bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–01–04
nine papers selected by
Xiong Weng, University of Edinburgh
  1. From fat to fate: how aging adipose tissue drives systemic metabolic aging.
  2. Linking single-cell multiomics with GWAS to reveal key regulators of disease risk.
  3. cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions.
  4. Convergent DNA methylation abnormalities at enhancers and bivalent promoters in human growth disorders.
  5. Multi-omic definition of metabolic obesity through adipose tissue-microbiome interactions.
  6. PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.
  7. Modeling Obesity and Weight Loss in Mice Using Novel AAV Approaches.
  8. Phosphoproteomics of aged insulin-resistant bone identifies P70S6K phosphorylation of AFF4 as a gene-specific transcriptional regulator.
  9. Protocol for targeted gene manipulation and thermogenic evaluation in mouse brown adipocytes.
  1. Biogerontology. 2025 Dec 27. 27(1): 30
    From fat to fate: how aging adipose tissue drives systemic metabolic aging.
    Haiyan Lin, Hongyu Li, Qiang Tang.
      Aging adipose tissue is a consequence of organismal aging and an "amplifier" that drives systemic metabolic disorders. This review proposes the conceptual framework of the "aging metabolic amplifier", systematically explaining how aging adipose tissue reshapes the microenvironment of distant organs through its secretory profile, thereby linking obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases. The concept of the "aging metabolic amplifier" emphasizes the important role of senescent adipocytes in systemic metabolic dysfunction, and systematically elaborates on their heterogeneous characteristics, autonomous and non-autonomous changes, as well as their mechanisms in ectopic lipid deposition, cardiovascular diseases, and cognitive decline. Currently, specific intervention strategies-such as activating the thermogenic program, eliminating senescent cells, regulating autophagy, and improving the microenvironment- have been proposed, providing potential therapeutic directions for delaying aging and related metabolic diseases.
    Keywords:  Adipose tissue; Aging; Inflammation; Intervention strategy; Metabolism
    DOI:  https://doi.org/10.1007/s10522-025-10376-y
  2. Nat Aging. 2026 Jan 02.
    Linking single-cell multiomics with GWAS to reveal key regulators of disease risk.
      
    DOI:  https://doi.org/10.1038/s43587-025-01047-1
  3. Nat Methods. 2025 Dec 31.
    cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Understanding how rare genetic variants influence complex traits remains a major challenge, particularly when these variants lie in noncoding regions of the genome. The effects of variants within candidate cis-regulatory elements (cCREs) often depend on the cell type, making interpretation difficult. Here we introduce cellSTAAR, which integrates whole-genome sequencing data with single-cell assay for transposase-accessible chromatin using sequencing data to capture variability in chromatin accessibility across cell types via the construction of cell-type-specific functional annotations and regulatory elements. To reflect the uncertainty in cCRE-gene linking, cellSTAAR uses a comprehensive strategy to link cCREs to their target genes. We applied cellSTAAR to data from the Trans-Omics for Precision Medicine consortium (n ≈ 60,000) and replicated our findings using the UK Biobank (n ≈ 190,000). Across four lipid traits, cellSTAAR improved the detection of biologically meaningful associations and enhanced biological interpretability. These results demonstrate the potential of cell-type-aware approaches to boost discovery in rare variant whole-genome sequencing association studies.
    DOI:  https://doi.org/10.1038/s41592-025-02919-5
  4. Epigenetics Chromatin. 2025 Dec 27.
    Convergent DNA methylation abnormalities at enhancers and bivalent promoters in human growth disorders.
    Marie E S Wheeler, Yoshiko Takahashi, Jihye Lee, Camille T Perez, Xiaoting Chen, Yuri Lee, Zachary S Pope, Daniella J Lu, Marcus Seldin, Ivan Marazzi, Hongseok Yun, Matthew T Weirauch, Minji Byun.
      Loss-of-function mutations in DNMT3A, a DNA methyltransferase, or NSD1, a histone methyltransferase, cause overgrowth syndromes. Conversely, disruption of the DNMT3A domain that binds NSD1-deposited H3K36 dimethylation (H3K36me2) results in growth restriction. To investigate the molecular basis of these opposing growth outcomes, we generated isogenic human embryonic stem cells carrying growth syndrome-associated mutations in DNMT3A and NSD1. Unexpectedly, both overgrowth- and growth restriction-associated DNMT3A mutations led to DNA hypomethylation in a shared subset of active enhancers, implicating H3K36me2 in directing enhancer methylation maintenance. In contrast, bivalent promoters-marked by both active and repressive histone modifications-showed divergent DNA methylation changes: hypermethylation in growth restriction-associated DNMT3A mutants and hypomethylation in overgrowth-associated DNMT3A or NSD1 loss-of-function mutants. These findings identify locus-specific DNA methylation defects as a common molecular feature and nominate dysregulated DNA methylation at bivalent promoters as a potential driver of abnormal growth phenotypes.
    Keywords:  Bivalent chromatin; DNA methylation; DNMT3A; Growth disorders; NSD1; Overgrowth syndrome
    DOI:  https://doi.org/10.1186/s13072-025-00650-1
  5. Nat Med. 2026 Jan 02.
    Multi-omic definition of metabolic obesity through adipose tissue-microbiome interactions.
    Rima M Chakaroun, Meenakshi Pradhan, Elias Björnson, Daniel Arvidsson, Jonatan Fridolfsson, Anders Gummesson, Marc Schoeler, Matthias Mitteregger, Gustav J Smith, Ingrid Larsson, Mats Börjesson, Matthias Blüher, Mathias Uhlén, Michael Stumvoll, Göran Bergström, Valentina Tremaroli, Fredrik Bäckhed.
      Obesity's metabolic heterogeneity is not fully captured by body mass index (BMI). Here we show that deep multi-omics phenotyping of 1,408 individuals defines a metabolome-informed obesity metric (metBMI) that captures adipose tissue-related dysfunction across organ systems. In an external cohort (n = 466), metBMI explained 52% of BMI variance and more accurately reflected adiposity than other omics models. Individuals with higher-than-expected metBMI had 2-5-fold higher odds of fatty liver disease, diabetes, severe visceral fat accumulation and attenuation, insulin resistance, hyperinsulinemia and inflammation and, in bariatric surgery (n = 75), achieved 30% less weight loss. This obesogenic signature aligned with reduced microbiome richness, altered ecology and functional potential. A 66-metabolite panel retained 38.6% explanatory power, with 90% covarying with the microbiome. Mediation analysis revealed a bidirectional, metabolite-centered host-microbiome axis, mediated by lipids, amino acids and diet-derived metabolites. These findings define an adipose-linked, microbiome-connected metabolic signature that outperforms BMI in stratifying cardiometabolic risk and guiding precision interventions.
    DOI:  https://doi.org/10.1038/s41591-025-04009-7
  6. Aging Cell. 2026 Jan;25(1): e70347
    PRKN-Mediated Ubiquitin-Proteasome Degradation of METTL3 Promotes Cellular Senescence.
    Liping Chen, Canfeng Zhang, Yuanlong Ge, Haoxian Zhou, Shenglong Yang, Wenjing Wei, Qinghua Zhou, Kaizhen Xiao, Guangyu Huang, Xiaocui Li, Jia Wang, Jinping Zheng, Ronghe Gu, Zhenyu Ju, Shu Wu.
      N6-methyladenosine (m6A) methylation, a dynamic and reversible modification of eukaryotic mRNAs, plays critical roles in diverse cellular processes. Although METTL3-mediated m6A deposition has been implicated in cellular senescence, the mechanisms controlling METTL3 stability and activity during senescence remain poorly defined. Here, we demonstrate that both m6A levels and METTL3 protein abundance are significantly reduced in replication-induced and stress-induced senescence models. METTL3 depletion promotes senescence by inducing telomere dysfunction via diminished expression of shelterin components TRF2 and POT1. Mechanistically, we identify PRKN (Parkin) as a senescence-associated E3 ubiquitin ligase that promotes METTL3 proteasomal degradation through K48-linked polyubiquitination at lysine 164. Genetic PRKN inhibition in pre-senescent cells rescues METTL3 expression, restores TRF2/POT1 levels, reduces telomere dysfunction-induced foci (TIFs), and attenuates senescence-associated β-galactosidase (SA-β-gal) activity. Crucially, PRKN overexpression accelerates telomere dysfunction and senescence in wild-type METTL3-expressing cells but not in cells expressing the ubiquitination-resistant K164R METTL3 mutant. Our findings establish METTL3 ubiquitination as a pivotal regulator of telomere integrity and senescence progression, unveiling a therapeutic target for age-related pathologies.
    Keywords:  METTL3; PRKN; m6A; senescence; telomere
    DOI:  https://doi.org/10.1111/acel.70347
  7. Obesity (Silver Spring). 2025 Dec 28.
    Modeling Obesity and Weight Loss in Mice Using Novel AAV Approaches.
    Hunter G Sellers, Zachary L Brown, Noureen S Khalil, Stephen B Haigh, Mitchell A Shivers, Tej V Patel, Austin T Joshua, Neal L Weintraub, Scott A Barman, Eric J Belin de Chantemele, Sergei A Kirov, David W Stepp, David J R Fulton.
       OBJECTIVE: This study utilized AAV gene delivery as an approach to induce and reverse hyperphagia in mice. We hypothesized that the delivery of orexigenic neuropeptides to the brain via AAV precipitates obesity and that the implementation of genetic switches to reverse transgene expression would elicit weight loss.
    METHODS: We utilized capsid-modified AAV-PHP.eB and AAV-CAP.B10 to deliver AgRP, NPY, a leptin superantagonist, and ghrelin to the mouse brain. Cre-LoxP, TETOFF, and cumate expression systems were used to alter transgene expression.
    RESULTS: Delivery of three out of four orexigenic neuropeptides to the brain precipitated severe obesity. Cre-mediated excision of AgRP from the brain caused a return to baseline weight, confounded by tamoxifen-associated weight loss. Doxycycline-mediated suppression of AgRP in a TETOFF vector paused weight gain but did not elicit weight loss. Cumate induction of AgRP in the brain was unaffected by systemic administration, suggesting that cumate inadequately penetrates the blood-brain barrier.
    CONCLUSIONS: Brain-targeted delivery of orexigenic peptides induces obesity in mice. This allows for temporally controlled, convenient, and robust preclinical models of obesity. The implementation of genetic switches enabled suppression/removal of AgRP expression, but we unexpectedly observed that removal of hyperphagic stimuli does not elicit robust weight loss.
    DOI:  https://doi.org/10.1002/oby.70081
  8. Nat Commun. 2025 Dec 31.
    Phosphoproteomics of aged insulin-resistant bone identifies P70S6K phosphorylation of AFF4 as a gene-specific transcriptional regulator.
    Mriga Dutt, Luoping Liao, Hani Jieun Kim, Ronnie Blazev, Audrey Chan, Hitesh Kore, Ayenachew Bezawork-Geleta, Li Dong, Isela Sarahi Rivera, Natalie K Y Wee, Jeffrey Molendijk, Julian P H Wong, Vanessa R Haynes, Veronica Uribe, Gordon S Lynch, Kelly A Smith, Magdalene K Montgomery, Matthew J Watt, Pengyi Yang, Garron T Dodd, Stephin J Vervoort, Natalie A Sims, Benjamin L Parker.
      Insulin action on the skeleton is essential for bone development and whole-body energy metabolism, however a global view of signaling in this tissue is lacking. Furthermore, whether there are signaling differences that drive the gene-specific activation under insulin-resistant (IR) or ageing conditions is unknown. Here, we perform a phosphoproteomic analysis of insulin signaling in the bones of young, lean, insulin-sensitive versus old, obese, IR mice revealing a rewiring of phosphorylation. We target dysregulated phosphoproteins in a zebrafish functional genomic screen of bone development and mineralization revealing candidates important for skeletal formation. One of these is ALF Transcription Elongation Factor 4 (AFF4), the core scaffold of the Super Elongation Complex and we show that phosphorylation of S831 on AFF4 is an insulin-dependent substrate of P70S6K and attenuated in aged, IR bone. Phosphorylation of S831 is defective in IR osteoblasts and associated with reduced transcriptional elongation at discrete locations in the genome. Mechanistically, we show phosphorylation of S831 increases recruitment of chromatin remodelers, ENL/AF9 to crotonylated histone via the YEATS domain, and promotes gene-specific activation. Our analysis identifies regulators of insulin action on the skeleton, further uncovering a mechanism of IR via locus-specific changes in transcriptional elongation and gene activation.
    DOI:  https://doi.org/10.1038/s41467-025-68106-4
  9. STAR Protoc. 2025 Dec 29. pii: S2666-1667(25)00723-3. [Epub ahead of print]7(1): 104317
    Protocol for targeted gene manipulation and thermogenic evaluation in mouse brown adipocytes.
    Jakub Bunk, Drishti Soni, Matthias Calderon, Bozena Samborska, Lawrence Kazak.
      Adeno-associated viruses (AAVs) are versatile, non-integrating vectors for in vivo gene delivery. We present a reproducible workflow for generating Cre-dependent FLEX-AAVs, quantifying viral titer, and performing localized injections for cell-type-specific transgene expression in mice. The protocol also details the assessment of thermogenic capacity in genetically modified brown adipocytes using Clark-type electrode respirometry. For complete details on the use and execution of this protocol, please refer to Bunk et al.1.
    Keywords:  gene expression; genetics; metabolism; molecular biology
    DOI:  https://doi.org/10.1016/j.xpro.2025.104317
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