-associated steatotic liver disease (42,163 cases and 1,646,254 controls). People in the highest versus lowest decile of a polygenic risk score for liver triglyceride content had 2.71-fold higher odds of cirrhosis and 7.47-fold higher odds of hepatocellular carcinoma. Plasma proteins associated with the liver triglyceride polygenic risk score were enriched for metabolic remodeling and inflammatory pathways, with liver-enriched protein signatures increasing and visceral adipose signatures decreasing with higher genetic risk. Together, these findings refine the genetic architecture of liver triglyceride content, linking polygenic susceptibility to downstream metabolic and inflammatory pathways and providing insights into the genetic basis of steatotic liver disease.
    DOI:  https://doi.org/10.1038/s41588-026-02794-6
  6. Cell. 2026 Oct 22. pii: S0092-8674(26)01205-5. [Epub ahead of print]
    MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss.
    Shuke Xiao, Alan Sheng-Hwa Tung, Jan Spaas, Sipei Fu, Xudong Chen, Tuan Kiet Trinh, Maria Dolores Moya-Garzon, Veronica L Li, Hannah T Cessna, Kentaro Ito, Saranya C Reghupaty, Chao Lin, Xuchao Lyu, Steffen H Raun, Miles D W Tyner, Arthur Germakovski, Jacob Tondreau, Megan Yeckley, Wei Wei, Michael R Howitt, Mark D Parker, Jason A Sprowl, Stephen M Hinshaw, Jonathan Z Long.
      Metabolites are increasingly recognized as circulating molecules that regulate physiology, yet the mechanisms that couple local intracellular production to organism-wide action remain poorly defined. Using the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) as a model system, we identify the orphan transporter MCT6/SLC16A5 as a physiologic intestinal Lac-Phe exporter. This mechanism controls the extent to which intracellularly synthesized Lac-Phe acquires systemic activity. MCT6 transports Lac-Phe in vitro, mediates Lac-Phe efflux in cells, and is required for maintaining normal circulating Lac-Phe levels in vivo, particularly following metformin treatment or high-intensity exercise. High-fat-diet-fed mice with global or intestinal epithelial-specific deletion of MCT6 exhibit resistance to metformin-associated weight loss. Bypassing the transport defect with exogenous Lac-Phe normalizes the body weight phenotype of MCT6-knockout (KO) mice. These data connect MCT6 to Lac-Phe and gut glycolytic flux and underscore the importance of transporter-mediated release in the conversion of an intracellular metabolic state into a circulating metabolite effector.
    Keywords:  Lac-Phe; MCT6; SLC16A5; circulating; lactate; metabolites; metformin; obesity; transporter; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2026.09.058
  7. Nat Genet. 2026 Oct 20.
    The landscape of gene loss and missense variation across the mammalian tree informs on gene essentiality.
    Calwing Liao, Robert Ye, Franjo Ivankovic, Jack M Fu, Raymond Walters, Chelsea Lowther, Elise Valkanas, Claire Churchhouse, Kaitlin E Samocha, Kerstin Lindblad-Toh, Elinor Karlsson, Michael Hiller, Michael E Talkowski, Benjamin M Neale.
      Patterns of gene and sequence preservation across species provide insight into gene essentiality under natural selection. Here we developed two interspecies constraint metrics across 462 mammalian species: Gene Identity Score of Mammalian Orthologs (GISMO), which quantifies gene loss weighted by evolutionary distance to humans, and GISMO-mis, which measures missense constraint using the ratio of missense to synonymous variation across mammals. Both metrics are strongly correlated with human loss of function, missense and dosage constraint derived from large-scale sequencing studies, yet are largely independent of coding sequence length. GISMO and GISMO-mis identify essential genes missed by existing human-only metrics, particularly short genes. Genes in the most constrained deciles are enriched for rare variant associations in disorders linked to reduced fecundity, including schizophrenia, autism and neurodevelopmental disorders, and show strong enrichment for common variant heritability. These deciles also exhibit reduced copy number variation, consistent with dosage sensitivity. In addition, GISMO improves prioritization of recessive disease genes and captures signatures of homozygous selection across the mammalian tree. Taken together, GISMO and GISMO-mis leverage deep mammalian evolution to provide complementary, length-robust measures of gene essentiality that strengthen disease-gene prioritization and illuminate the selective forces shaping human biology.
    DOI:  https://doi.org/10.1038/s41588-026-02783-9
  8. Nat Commun. 2026 Sep 23. pii: 11048. [Epub ahead of print]17(1):
    Inducible chronic NAD deficiency in mice reveals multi-systemic phenotypical, metabolic, and transcriptional changes.
    Andres Benitez-Rosendo, Morgan B Feuz, Claudia C S Chini, Gina M Warner, Gina L Ciccio Lopez, Gustavo H Souza, Katrina Rae Bueser, Sonu Kashyap, Laura Colman, Katie L Thompson, Delaram Zamani Mazdeh, Sierra A Lopez, Laura B Miller, Alexie E Zwerdling, Miles K Wandersee, Thais R Peclat, Sara Peixoto Rabelo, Karina S Kanamori, Fernanda C Pereira, Heidi S Cordeiro, Jessica L Strange, Naiara C Lucredi, Luiza Palmieri Serrano, Rakesh Kaundal, Jason D Doles, Jennifer L Rowsey, Joshua N Farr, Sundeep Khosla, Ralph G Meyer, Mirella L Meyer-Ficca, Eduardo N Chini.
      Nicotinamide adenine dinucleotide (NAD) is a metabolic cofactor regulating energy metabolism, epigenetics, DNA repair, and signaling. Although NAD declines with vitamin B3 deficiency, disease, and aging, systemic consequences of chronic depletion remain unclear. Here, we characterize an in vivo model of inducible NAD deficiency using acquired niacin dependency (ANDY) mice, in which NAD synthesis becomes dependent on dietary niacin. On a niacin-free diet, ANDY mice developed widespread tissue NAD depletion and sex-independent multisystem abnormalities, including kyphosis, reduced bone, lean, and fat mass, impaired exercise capacity, fur browning, frailty, cataracts, disrupted energy homeostasis, and shortened lifespan. NAD depletion was accompanied by tissue inflammation and cellular senescence. Transcriptomic analyses revealed broad metabolic remodeling and only partial overlap with chronological aging. Senolytic treatment partially improved functional decline without restoring NAD. In contrast, dietary niacin repletion reversed phenotypic, biochemical, senescence-associated, and transcriptional abnormalities, demonstrating that recovery of tissue NAD levels restored systemic function.
    DOI:  https://doi.org/10.1038/s41467-026-77996-x
  9. Nat Genet. 2026 Oct 19.
    Establishing Polycomb regulatory landscapes in human early development.
    Xiaoyu Hu, Chuanxin Zhang, Bofeng Liu, Fangnong Lai, Shuiying Ma, Zhenzhen Hou, Qizhe Shao, Ling Liu, Xukun Lu, Guanling Yu, Hui Liu, Zhen Yang, Ning Wang, Xi Wu, Zili Lin, Lijuan Wang, Yongli Shan, Guangjin Pan, Di Chen, Bo Zhang, Lei Jin, Han Zhao, Keliang Wu, Zi-Jiang Chen, Wei Xie.
      H2AK119ub (H2Aub) and H3K27me3, which are deposited by the Polycomb group (PcG) complexes PRC1 and PRC2, respectively, cooperatively repress developmental genes. However, in human preimplantation embryos, H3K27me3 undergoes genome-wide erasure and subsequent restoration. How H3K27me3 is reestablished and whether PcG complexes still regulate gene repression in human embryos remain unknown. Here, we profiled H2Aub dynamics from human gametes to blastocysts. H2Aub emerges in GC-rich regions as early as the two-cell stage, progressively accumulates at both active and inactive genes, and further culminates at PcG targets in later stages. H3K27me3 is weakly correlated with H2Aub in oocytes and two-cell embryos but colocalizes with H2Aub at H3K4me3-depleted, inactive PcG targets in blastocysts. Loss of H2Aub abolishes H3K27me3 reestablishment at PcG targets causing moderate derepression, accompanied by ectopic H3K27me3 deposition and impaired embryonic development. Finally, H2Aub and DNA methylation cooperatively maintain H3K27me3 patterning in human embryonic stem cells. Therefore, H2Aub-dependent H3K27me3 deposition underlies the earliest establishment of Polycomb repression in humans.
    DOI:  https://doi.org/10.1038/s41588-026-02764-y
  10. Nat Genet. 2026 Oct 21.
    Leveraging genomic deep learning models for the prediction of noncoding variant effects.
    Pooja Kathail, Ayesha Bajwa, Nilah M Ioannidis.
      Characterizing noncoding variant function remains an important challenge in human genetics. Genomic deep learning models have emerged as a promising approach to enable in silico prediction of variant effects. These models include supervised sequence-to-activity models, which predict molecular phenotypes such as genome-wide chromatin states or gene expression levels directly from DNA sequence, and self-supervised genomic language models. Here we review progress in leveraging these models for noncoding variant effect prediction. We describe practical considerations for making such predictions and categorize the types of ground-truth data used to evaluate variant effect predictions, providing insight into the settings in which current models are most useful. Our Review highlights key considerations for practitioners and opportunities for improvement in model development and evaluation.
    DOI:  https://doi.org/10.1038/s41588-026-02769-7
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