bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–02–08
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice.
  2. Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations.
  3. PRMT3-mediated post-translational adaptation to fasting regulates metabolic flexibility.
  4. Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
  5. Regulation of STING activation by phosphoinositide and cholesterol.
  6. Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
  7. Age and sex influence transcriptomic responses to statin therapy that control liver aging during systemic metabolic dysfunction.
  8. Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
  9. NAD+ sensing by PARP7 regulates the C/EBPβ-dependent transcription program during adipogenesis.
  10. Mitochondrial superoxide signals shield the nucleus to delay ageing.
  11. Single-cell exon deletion profiling reveals splicing events that shape gene expression and cell state dynamics.
  1. Apoptosis. 2026 Feb 02. 31(2): 63
    SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice.
    Chenxi Xiao, Zhenghua Su, Jialin Zhao, Yajie Hu, Mengting He, Shenhan Xu, Ruoxue Chen, Jie Xu, Jun Chang, Chengshou Lin, Xinhua Liu, Wugui Chen.
      Beige adipocytes play a key role in non-shivering thermogenesis. SEMA3E, a member of the class 3 semaphorin family, is involved in various pathological processes, but its role in adipocyte differentiation and thermogenesis remains unclear. Here, we found SEMA3E expression increased in inguinal white adipose tissue (iWAT) following cold exposure or β-adrenergic agonist CL316,243 stimulation. In vitro, loss- and gain-of-function experiments revealed that SEMA3E promoted beige adipocyte differentiation and enhanced thermogenic genes expression. In vivo, fat transplantation experiments indicated that SEMA3E promoted adipogenesis. Furthermore, adeno-associated virus (AAV)-mediated SEMA3E knockdown in iWAT impaired thermogenesis in mice exposed to cold or CL316,243. RNA-Seq analysis linked SEMA3E to mitochondrial oxidative phosphorylation, and its knockdown reduced mitochondrial respiration by downregulating respiratory chain components expression and lowering mitochondrial oxygen consumption rate. Mechanistically, gene set enrichment analysis suggested SEMA3E regulated beige adipocyte differentiation via the Wnt/β-catenin pathway. SEMA3E knockdown delayed β-catenin degradation, while inhibiting this pathway with IWR-1 rescued the suppressed differentiation and thermogenic genes expression. In conclusion, these findings highlight the crucial role of SEMA3E in beige adipocyte differentiation and thermogenesis.
    Keywords:  Beige adipocyte; Differentiation; SEMA3E; Thermogenesis; β-catenin
    DOI:  https://doi.org/10.1007/s10495-026-02276-4
  2. Nat Commun. 2026 Feb 06.
    Whole-genome sequencing analysis of anthropometric traits in 672,976 individuals reveals convergence between rare and common genetic associations.
    Gareth Hawkes, Harrison I W Wright, Robin N Beaumont, Kartik Chundru, Aimee Hanson, Leigh Jackson, Anna Murray, Kashyap Patel, Timothy M Frayling, Caroline F Wright, Andrew R Wood, Michael N Weedon.
      GWAS have generally focused on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we use whole-genome sequencing data to evaluate the contribution to and architecture of rare non-coding variants for three commonly studied anthropometric traits: height, BMI and waist-hip ratio adjusted for BMI. Analysing 447,461 individuals in the UK Biobank for discovery and 225,515 individuals in All of Us for replication, we identify 90 rare and low-frequency single variant associations, including two independent rare variants upstream of IGF2BP2 that substantially reduce waist-hip ratio adjusted for BMI, but have distinct effects on other adiposity traits. We further identify 135 coding variant aggregates. For example, UBR3 protein-truncating variants are associated with a 2.7 kg/m2 increase in BMI. We additionally identify 51 non-coding variant aggregate associations, including one in the 5'UTR of FGF18 associated with up to 6 cm effects on height. We show that 97% of rare variant associations occur near GWAS-identified loci, demonstrating convergence of rare and common variant associations. Finally, we show that ultra rare variants explain a small fraction of heritability compared to common variants for these traits, that heritability is largely shared across ancestries, and that it concentrates around common variant loci.
    DOI:  https://doi.org/10.1038/s41467-026-69208-3
  3. Nat Commun. 2026 Feb 02.
    PRMT3-mediated post-translational adaptation to fasting regulates metabolic flexibility.
    Zhengyun Huang, Xiangpeng Liu, Xiyue Chen, You Zhou, Qian Chen, Yan Liu, Hongyun Zhu, Ken Cheng, Yu Feng, Miren Dong, Linsheng Song, Lingling Wang, Shiqi Liu, Tizhong Shan, Shihuan Kuang, Yingying Dong, Antonio Vidal-Puig, Yong Zhang, Zhihao Jia.
      Obesity impairs metabolic flexibility-the capacity to adapt to fluctuating energy demands. Emerging evidence suggests that dietary interventions, particularly time-restricted feeding (TRF), may help restore this flexibility. In this study, we demonstrate that feeding upregulates PRMT3 and asymmetric dimethylarginine (ADMA)-containing proteins via insulin-pAKT signaling, while fasting reduces their expression. Pharmacological inhibition of PRMT3 attenuates diet-induced obesity (DIO) and enhances adipocyte glycolysis in male mice. Mechanistically, PRMT3 drives the expression of citrate transporter SLC25A1 during feeding through direct arginine methylation. A 16:8 TRF regimen normalizes PRMT3 and ADMA levels while suppressing SLC25A1 expression. Notably, PRMT3 inhibition recapitulates the metabolic benefits of 16:8 TRF and improves metabolic flexibility. Furthermore, adipocyte-specific deletion of Slc25a1 in male mice protects against DIO and enhances insulin sensitivity. Collectively, these findings identify PRMT3-mediated arginine methylation in vWAT as a nutrient-responsive regulatory axis that impairs metabolic flexibility in obesity, which is a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-68883-6
  4. Cell Metab. 2026 Feb 03. pii: S1550-4131(26)00003-3. [Epub ahead of print]38(2): 257-259
    Lactate-driven mitochondrial pretenders hijack hippocampal function after excessive exercise.
    Filip J Larsen.
      Huang et al.1 show a J-shaped relationship between vigorous activity and cognitive decline, with maximal benefit ∼1,000-1,300 MET-min/week and harm with excessive exercise. Using UK Biobank data, mechanistic models, and an RCT, they implicate lactate-driven mitochondria-derived vesicles that reach the hippocampus, disrupt synapses, and impair cognition.
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.003
  5. Nature. 2026 Feb 04.
    Regulation of STING activation by phosphoinositide and cholesterol.
    Jie Li, Jay Xiaojun Tan, Zhijian J Chen, Xuewu Zhang, Xiao-Chen Bai.
      Stimulator of interferon genes (STING) is an essential adaptor in the cytosolic DNA-sensing innate immune pathway1. STING is activated by cyclic GMP-AMP (cGAMP) produced by the DNA sensor cGAMP synthase (cGAS)2-5. cGAMP-induced high-order oligomerization and translocation of STING from the endoplasmic reticulum to the Golgi and post-Golgi vesicles are critical for STING activation6-11. Other studies have shown that phosphatidylinositol phosphates (PtdInsPs) and cholesterol also have important roles in STING activation, but the underlying mechanisms remain unclear12-17. Here we demonstrate that cGAMP-induced high-order oligomerization of STING is enhanced strongly by phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2 and PtdIns(4,5)P2, and by PtdIns4P to a lesser extent. Our cryo-electron microscopy structures reveal that PtdInsPs together with cholesterol bind at the interface between STING dimers, directly promoting the high-order oligomerization. The structures also provide an explanation for the preference of the STING oligomer to different PtdInsPs. Mutational and biochemical analyses confirm the binding modes of PtdInsPs and cholesterol and their roles in STING activation. Our findings shed light on the regulatory mechanisms of STING mediated by specific lipids, which may underlie the role of intracellular trafficking in dictating STING signalling.
    DOI:  https://doi.org/10.1038/s41586-025-10076-0
  6. Cell Death Dis. 2026 Feb 02. 17(1): 195
    Reversible arginine methylation regulates mitochondrial IDH2 activity: coordinated control by CARM1 and KDM3A/4A.
    Yena Cho, Jessica Winarto, Dae-Geun Song, Dong Hee Na, Kyo Bin Kang, Su-Nam Kim, Yong Kee Kim.
      Mitochondria are essential for cellular homeostasis, supplying key metabolites and energy. While post-translational modifications regulate mitochondrial enzymes, their roles remain less explored compared to those in the nucleus and cytoplasm. Here, we demonstrate that reversible arginine methylation governs the activity of several mitochondrial enzymes, with a particular focus on isocitrate dehydrogenase 2 (IDH2). We identify coactivator-associated arginine methyltransferase 1 (CARM1) as a mitochondrial enzyme that asymmetrically dimethylates IDH2 at R188, leading to enzymatic inhibition while enhancing protein stability. This modification is dynamically reversed by the lysine demethylases KDM3A and KDM4A, which restore IDH2 activity. Notably, despite its reduced stability, demethylated IDH2 promotes α-ketoglutarate production, enhancing mitochondrial membrane potential and oxygen consumption. These findings highlight the critical role of reversible arginine methylation in fine-tuning mitochondrial enzyme function and maintaining mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41419-026-08444-3
  7. Hepatology. 2026 Feb 02.
    Age and sex influence transcriptomic responses to statin therapy that control liver aging during systemic metabolic dysfunction.
    David S Umbaugh, Liuyang Wang, Kuo Du, Rajesh Kumar Dutta, Seh Hoon Oh, Georgia Sofia Karachaliou, Manal F Abdelmalek, Ayako Suzuki, Anna Mae Diehl.
       BACKGROUND AND AIMS: Older age increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined.
    APPROACH AND RESULTS: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use strongly associated with suppression of senescence-related pathways. Statin use also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort.
    CONCLUSIONS: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.
    Keywords:  MASLD; Statins; ferroptosis; senescence
    DOI:  https://doi.org/10.1097/HEP.0000000000001704
  8. Cell Metab. 2026 Jan 29. pii: S1550-4131(26)00001-X. [Epub ahead of print]
    Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML.
    Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T Jordan, Tong-Jin Zhao, Haobin Ye.
      Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.
    Keywords:  NAD(+); OGDH complex; SLC25A51; leukemia; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.001
  9. Cell Rep. 2026 Jan 30. pii: S2211-1247(26)00007-0. [Epub ahead of print]45(2): 116929
    NAD+ sensing by PARP7 regulates the C/EBPβ-dependent transcription program during adipogenesis.
    MiKayla S Stokes, Yoon Jung Kim, Yonghyeon Kim, Sneh Koul, Shu-Ping Chiu, Chenqian Liu, Morgan Dasovich, Josue Zuniga, Tulip Nandu, Dan Huang, Thomas P Mathews, Ashley Solmonson, Cristel V Camacho, W Lee Kraus.
      We identified poly(ADP-ribose) polymerase 7 (PARP7), a mono(ADP-ribosyl) transferase, as a regulator of C/EBPβ-dependent proadipogenic gene expression. PARP7 functions as a nuclear NAD+ sensor; at higher nuclear NAD+ concentrations in undifferentiated preadipocytes, PARP7 is catalytically active for auto-mono(ADP-ribosyl)ation (autoMARylation). As nuclear NAD+ concentrations decline upon differentiation, autoMARylation decreases dramatically. AutoMARylation promotes instability of PARP7 through an E3 ligase-ubiquitin-proteasome pathway mediated by the ubiquitin E3 ligases DTX2 and RNF114, which ubiquitylate MARylated PARP7. Stabilized PARP7 serves as a coregulator of C/EBPβ by stimulating p300-mediated histone H3 lysine 27 acetylation and the binding of C/EBPβ across the genome. Genetic depletion of PARP7 in mice promotes decreased body weight in mice fed a high-fat diet, reduced fat mass, inhibition of adipogenesis during mammary gland involution, and a reduction in lipid synthesis. Collectively, our results extend the biology of PARP7 to adipogenesis and elucidate the molecular mechanisms underlying a PARP7-p300-H3K27ac-C/EBPβ pathway for proadipogenic gene regulation.
    Keywords:  ADP-ribosylation; C/EBPβ; CP: metabolism; CP: molecular biology; H3 lysine 27 acetylation; MART; NAD(+); PARP7; adipogenesis; mono(ADP-ribosyl)transferase; p300; transcription; ubiquitylation
    DOI:  https://doi.org/10.1016/j.celrep.2026.116929
  10. Nat Metab. 2026 Feb 03.
    Mitochondrial superoxide signals shield the nucleus to delay ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01461-8
  11. Nat Commun. 2026 Feb 03. 17(1): 1218
    Single-cell exon deletion profiling reveals splicing events that shape gene expression and cell state dynamics.
    Bandana Kumari, Arun Prasath Damodaran, Wilfried M Guiblet, Mei-Sheng Xiao, Amit K Behera, Tyler A On, Carl E McIntosh, Maxwell Teszler, Chelsee Holloway, Sandra Le, Nikhil Parab, Yongmei Zhao, Michael Aregger, Thomas Gonatopoulos-Pournatzis.
      Alternative splicing is a pervasive gene regulatory mechanism critical for diversifying the human proteome. To systematically investigate its role in cell fate determination, we develop scCHyMErA-Seq, a scalable CRISPR-based exon deletion screening platform integrated with 10x Genomics single-cell transcriptomic readouts. This tool enables efficient exon deletion while simultaneously capturing Cas9/Cas12a guides and polyadenylated transcripts at single-cell resolution. Applying scCHyMErA-Seq to high-throughput profiling of alternative cassette exons, we identify numerous exons with pronounced regulatory effects on gene expression and cell cycle progression. Analysis of the alternative NRF1 exon-7 demonstrates that its inclusion modulates NRF1's regulatory function by influencing its recruitment to the promoters of target genes. Importantly, gene expression profiles generated using scCHyMErA-Seq accurately recapitulate findings from traditional, labor-intensive orthogonal methods, while offering enhanced scalability and efficiency. Overall, scCHyMErA-Seq represents a versatile platform for systematically unraveling the functional impact of alternative splicing by directly linking specific splicing variants to transcriptional phenotypes.
    DOI:  https://doi.org/10.1038/s41467-026-68774-w
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