bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–01–11
eighteen papers selected by
Xiong Weng, University of Edinburgh
  1. ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness.
  2. The ubiquitin E3 ligase HRD1 restricts hepatic lipid metabolism by suppressing PPARα-driven m6A RNA modification.
  3. Mitochondrial control of fuel switching via carnitine biosynthesis.
  4. Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
  5. Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells.
  6. The dorsal aortic compartment is a developmental source of brown adipose tissue in mice.
  7. Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.
  8. Taurine transporter SLC6A6 expression promotes mesenchymal stromal cell function.
  9. A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
  10. Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of human beige adipocytes.
  11. Mitochondrial DNA Methylation: Existence, Localization, and Function
  12. GIPC2 regulation of the PKM2/SREBP1 signaling axis controls adipogenic differentiation of mesenchymal stem cells.
  13. Epigenetic aging and lifespan reflect reproductive history in the Finnish Twin Cohort.
  14. Benign form of monogenic obesity conferred by the melanocortin 4 receptor.
  15. Mitochondrial dynamics and signaling in stem cell differentiation.
  16. The rs713586 risk variant dysregulates ADCY3 rather than DNAJC27, leading to obesity through ZFP42-TET1-mediated DNA methylation.
  17. Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program.
  18. Nat10-mediated ac4C epitranscriptomics orchestrates hematopoietic stem/progenitor cell fate determination via translation control.
  1. Sci Adv. 2026 Jan 09. 12(2): eadz1385
    ERα activates NAMPT/IL-33 signaling to enhance beige thermogenesis and metabolic fitness.
    Ruoci Hu, Jooman Park, Yanyu Qian, Shaolei Xiong, Ahmad Hamza Elsabbagh, Aditya Chhikara, Huailing Fan, Zuoxiao Shi, Lifeng Liu, Yanhui Li, Zhenyuan Song, Abeer M Mahmoud, Jiwang Chen, Joseph A Baur, Yanlin He, Brian T Layden, Zhenqi Zhou, Pingwen Xu, Sang-Ging Ong, Zilai Wang, Yuwei Jiang.
      Beige adipocytes are inducible thermogenic fat cells that emerge within white adipose tissue (WAT) in response to thermogenic stimuli and confer metabolic benefits. However, obesity impairs the generation of beige adipocytes, and the underlying mechanisms remain poorly understood. Here, we show that obesity leads to a loss of adipose progenitor cells (APCs) in WAT, accompanied by reduced estrogen (E2) levels and nicotinamide phosphoribosyltransferase (NAMPT) expression. Supplementation with E2 or nicotinamide mononucleotide (NMN), an NAMPT-derived nicotinamide adenine dinucleotide (NAD+) precursor, restores beige adipogenesis in diet-induced obese mice. Mechanistically, estrogen receptor α (ERα) in APCs is required for beige fat formation by promoting Nampt transcription. We further demonstrate that NAMPT is both necessary and sufficient to drive APC proliferation and differentiation, with interleukin-33 (IL-33) acting downstream to mediate these effects. These findings uncover a critical ERα/NAMPT/IL-33 axis that preserves progenitor function and thermogenic capacity, offering a potential therapeutic strategy to combat obesity-induced beige fat failure and associated metabolic dysfunction.
    DOI:  https://doi.org/10.1126/sciadv.adz1385
  2. Sci Signal. 2026 Jan 06. 19(919): eadx8300
    The ubiquitin E3 ligase HRD1 restricts hepatic lipid metabolism by suppressing PPARα-driven m6A RNA modification.
    Hyunbae Kim, Pattaraporn Thepsuwan, Juncheng Wei, Donghong Ju, Qi Chen, Xiaohong Zhang, Li Li, Jie Xu, Xin Tong, Shengyi Sun, Chuan He, Lei Yin, Deyu Fang, Kezhong Zhang.
      Hepatic lipid metabolism is regulated by circadian rhythms and dynamically responds to nutrient availability, such that lipid synthesis, oxidation, and storage are temporally coordinated. We demonstrated that the endoplasmic reticulum (ER)-localized E3 ubiquitin ligase HRD1 stimulated lipid accumulation in the liver by decreasing the N6-methyladenosine (m6A) methylation and expression of mRNAs encoding factors involved in lipid metabolism. In mouse livers, m6A RNA modification and the expression of mRNAs encoding the m6A writer METTL14 and the m6A reader YTHDF3 were under circadian control and inversely correlated with the abundance of HRD1. m6A RNA sequencing analyses revealed that HRD1 and the m6A writer METTL14 had opposing roles in the m6A modification and expression of mRNAs encoding factors involved in fatty acid metabolism. In vivo, hepatic lipid accumulation and triglyceride amounts were decreased in mice with hepatic HRD1 deficiency fed a high-fat diet but increased in mice with hepatic METTL14 or YTHDF deficiency fed normal chow. Mechanistically, HRD1 mediated the polyubiquitination and degradation of PPARα, which transcriptionally activated METTL14 and YTHDF3 expression in the liver. Our work identifies a pathway regulated by circadian rhythms or nutrients in which HRD1 promotes the degradation of PPARα to decrease the m6A modification and expression of hepatic mRNAs encoding factors involved in lipid metabolism.
    DOI:  https://doi.org/10.1126/scisignal.adx8300
  3. Science. 2026 Jan 08. eady5532
    Mitochondrial control of fuel switching via carnitine biosynthesis.
    Christopher Auger, Hiroshi Nishida, Bo Yuan, Guilherme Martins Silva, Masanori Fujimoto, Mark Li, Daisuke Katoh, Dandan Wang, Melia Granath-Panelo, Jihoon Shin, Rose Witte, Jin-Seon Yook, Anthony R P Verkerke, Alexander S Banks, Sheng Hui, Lijun Sun, Shingo Kajimura.
      Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.
    DOI:  https://doi.org/10.1126/science.ady5532
  4. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00529-7. [Epub ahead of print]38(1): 33-49.e10
    Dual inhibition of ACLY and ACSS2 by EVT0185 reduces steatosis, hepatic stellate cell activation, and fibrosis in mouse models of MASH.
    Fiorella Di Pastena, Jaya Gautam, James S V Lally, Russta Fayyazi, Estelle Grasset, Dipankar Bhattacharya, Gio Fidelito, Elham Ahmadi, Logan K Townsend, Battsetseg Batchuluun, Daniela Carmen Oniciu, Spencer Heaton, Roger S Newton, Theodoros Tsakiridis, Evangelia E Tsakiridis, Suhrid Banskota, Parneet Deo, François Briand, Kat Hall, Eunice Lee, Vijayaragavan Muralidharan, Matthew J Watt, Scott L Friedman, Dongdong Wang, Gregory R Steinberg.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, and fibrosis driven by hepatic stellate cell (HSC) activation. Acetyl-CoA is central to de novo lipogenesis (DNL) and cholesterol synthesis and is generated from citrate via ATP citrate lyase (ACLY) or from acetate via acetyl-CoA synthetase (ACSS2). Here, we demonstrate that a dual inhibitor of ACLY and ACSS2, EVT0185, reduces serum and liver triglycerides, insulin resistance, and fibrosis. EVT0185 directly suppresses HSC activation in vivo and in vitro, with spatial transcriptomics and single-cell RNA sequencing revealing inhibition of acetate metabolism via ACSS2 and cholesterol synthesis as key drivers of the phenotype. EVT0185 also inhibits de novo lipogenesis in human liver slices and blocks TGFβ1-induced activation of primary human HSCs. These findings suggest that targeting cholesterol and acetate metabolism through dual ACLY and ACSS2 inhibition represents a promising therapeutic approach for MASH and liver fibrosis.
    Keywords:  EVT0185; HSCs; MASH; acetate; acetyl-CoA metabolism; cholesterol; fibrosis; hepatic stellate cells; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.015
  5. Nat Metab. 2026 Jan 08.
    Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells.
    Zhiming Liu, Yi Chen, Jinhua Yan, Yu Yuan, Qianyi Wan, Rui Zhao, Fang Fu, Xinxin Fan, Yawen Deng, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Jinbao Ye, Haiyang Chen.
      Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose-gut axis as a therapeutic target for obesity-associated intestinal disorders.
    DOI:  https://doi.org/10.1038/s42255-025-01425-4
  6. Nat Commun. 2026 Jan 07. 17(1): 286
    The dorsal aortic compartment is a developmental source of brown adipose tissue in mice.
    Sophie Heider, Cornelius Fischer, Ali Kerim Secener, Pedro Vallecillo-Garcı́a, Georgios Kotsaris, Zarah G Meisen, Verena Pawolski, Claudia Giesecke-Thiel, Thomas Conrad, Tim J Schulz, Sascha Sauer, Sigmar Stricker.
      White adipose tissue primarily stores energy while brown adipose tissue dissipates energy as heat, holding promise for therapeutic use. Brown adipose tissue in the anterior trunk is believed to derive from the somitic mesoderm, although some depots are of partially unknown origin. Here we show that the subscapular, lateral, cervical and peri-aortic brown adipose depots, but not the interscapular depot, are in part formed by a non-somitic source. Single-cell sequencing along with genetic lineage tracing indicates that at embryonic day 9.5 the dorsal aorta compartment harbors multipotent mesenchymal progenitors expressing the transcription factor Osr1. Spreading laterally from the dorsal aortic midline, these cells contribute to adipose, cartilage and myogenic lineages. This study uncovers an alternative source of brown adipose tissue and suggests that a fraction of dorsal aorta-associated mesenchymal Osr1+ cells may represent the in vivo correlate of a multipotent progenitor cell type so far only characterized in vitro, the mesoangioblast.
    DOI:  https://doi.org/10.1038/s41467-025-68147-9
  7. Nat Commun. 2026 Jan 06. 17(1): 57
    Sirt6 deficiency in mast cells promotes adipose fibroinflammation in obesity through galectin-3 signaling.
    Mi-Young Song, Yong Geun Jeon, Jae Do Yang, Young Jae Moon, Jae Bum Kim, Eun Ju Bae, Byung-Hyun Park.
      Mast cells (MCs) play a key role in obesity and insulin resistance, though the mechanisms driving adipose dysfunction remain unclear. We find that Sirt6 expression in MCs decreases with obesity in both male mice and humans. Selective depletion of Sirt6 in MCs worsens inflammation, fibrosis, and metabolic dysfunction in diet-induced obesity. Adoptive transfer of MC-deficient KitW-sh/W-sh mice with Sirt6-deficient MCs leads to greater weight gain on a high-fat diet compared to transfer with wild-type MCs; however, this effect is absent when the transferred MCs lack both Sirt6 and galectin-3. Mechanistically, Sirt6 deacetylates H3K9 at the Lgals3 promoter, inhibiting galectin-3 production and protecting against M1 macrophage polarization and adipose tissue fibrosis. Single-cell RNA sequencing reveals a fibroinflammatory MC subpopulation dominating in the adipose tissue of Sirt6 knockout mice. Targeting Sirt6 activation or galectin-3 inhibition in MCs may represent a therapeutic approach for obesity-associated adipose fibroinflammation and insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-025-66040-z
  8. Cell Death Dis. 2026 Jan 08. 17(1): 14
    Taurine transporter SLC6A6 expression promotes mesenchymal stromal cell function.
    Christina M Kaszuba, Benjamin J Rodems, Sonali Sharma, Cameron D Baker, Edgardo I Franco, Takashi Ito, Palomi Schacht, Kyle P Jerreld, Emily A Johnson, Bradley R Smith, Chen Yu, Emily R Quarato, Francisco A Chaves, Jane L Liesveld, Laura M Calvi, Hani A Awad, Roman A Eliseev, Jeevisha Bajaj.
      Mesenchymal stromal cell (MSC) differentiation is critical for the development, maintenance, and repair of bone tissue. MSCs also play a key role in regulating self-renewal and differentiation of normal hematopoietic and leukemic stem cells. Our prior work has identified a key role of taurine produced by bone marrow osteolineage cells in supporting the growth of taurine transporter (TauT or Slc6a6) expressing leukemia cells. Here, we analyze multiple murine non-hematopoietic bone marrow single-cell RNA-sequencing datasets and discover that TauT expression is enriched in MSCs in vivo. Although taurine supplements have been shown to mitigate bone defects in aged mice, its role in regulating MSC populations that give rise to bone cells is poorly understood. Using TauT genetic loss-of-function murine models, we find that TauT loss impacts murine MSC populations in vivo and impairs MSC osteogenic differentiation in vitro. This is associated with decreased bone mineral density and bone strength in young and aged TauT knockout mice. Importantly, shRNA-based knockdown of TAUT expression in primary human donor MSCs reduces osteogenic differentiation. TauT null MSCs are unable to support self-renewal and expansion of co-cultured hematopoietic stem and progenitor populations, indicating broad functional defects. Mechanistically, TauT loss results in downregulation of inositol metabolism, increased oxidative stress, and reduced Wnt/β-catenin signaling, which induce MSC senescence. Collectively, our data identifies taurine as a key regulator of MSC maintenance and osteogenic fate determination.
    DOI:  https://doi.org/10.1038/s41419-025-08233-4
  9. Nat Metab. 2026 Jan 08.
    A catecholamine-independent pathway controlling adaptive adipocyte lipolysis.
    Xiao Zhang, Sreejith S Panicker, Jordan M Bollinger, Anurag Majumdar, Rami Kheireddine, Lila F Dabill, Clara Kim, Brian Kleiboeker, Fengrui Zhang, Yongbin Chen, Kristann L Magee, Brian S Learman, Adam Kepecs, Gretchen A Meyer, Jun Liu, Steven A Thomas, Irfan J Lodhi, Ormond A MacDougald, Erica L Scheller.
      Several adipose depots, including constitutive bone marrow adipose tissue, resist conventional lipolytic cues. However, under starvation, wasting or cachexia, the body eventually catabolizes stable adipocytes through unknown mechanisms. Here we developed a mouse model of brain-evoked depletion of all fat, including stable constitutive bone marrow adipose tissue, independent of food intake, to study this phenomenon. Genetic, surgical and chemical approaches demonstrated that catabolism of stable adipocytes required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system and catecholamines. Instead, concurrent hypoglycaemia and hypoinsulinaemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors including G0s2. This was also sufficient to delipidate classical adipose depots and was recapitulated in tumour-associated cachexic mice. Overall, this defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent catecholamine-independent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
    DOI:  https://doi.org/10.1038/s42255-025-01424-5
  10. Commun Biol. 2026 Jan 08.
    Multimodal epigenetic and enhancer network remodeling shape the transcriptional landscape of human beige adipocytes.
    Sarah Hazell Pickering, Natalia M Galigniana, Mohamed Abdelhalim, Anita L Sørensen, Julia Madsen-Østerbye, Manuela Zucknick, Philippe Collas, Nolwenn Briand.
      Epigenetic regulation is a key determinant of adipocyte fate, driving the differentiation toward white or thermogenic beige phenotypes in response to environmental cues. To dissect the mechanisms orchestrating this plasticity in human adipocytes, we conducted an integrative analysis of transcriptomic, epigenomic and enhancer connectome dynamics throughout white and beige adipogenesis. Using a machine learning approach, we show that the white transcriptional program is tightly linked to promoter-level modulation of H3K27ac and chromatin accessibility, whereas the beige-specific induction of mitochondrial genes is driven by promoter remodeling of H3K4me3, underscoring distinct epigenetic mechanisms for white or beige specification. Adipocyte beiging is accompanied by a targeted reorganization of the 3D genome, characterized by increased recruitment of short-range enhancers controlling thermogenesis genes, enriched for C/EBP transcription factor binding sites. Our findings highlight the multimodal regulation of the beige adipocyte fate, driven by the interplay of chromatin state transitions, enhancer rewiring, and transcription factor dynamics.
    DOI:  https://doi.org/10.1038/s42003-025-09469-8
  11. Postepy Biochem. 2025 12 16. 71(4): 369-382
    Mitochondrial DNA Methylation: Existence, Localization, and Function
    Laura Łuczak, Katarzyna Tońska.
      Epigenetic regulation of gene expression is an intensively studied area of molecular biology. It includes cytosine methylation, whose mechanism of action in nuclear DNA is relatively well understood. This process is mediated by enzymes from the DNA methyltransferase family. Hydroxymethylation is, considered both an intermediate step in cytosine demethylation and a potentially independent mechanism of regulation of gene expression. Functional significance—and even the presence—of methylation within mitochondrial DNA (mtDNA) remains a matter of debate. Accumulated evidence indicates that methylation and hydroxymethylation may play important role in mitochondria. Although epigenetic regulation of gene expression in mitochondria is not yet fully understood, the current state of knowledge suggests that it may influence proper cellular function and the pathogenesis of numerous diseases.
    DOI:  https://doi.org/10.18388/pb.2021_632
  12. Cell Death Dis. 2026 Jan 07. 17(1): 5
    GIPC2 regulation of the PKM2/SREBP1 signaling axis controls adipogenic differentiation of mesenchymal stem cells.
    Jiayi Wang, Chengqi Xin, Zhaokai Sun, Mengke Zhao, Yaoyao Zan, Zhongyue Lv, Shuaiyu Zhu, Jing Liu, Liang Wang.
      Mesenchymal stem cell (MSC) differentiation is a cornerstone of regenerative medicine with a wide range of applications in tissue engineering and translational therapies. However, the molecular mechanisms underlying MSC differentiation remain incompletely understood, preventing the full leveraging of their therapeutic potential. Central to these complex molecular networks are dynamic protein-protein interactions, with scaffolding proteins serving as master coordinators. GAIP-interacting protein C-terminus 2 (GIPC2) functions as an adaptor protein involved in mediating such interactions and may influence MSC fate by regulating differentiation-related signaling pathways. In this study, we identified GIPC2 as a novel regulator of adipogenic differentiation in human umbilical cord-derived MSCs (UC-MSCs). Mechanistically, GIPC2 interacts directly with pyruvate kinase M2 (PKM2) via its PDZ domain, promoting PKM2 nuclear translocation. In the nucleus, PKM2 facilitates the activation of sterol regulatory element-binding protein 1 (SREBP1), a transcription factor essential for lipid biosynthesis and adipocyte maturation. Our findings show that GIPC2 drives MSC adipogenic differentiation by orchestrating the PKM2-SREBP1 signaling axis. This study reveals a previously unrecognized regulatory mechanism, highlighting the pivotal role of GIPC2 at the intersection of metabolic regulation and transcriptional control. These insights not only deepen our understanding of MSC differentiation but also open new avenues for enhancing MSC-based therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41419-025-08088-9
  13. Nat Commun. 2026 Jan 08. 17(1): 44
    Epigenetic aging and lifespan reflect reproductive history in the Finnish Twin Cohort.
    Mikaela Hukkanen, Anna Kankaanpää, Aino Heikkinen, Jaakko Kaprio, Robin Cristofari, Miina Ollikainen.
      Reproductive history is closely linked to health, yet its relationship with biological aging and survival remains uncertain. We investigated this in the Finnish Twin Cohort, a population-based study that enables modeling of full childbearing history while controlling for common risk factors, through questionnaires and civil registries. We model the association between reproductive trajectories and survival in 14,836 women, and assess biological aging in a subset of 1054 participants using the PCGrimAge, an algorithm trained to predict biological aging and mortality risk from DNA methylation. We identify six distinct reproductive trajectories describing different timing and number of childbearing events. Women with the most live births throughout their lives (mean 6.8, SD 2.4) and nulliparous women showed accelerated aging and elevated mortality risk. These findings support the disposable soma theory of aging in modern humans, and provide valuable insights into the genetic and lifestyle-related determinants of lifespan.
    DOI:  https://doi.org/10.1038/s41467-025-67798-y
  14. Cell Metab. 2026 Jan 06. pii: S1550-4131(25)00537-6. [Epub ahead of print]38(1): 12-13
    Benign form of monogenic obesity conferred by the melanocortin 4 receptor.
    Anke Hinney, Triinu Peters, Luisa Sophie Rajcsanyi.
      Mutations that impair the function of the melanocortin 4 receptor (MC4R) cause severe obesity in both heterozygous and homozygous carriers. However, recent findings indicate that individuals with this form of monogenic obesity may be unexpectedly protected against dyslipidemia and cardiovascular diseases.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.006
  15. J Cell Sci. 2026 Jan 01. pii: jcs263847. [Epub ahead of print]139(1):
    Mitochondrial dynamics and signaling in stem cell differentiation.
    Rahul Kumar Verma, Somya Madan, Richa Rikhy.
      Mitochondrial dynamics are defined by the continuous processes of fusion and fission that regulate mitochondrial shape, distribution and activity. They are also involved in cellular functions of mitochondria, such as energy production, metabolic adaptation, apoptosis and cellular stress responses. Consequently, these organelle dynamics play a crucial role in development, growth, differentiation and disease. Mitochondrial morphology is controlled by Drp1 (also known as DNM1L) and Fis1, which drive fission, whereas Opa1, Mfn1 and Mfn2 mediate fusion. The transcription, activation and degradation of these proteins are often regulated by signaling cascades that are crucial for stem cell maintenance and differentiation. In turn, mitochondrial dynamics regulate key outcomes of these pathways. We explore the interplay between mitochondrial fusion and fission proteins and such signaling pathways, including Notch, receptor tyrosine kinase, JNK, Hippo and mTOR signaling, finding that stem cell renewal and differentiation states are dependent on the regulation of signaling pathways by mitochondrial morphology and activity. Overall, this Review highlights how mitochondrial morphology and activity crucially regulate stem cell division for renewal and differentiation, examining their impact across diverse systems.
    Keywords:  Drp1; Marf; Mfn; Mitochondria; Opa1; Signaling; Stem cells
    DOI:  https://doi.org/10.1242/jcs.263847
  16. EBioMedicine. 2026 Jan 05. pii: S2352-3964(25)00562-6. [Epub ahead of print]123 106112
    The rs713586 risk variant dysregulates ADCY3 rather than DNAJC27, leading to obesity through ZFP42-TET1-mediated DNA methylation.
    Weina Wang, Yuwei Liu, Sheng Dong, Xiaoman Wu, Fei Zhang, Xizhi Wang, Xueying Zhang, Xiaoyu Hu, Zhenshan Wang.
       BACKGROUND: Human genetic analyses have identified numerous single-nucleotide polymorphism (SNP) loci in noncoding regions associated with obesity-related traits; however, the functional contributions of such SNP loci to obesity are largely unknown. The noncoding variant rs713586, with its risk allele C, is linked to two candidate genes, DNAJC27 and ADCY3, potentially implicated in obesity. However, whether rs713586 primary targets ADCY3 or DNAJC27 gene to regulate body weight and what molecular mechanisms underlie this process remain unclear.
    METHODS: We conducted bioinformatics analyses using BMI data from the UK biobank and GIANT consortium, and prioritised functional variants on chromosome 2 linked to ADCY3 gene for experimental validation. The variant rs713586 was identified as a functional regulator of ADCY3 and DNAJC27 expression. We investigated the molecular mechanisms by which rs713586 participates in obesity through epigenetic regulation. Dual-luciferase reporter assay and genome-editing in cell lines were conducted to assess the impacts of the rs713586-C risk allele or a proximal enhancer (Enh) on ADCY3 and DNAJC27 promoter activity and expression levels. CRISPR/Cas9-mediated knockout of Dnajc27 was performed in mice to evaluate its role in obesity. Mechanistic studies examined the interactions between the rs713586-T or -C alleles and the transcription factor ZFP42. Additionally, we assessed the DNA methylation patterns within the Enh and promoter regions of ADCY3 to evaluate their impact on ADCY3 expression.
    FINDINGS: First, the rs713586-C risk allele significantly reduced the promoter activity of ADCY3 and DNAJC27 and thus reduced their expression levels. However, Dnajc27 knockout mice did not develop obesity, thereby excluding DNAJC27 as the target gene through which rs713586 mediates obesity. Further, we demonstrate that the rs713586-C allele impaired ZFP42 binding, leading to decreased TET1 recruitment and increased DNA methylation in the Enh and promoter regions of ADCY3, ultimately suppressing its expression. Given that ADCY3 is a well-established gene involved in obesity, we conclude that the rs713586-C risk allele may associated with obesity susceptibility, concomitant with downregulated ADCY3 expression.
    INTERPRETATION: Our findings establish the rs713586-ZFP42-TET1-ADCY3 epigenetic regulatory axis, providing insights into the mechanism of rs713586-mediated obesity pathogenesis.
    FUNDING: National Natural Science Foundation of China and Natural Science Foundation of Hebei Province of China (32470645, 32070567, 32202840), and Priority-Funded Postdoctoral Research Project, Zhejiang Province (ZJ2025118). Full funding details are provided in the Acknowledgements.
    Keywords:  ADCY3; DNAJC27; Methylation; Obesity; rs713586
    DOI:  https://doi.org/10.1016/j.ebiom.2025.106112
  17. Nat Commun. 2026 Jan 08.
    Time-resolved multiomics profiling reveals chromatin O-GlcNAc modification promotes senescence-associated transcriptional program.
    Nana Zhang, Ran Zhao, Xiaomin Zhong, Qian Dong, Yajie Liu, Kairan Yu, Lirui Han, Fanxu Meng, Jiaxuan Wu, Qiushi Chen, Xuechen Li, Qingbin Chen, Keren Zhang, Huang Huang, Jianing Zhang, Sijin Wu, Yan Ren, Wei Wang, Yubo Liu.
      O-GlcNAc modification is a key cellular signal, but its role in regulating senescence-associated transcription remains poorly understood. Here, we apply a time-resolved chemical genomics strategy to map dynamic O-GlcNAc chromatin-associated proteins (OCPs) during oncogene-induced senescence (OIS) in primary human fibroblasts. Chromatin O-GlcNAc modification continues to accumulate, while 1,987 senescence-associated OCPs undergo dynamic shifts in genomic occupancy across diverse epigenetic chromatin states and display bimodal regulatory activities within the 3,466-gene senescence transcriptome. O-GlcNAc facilitates the formation of dual-function complexes: TF-SWI/SNF activates senescence-associated secretory phenotype (SASP) genes at promoters, whereas NuRD enforces the repression of cell-cycle regulators at enhancers. Furthermore, we identify O-GlcNAc modified JUN and GATAD2A as key regulators of OIS phenotypes in both in vitro and in vivo models of senescence-driven tumorigenesis. These findings reveal dynamic regulation and chromatin organization principles of O-GlcNAc-related epigenetic factors, providing insights into cellular senescence and potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-68143-z
  18. Sci Adv. 2026 Jan 09. 12(2): eady0301
    Nat10-mediated ac4C epitranscriptomics orchestrates hematopoietic stem/progenitor cell fate determination via translation control.
    Feng Huang, Yushuai Wang, Weiwei Gao, Xiuxin Zhang, Jiajia Zhou, Ying Yang, Hongjie Mo, Minhan Wang, Qi Chen, Guangdun Peng, Jianjun Chen, Huilin Huang, Hengyou Weng.
      Epigenetic regulation is crucial for balancing hematopoietic stem cell (HSC) self-renewal and differentiation, thereby maintaining hematopoietic homeostasis. Although Nat10-mediated RNA ac4C modification has been implicated in malignant hematopoiesis, its role in normal hematopoiesis remains unexplored. Here, we developed ULAC-seq to map ac4C in rare hematopoietic stem/progenitor cells (HSPCs) and revealed dynamic, cell-type-specific ac4C patterns, peaking in megakaryocyte-erythroid progenitors (MEPs), correlating with elevated Nat10 expression. Nat10 knockout disrupts HSC self-renewal and arrests MEP differentiation, leading to fetal and postnatal hematopoietic failure. Mechanistically, Nat10 deposits ac4C on mRNAs encoding key hematopoietic transcription regulators (e.g., Nfix), thereby enhancing their translation. Nat10 loss reduces Nfix protein levels and suppresses expression of its target genes (e.g., Mpl) that govern HSPC fate, while Nfix reconstitution rescues colony-forming defects in Nat10-null HSPCs. Our findings reveal that Nat10 orchestrates hematopoiesis through ac4C-dependent translational control of transcriptional factors, establishing an epitranscriptome-transcriptome regulatory axis essential for HSC maintenance and function.
    DOI:  https://doi.org/10.1126/sciadv.ady0301
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