bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–02–01
eight papers selected by
Xiong Weng, University of Edinburgh
  1. Dnmt3b Deficiency in Adipocyte Progenitor Cells Ameliorates Obesity in Female Mice.
  2. Pan-Epigenetic Age Prediction in Mammals.
  3. Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
  4. Bempedoic acid directly binds and activates PPARα.
  5. Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
  6. PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation.
  7. A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis.
  8. DNMT1 Facilitates the Progression of MASLD by Impeding Transcription Mediated by HNF4α and PPARα.
  1. Int J Mol Sci. 2026 Jan 15. pii: 861. [Epub ahead of print]27(2):
    Dnmt3b Deficiency in Adipocyte Progenitor Cells Ameliorates Obesity in Female Mice.
    Yifei Huang, Sean Yu, Qiang Cao, Weiqing Tang, Jia Jing, Bingzhong Xue, Hang Shi.
      Obesity arises from chronic energy imbalance, where energy intake exceeds energy expenditure. Emerging evidence supports a key role of DNA methylation in the regulation of adipose tissue development and metabolism. We have recently discovered a key role of DNA methylation, catalyzed by DNA methyltransferase 1 or 3a (Dnmt1 or 3a), in the regulation of adipocyte differentiation and metabolism. Here, we aimed to investigate the role of adipose progenitor cell Dnmt3b-an enzyme mediating de novo DNA methylation-in energy metabolism and obesity. We generated a genetic model with Dnmt3b knockout in adipocyte progenitor cells (PD3bKO) by crossing Dnmt3b floxed mice with Platelet-derived growth factor receptor alpha (PDGFRα) Cre mice. Dnmt3b deletion in adipocyte progenitors enhanced thermogenic gene expression in brown adipose tissue, increased overall energy expenditure, and mitigated high-fat diet (HFD)-induced obesity in female mice. PD3bKO mice also displayed a lower respiratory exchange ratio (RER), indicative of a metabolic shift favoring fat utilization as an energy source. Furthermore, female PD3bKO mice exhibited improved insulin sensitivity alongside their lean phenotype. In contrast, male PD3bKO mice showed no changes in body weight but demonstrated decreased insulin sensitivity, revealing a sexually dimorphic metabolic response to Dnmt3b deletion in adipose progenitor cells. These findings underscore the critical role of Dnmt3b in regulating energy homeostasis, body weight, and metabolic health, with significant implications for understanding sex-specific mechanisms of obesity and metabolism.
    Keywords:  DNA methylation; Dnmt3b; obesity
    DOI:  https://doi.org/10.3390/ijms27020861
  2. Aging Cell. 2026 Feb;25(2): e70380
    Pan-Epigenetic Age Prediction in Mammals.
    Zane Koch, Adam Li, Trey Ideker.
      Epigenetic remodeling is a hallmark of aging, yet which epigenetic layers are most affected during aging-and the extent to which they are interrelated-is not well understood. Here, we perform a comprehensive analysis of epigenetic aging encompassing 6 histone marks and DNA methylation measured across 12 tissues from > 1000 humans and mice. We identify a synchronized pattern of age-related changes across these epigenetic layers, with all changes converging upon a common set of genes. Notably, an epigenetic clock based on these genes can accurately predict age using data from any layer (Spearman ρ: 0.70 in humans, 0.81 in mice). Applying this "pan-epigenetic" clock, we observe that histone modification and DNA methylation profiles agree in the prediction of which individuals are aging more rapidly or slowly. These results demonstrate that epigenetic modifications are subject to coordinated remodeling over the lifespan, offering a unified view of epigenetic aging.
    DOI:  https://doi.org/10.1111/acel.70380
  3. Science. 2026 Jan 29. 391(6784): 504-510
    Heritability of intrinsic human life span is about 50% when confounding factors are addressed.
    Ben Shenhar, Glen Pridham, Thaís Lopes De Oliveira, Naveh Raz, Yifan Yang, Joris Deelen, Sara Hägg, Uri Alon.
      How heritable is human life span? If genetic heritability is high, longevity genes can reveal aging mechanisms and inform medicine and public health. However, current estimates of heritability are low-twin studies show heritability of only 20 to 25%, and recent large pedigree studies suggest it is as low as 6%. Here we show that these estimates are confounded by extrinsic mortality-deaths caused by extrinsic factors such as accidents or infections. We use mathematical modeling and analyses of twin cohorts raised together and apart to correct for this factor, revealing that heritability of human life span due to intrinsic mortality is above 50%. Such high heritability is similar to that of most other complex human traits and to life-span heritability in other species.
    DOI:  https://doi.org/10.1126/science.adz1187
  4. Cell Metab. 2026 Jan 26. pii: S1550-4131(25)00549-2. [Epub ahead of print]
    Bempedoic acid directly binds and activates PPARα.
    Christina Papa, Alina Rose, Hugo N G Martin, Abibe Useini, Florian Geier, Longsheng Liao, Jesús Rafael Rodríguez-Aguilera, Philipp Valina-Allo, Anne Hoffmann, Andrey Tvardovskiy, Faiqa Zulfqar, Andrea Zimmerman, Gerda Schicht, Fritzi Ott, Christiane Körner, Beatrice Engelmann, Ulrike Rolle-Kampczyk, Martin von Bergen, Matthias Meier, Till Bartke, Daniel Seehofer, Nora Klöting, Madlen Matz-Soja, Georg Damm, Jes-Niels Boeckel, Joerg M Buescher, Matthias Blüher, Ulrich Laufs, Olga Bondareva, Norbert Sträter, Georg Künze, John T Heiker, Bilal N Sheikh.
      Bempedoic acid (BA) is a recently approved drug that lowers cholesterol and hepatic lipids, yet its mechanism of action remains incompletely understood. Here, we combine transcriptomic, biochemical, and structural approaches to show that BA directly binds to and activates peroxisome proliferator-activated receptor alpha (PPARα). BA treatment robustly induced PPARα signaling and fatty acid oxidation in primary hepatocytes and mouse liver. Through X-ray crystallography, we uncovered that BA binds to the ligand-binding domain of PPARα and stabilizes its active conformation. BA activated PPARα target genes independently of very-long-chain acyl-coenzyme A (CoA) synthetase (ACSVL1), the liver-enriched enzyme that converts BA to its bempedoyl-CoA form. Notably, BA-mediated induction of fatty acid oxidation required PPARα. Together, this work reveals direct PPARα activation as a key mechanism of BA action, providing a molecular basis for its lipid-lowering effects and suggesting broader therapeutic potential beyond the liver.
    Keywords:  PPAR; cardiovascular; cholesterol; lipids; metabolism; transcription
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.018
  5. Nat Aging. 2026 Jan 29.
    Comparative analysis of senolytic drugs reveals mitochondrial determinants of efficacy and resistance.
    Masahiro Wakita, Koyu Ito, Kaho Fujii, Dai Sakamoto, Takumi Mikawa, Sho Sugawara, Xiangyu Zhou, Jeong Hoon Park, Hideka Miyagawa, Daisuke Motooka, Emi Ogasawara, Naotada Ishihara, Akiko Takahashi, Hiroshi Kondoh, Eiji Hara.
      Cellular senescence contributes to aging and disease, and senolytic drugs that selectively eliminate senescent cells hold therapeutic promise. Although over 20 candidates have been reported, their relative efficacies remain unclear. Here we systematically compared 21 senolytic agents using a senolytic specificity index, identifying the Bcl-2 inhibitor ABT263 and the BET inhibitor ARV825 as most effective senolytics across fibroblast and epithelial senescence models. However, even upon extended treatment with these most potent senolytics, a proportion of senescent cells remained viable. We found that senolytic resistance was driven by maintenance of mitochondrial integrity through V-ATPase-mediated clearance of damaged mitochondria. Imposing mitochondrial stress via metabolic workload enhanced the senolytic efficacies of ABT263 and ARV825 in vitro, and in mouse models, ketogenic diet adoption or SGLT2 inhibition similarly potentiated ABT263-induced and ARV825-induced senolysis, reducing metastasis and tumor growth. These findings suggest that mitochondrial quality control is a key determinant of resistance to ABT263-induced and ARV825-induced senolysis, providing a possible framework for rational combination senotherapies.
    DOI:  https://doi.org/10.1038/s43587-025-01057-z
  6. Adv Sci (Weinh). 2026 Jan 29. e23139
    PIK3CA Mutations Downregulate PPT1 to Promote Adipogenesis by Suppressing P300 Depalmitoylation and Phase Separation.
    Hongrui Chen, Zening Huang, Rui Chang, Wei Gao, Yajing Qiu, Bin Sun, Chen Hua, Xiaoxi Lin.
      PIK3CA mutations drive benign adipose overgrowth in facial infiltrating lipomatosis (FIL), but the downstream molecular mechanisms remain incompletely understood. This study investigated the role of palmitoyl-protein thioesterase 1 (PPT1)-mediated depalmitoylation in regulating aberrant adipogenesis induced by mutant PIK3CA. Using single-cell RNA-seq, molecular dynamics simulations, and functional assays in primary human FIL adipose-derived stem and progenitor cells (ASPCs), immortalized cell lines, and mouse models, we dissected the signaling pathway linking PIK3CA mutation to adipogenesis. Techniques included ChIP-qPCR, acyl-biotin exchange assays, luciferase reporter assays, and RNA/ATAC sequencing. PIK3CA mutations transcriptionally repressed PPT1 via PI3K-AKT-c-JUN signaling. Downregulated PPT1 enhanced palmitoylation of the transcriptional coactivator P300 at C1176. This modification stabilized P300 by impairing its interaction with HSC70 and subsequent chaperone-mediated lysosomal degradation. Furthermore, C1176 palmitoylation inhibited P300 phase separation, thereby preserving its histone acetyltransferase activity. Sustained P300 activity promoted chromatin accessibility and expression of adipogenic genes, driving excessive adipogenesis in FIL. These findings established a novel "palmitoylation-phase separation-epigenetic regulation" axis in cellular fate determination and revealed PPT1 and P300 as potential therapeutic targets for FIL.
    Keywords:  PIK3CA; adipogenesis; palmitoylation; phase separation
    DOI:  https://doi.org/10.1002/advs.202523139
  7. Cell. 2026 Jan 28. pii: S0092-8674(25)01478-3. [Epub ahead of print]
    A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis.
    Gabriella N L Chua, Emily C Beckwitt, Victoria Miller-Browne, Olga Yurieva, Dan Zhang, Bryce J Katch, Nina Y Yao, John W Watters, Kaitlin Abrantes, Ryogo Funabiki, Xiaolan Zhao, Michael E O'Donnell, Shixin Liu.
      The ring-shaped sliding clamp proliferating cell nuclear antigen (PCNA) enables DNA polymerases to perform processive DNA synthesis during replication and repair. The loading of PCNA onto DNA is catalyzed by the ATPase clamp-loader replication factor C (RFC). Using a single-molecule platform to visualize the dynamic interplay between PCNA and RFC on DNA, we unexpectedly discovered that RFC continues to associate with PCNA after loading, contrary to the conventional view. Functionally, this clamp-loader/clamp (CLC) complex is required for processive DNA synthesis by polymerase ẟ (Polẟ), as the PCNA-Polẟ assembly is inherently unstable. This architectural role of RFC is dependent on the BRCA1 C-terminal homology (BRCT) domain of Rfc1, and mutation of its DNA-binding residues causes sensitivity to genotoxic stress in vivo. We further showed that flap endonuclease I (FEN1) can also stabilize the PCNA-Polẟ interaction and mediate robust synthesis. Overall, our work revealed that, beyond their canonical enzymatic functions, PCNA-binding proteins harbor non-catalytic functions important for DNA replication and genome maintenance.
    Keywords:  DNA damage; DNA replication; FEN1; Okazaki fragment; PCNA; Polδ; RFC; clamp loader; genome maintenance; sliding clamp
    DOI:  https://doi.org/10.1016/j.cell.2025.12.029
  8. Clin Mol Hepatol. 2026 Jan 27.
    DNMT1 Facilitates the Progression of MASLD by Impeding Transcription Mediated by HNF4α and PPARα.
    Hyun Ahm Sohn, Hanyong Go, Tae Hyeon An, Jun Min Lee, Hee-Jin Kim, Keeok Haam, Amal Magdy, Hyo-Jung Jung, Yang-Ji Shin, Hyun Jung Lim, Yujin Jeong, Yejin Bae, Youngae Jung, Seong-Hwan Park, Kyung Chan Park, Myeong Jun Song, Eun-Wie Cho, Eun-Soo Kwon, Jeong Hwan Park, Murim Choi, Geum-Sook Hwang, Dong Hyeon Lee, Stefano Romeo, Kyoung-Jin Oh, Won Kim, Mirang Kim.
       Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Aberrant DNA methylation, which is primarily maintained by DNA methyltransferase 1 (DNMT1), has been linked to metabolic dysregulation; however, its contribution to MASLD pathogenesis remains poorly defined. This study aimed to elucidate the role of DNMT1-mediated methylation in transcriptional regulation during MASLD progression and to determine whether DNMT1 inhibition can reverse disease-associated epigenetic and transcriptional alterations.
    Methods: We conducted integrated analyses of the liver transcriptome (n = 131) and DNA methylome (n = 106) of patients with biopsy-proven MASLD. We evaluated the effect of DNMT1 inhibition with 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) on a diet-induced MASLD mouse model. Multiomics approaches, including DNA methylome profiling, lipidomics, bulk and single-nucleus RNA sequencing, and chromatin immunoprecipitation sequencing, were applied to elucidate the role of DNMT1-mediated DNA methylation in regulating pathogenic gene expression.
    Results: DNA methylome profiling revealed increased methylation variability associated with increased DNMT1 expression in MASLD patients. DNMT1 inhibition ameliorated dysregulated lipid metabolism by reducing hepatic triacylglycerol accumulation and inflammation. Aza-TdC treatment partially reversed MASLD-related hypermethylation of hepatocyte nuclear factor 4 alpha (HNF4α)- and peroxisome proliferator-activated receptor alpha (PPARα)-regulated genes, restoring their transcriptional activity. Notably, Aza-TdC reactivated the gluconeogenic enzyme-encoding gene phosphoenolpyruvate carboxykinase 1 (PCK1), which was hypermethylated and transcriptionally repressed in MASLD. Targeted DNA methylation of the PCK1 promoter using CRISPRoff confirmed the direct epigenetic regulation of PCK1 expression.
    Conclusions: Targeting DNMT1 may mitigate lipid dysregulation and inflammation by reversing hypermethylation and restoring HNF4α- and PPARα-dependent gene transcription, highlighting DNMT1 as a potential therapeutic target for MASLD.
    Keywords:  DNA methylation; DNMT1; HNF4α; MASLD; PPARα
    DOI:  https://doi.org/10.3350/cmh.2025.1099
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