bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–04–20
eighteen papers selected by
Xiong Weng, University of Edinburgh
  1. Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.
  2. Coupling of ribosome biogenesis and translation initiation in human mitochondria.
  3. Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
  4. GDF15 links adipose tissue lipolysis with anxiety.
  5. Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
  6. Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance.
  7. Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling.
  8. Cytosolic cytochrome c represses ferroptosis.
  9. Signalling from adipose tissue to the brain is not just about leptin.
  10. Insulin resistance in type 2 diabetes mellitus.
  11. Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.
  12. Selective identification of epigenetic regulators at methylated genomic sites by SelectID.
  13. Multi-zonal liver organoids from human pluripotent stem cells.
  14. Crystal structure of Isthmin-1 and reassessment of its functional role in pre-adipocyte signaling.
  15. Twenty years of genome-wide association studies.
  16. SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis.
  17. Gene clusters linked to insulin resistance identified in a genome-wide study of the Taiwan Biobank population.
  18. Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
  1. Cell Metab. 2025 Apr 09. pii: S1550-4131(25)00207-4. [Epub ahead of print]
    Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling.
    Baiyu He, Kyle D Copps, Oliver Stöhr, Beikl Liu, Songhua Hu, Shakchhi Joshi, Marcia C Haigis, Morris F White, Hao Zhu, Rongya Tao.
      Hepatic insulin sensitivity is critical for systemic glucose and lipid homeostasis. The liver is spatially organized into zones in which hepatocytes express distinct metabolic enzymes; however, the functional significance of this zonation to metabolic dysregulation caused by insulin resistance is undetermined. Here, we used CreER mice to selectively disrupt insulin signaling in periportal (PP) and pericentral (PC) hepatocytes. PP-insulin resistance has been suggested to drive combined hyperglycemia and excess lipogenesis in individuals with type 2 diabetes. However, PP-insulin resistance in mice impaired lipogenesis and suppressed high-fat diet (HFD)-induced hepatosteatosis, despite elevated gluconeogenesis and insulin. In contrast, PC-insulin resistance reduced HFD-induced PC steatosis while preserving normal glucose homeostasis, in part by shifting glycolytic metabolism from the liver to the muscle. These results demonstrate distinct roles of insulin in PP versus PC hepatocytes and suggest that PC-insulin resistance might be therapeutically useful to combat hepatosteatosis without compromising glucose homeostasis.
    Keywords:  de novo lipogenesis; gluconeogenesis; hepatic glucose production; insulin resistance; insulin signaling; lipid metabolism; liver zonation; pericentral hepatocytes; periportal hepatocytes
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.015
  2. Nat Commun. 2025 Apr 17. 16(1): 3641
    Coupling of ribosome biogenesis and translation initiation in human mitochondria.
    Marleen Heinrichs, Anna Franziska Finke, Shintaro Aibara, Angelique Krempler, Angela Boshnakovska, Peter Rehling, Hauke S Hillen, Ricarda Richter-Dennerlein.
      Biogenesis of mitoribosomes requires dedicated chaperones, RNA-modifying enzymes, and GTPases, and defects in mitoribosome assembly lead to severe mitochondriopathies in humans. Here, we characterize late-step assembly states of the small mitoribosomal subunit (mtSSU) by combining genetic perturbation and mutagenesis analysis with biochemical and structural approaches. Isolation of native mtSSU biogenesis intermediates via a FLAG-tagged variant of the GTPase MTG3 reveals three distinct assembly states, which show how factors cooperate to mature the 12S rRNA. In addition, we observe four distinct primed initiation mtSSU states with an incompletely matured rRNA, suggesting that biogenesis and translation initiation are not mutually exclusive processes but can occur simultaneously. Together, these results provide insights into mtSSU biogenesis and suggest a functional coupling between ribosome biogenesis and translation initiation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-58827-x
  3. Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027
    Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
    Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.
      Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
    Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
  4. Nat Metab. 2025 Apr 15.
    GDF15 links adipose tissue lipolysis with anxiety.
    Logan K Townsend, Dongdong Wang, Carly M Knuth, Russta Fayyazi, Ahmad Mohammad, Léa J Becker, Evangelia E Tsakiridis, Eric M Desjardins, Zeel Patel, Celina M Valvano, Junfeng Lu, Alice E Payne, Ofure Itua, Kyle D Medak, Daniel M Marko, Jonathan D Schertzer, David C Wright, Shawn M Beaudette, Katherine M Morrison, André C Carpentier, Denis P Blondin, Rebecca E K MacPherson, Jordan G McCall, Marc G Jeschke, Gregory R Steinberg.
      Psychological stress changes both behaviour and metabolism to protect organisms. Adrenaline is an important driver of this response. Anxiety correlates with circulating free fatty acid levels and can be alleviated by a peripherally restricted β-blocker, suggesting a peripheral signal linking metabolism with behaviour. Here we show that adrenaline, the β3 agonist CL316,243 and acute restraint stress induce growth differentiation factor 15 (GDF15) secretion in white adipose tissue of mice. Genetic inhibition of adipose triglyceride lipase or genetic deletion of β-adrenergic receptors blocks β-adrenergic-induced increases in GDF15. Increases in circulating GDF15 require lipolysis-induced free fatty acid stimulation of M2-like macrophages within white adipose tissue. Anxiety-like behaviour elicited by adrenaline or restraint stress is eliminated in mice lacking the GDF15 receptor GFRAL. These data provide molecular insights into the mechanisms linking metabolism and behaviour and suggest that inhibition of GDF15-GFRAL signalling might reduce acute anxiety.
    DOI:  https://doi.org/10.1038/s42255-025-01264-3
  5. Sci Adv. 2025 Apr 18. 11(16): eads1842
    Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging.
    Kristina Bubb, Julia Etich, Kristina Probst, Tanvi Parashar, Maximilian Schuetter, Frederik Dethloff, Susanna Reincke, Janica L Nolte, Marcus Krüger, Ursula Schlötzer-Schrehard, Julian Nüchel, Constantinos Demetriades, Patrick Giavalisco, Jan Riemer, Bent Brachvogel.
      Decline of mitochondrial respiratory chain (mtRC) capacity is a hallmark of mitochondrial diseases. Patients with mtRC dysfunction often present reduced skeletal growth as a sign of premature cartilage degeneration and aging, but how metabolic adaptations contribute to this phenotype is poorly understood. Here we show that, in mice with impaired mtRC in cartilage, reductive/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.
    DOI:  https://doi.org/10.1126/sciadv.ads1842
  6. Nat Commun. 2025 Apr 17. 16(1): 3678
    Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance.
    Naoki Kobayashi, Yukiko Okazaki, Aya Iwane, Kazuo Hara, Momoko Horikoshi, Motoharu Awazawa, Kotaro Soeda, Maya Matsushita, Takayoshi Sasako, Kotaro Yoshimura, Nobuyuki Itoh, Kenta Kobayashi, Yasuyuki Seto, Toshimasa Yamauchi, Hiroyuki Aburatani, Matthias Blüher, Takashi Kadowaki, Kohjiro Ueki.
      Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.
    DOI:  https://doi.org/10.1038/s41467-025-58836-w
  7. PLoS Biol. 2025 Apr 14. 23(4): e3003112
    Liver gene expression and its rewiring in hepatic steatosis are controlled by PI3Kα-dependent hepatocyte signaling.
    Marion Régnier, Arnaud Polizzi, Tiffany Fougeray, Anne Fougerat, Prunelle Perrier, Karen Anderson, Yannick Lippi, Sarra Smati, Céline Lukowicz, Frédéric Lasserre, Edwin Fouche, Marine Huillet, Clémence Rives, Blandine Tramunt, Claire Naylies, Géraldine Garcia, Elodie Rousseau-Bacquié, Justine Bertrand-Michel, Cécile Canlet, Sylvie Chevolleau-Mege, Laurent Debrauwer, Christophe Heymes, Rémy Burcelin, Thierry Levade, Pierre Gourdy, Walter Wahli, Yuna Blum, Laurence Gamet-Payrastre, Sandrine Ellero-Simatos, Julie Guillermet-Guibert, Phillip Hawkins, Len Stephens, Catherine Postic, Alexandra Montagner, Nicolas Loiseau, Hervé Guillou.
      Insulin and other growth factors are key regulators of liver gene expression, including in metabolic diseases. Most of the phosphoinositide 3-kinase (PI3K) activity induced by insulin is considered to be dependent on PI3Kα. We used mice lacking p110α, the catalytic subunit of PI3Kα, to investigate its role in the regulation of liver gene expression in health and in metabolic dysfunction-associated steatotic liver disease (MASLD). The absence of hepatocyte PI3Kα reduced maximal insulin-induced PI3K activity and signaling, promoted glucose intolerance in lean mice and significantly regulated liver gene expression, including insulin-sensitive genes, in ad libitum feeding. Some of the defective regulation of gene expression in response to hepatocyte-restricted insulin receptor deletion was related to PI3Kα signaling. In addition, though PI3Kα deletion in hepatocytes promoted insulin resistance, it was protective against steatotic liver disease in diet-induced obesity. In the absence of hepatocyte PI3Kα, the effect of diet-induced obesity on liver gene expression was significantly altered, with changes in rhythmic gene expression in liver. Altogether, this study highlights the specific role of p110α in the control of liver gene expression in physiology and in the metabolic rewiring that occurs during MASLD.
    DOI:  https://doi.org/10.1371/journal.pbio.3003112
  8. Cell Metab. 2025 Apr 08. pii: S1550-4131(25)00149-4. [Epub ahead of print]
    Cytosolic cytochrome c represses ferroptosis.
    Xinxin Song, Zhuan Zhou, Jiao Liu, Jingbo Li, Chunhua Yu, Herbert J Zeh, Daniel J Klionsky, Brent R Stockwell, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.
    Keywords:  apoptosis; cytochrome c; ferroptosis; protein complex
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.014
  9. Nat Metab. 2025 Apr 15.
    Signalling from adipose tissue to the brain is not just about leptin.
    Peter Arner.
      
    DOI:  https://doi.org/10.1038/s42255-025-01277-y
  10. Nat Rev Endocrinol. 2025 Apr 17.
    Insulin resistance in type 2 diabetes mellitus.
    Domenico Accili, Zhaobing Deng, Qingli Liu.
      Insulin resistance is an integral pathophysiological feature of type 2 diabetes mellitus. Here, we review established and emerging cellular mechanisms of insulin resistance, their complex integrative features and their relevance to disease progression. While recognizing the heterogeneity of the elusive fundamental disruptions that cause insulin resistance, we endorse the view that effector mechanisms impinge on insulin receptor signalling and its relationship with plasma levels of insulin. We focus on hyperinsulinaemia and its consequences: acutely impaired but persistent insulin action, with reduced ability to lower glucose levels but preserved lipid synthesis and lipoprotein secretion. We emphasize the role of insulin sensitization as a therapeutic goal in type 2 diabetes mellitus.
    DOI:  https://doi.org/10.1038/s41574-025-01114-y
  11. Cell Rep. 2025 Apr 16. pii: S2211-1247(25)00362-6. [Epub ahead of print]44(5): 115591
    Simultaneous in vivo multi-organ fluxomics reveals divergent metabolic adaptations in liver, heart, and skeletal muscle during obesity.
    Mohsin Rahim, Tomasz K Bednarski, Clinton M Hasenour, Deveena R Banerjee, Irina Trenary, Jamey D Young.
      We present an isotope-based metabolic flux analysis (MFA) approach to simultaneously quantify metabolic fluxes in the liver, heart, and skeletal muscle of individual mice. The platform was scaled to examine metabolic flux adaptations in age-matched cohorts of mice exhibiting varying levels of chronic obesity. We found that severe obesity increases hepatic gluconeogenesis and citric acid cycle flux, accompanied by elevated glucose oxidation in the heart that compensates for impaired fatty acid oxidation. In contrast, skeletal muscle fluxes exhibit an overall reduction in substrate oxidation. These findings demonstrate the dichotomy in fuel utilization between cardiac and skeletal muscle during worsening metabolic disease and demonstrate the divergent effects of obesity on metabolic fluxes in different organs. This multi-tissue MFA technology can be extended to address important questions about in vivo regulation of metabolism and its dysregulation in disease, which cannot be fully answered through studies of single organs or isolated cells/tissues.
    Keywords:  CP: Metabolism; cardiac metabolism; fluxomics; isotope labeling; liver metabolism; metabolic flux analysis; metabolomics; muscle metabolism; obesity; steatotic liver disease; systems biology
    DOI:  https://doi.org/10.1016/j.celrep.2025.115591
  12. Nat Commun. 2025 Apr 18. 16(1): 3709
    Selective identification of epigenetic regulators at methylated genomic sites by SelectID.
    Wenchang Qian, Penglei Jiang, Mingming Niu, Yujuan Fu, Deyu Huang, Dong Zhang, Ying Liang, Qiwei Wang, Yingli Han, Xin Zeng, Yixin Shi, Lingli Jiang, Zebin Yu, Jinxin Li, Huan Lu, Hong Wang, Baohui Chen, Pengxu Qian.
      DNA methylation is a significant component in proximal chromatin regulation and plays crucial roles in regulating gene expression and maintaining the repressive state of retrotransposon elements. However, accurate profiling of the proteomics which simultaneously identifies specific DNA sequences and their associated epigenetic modifications remains a challenge. Here, we report a strategy termed SelectID (selective profiling of epigenetic control at genome targets identified by dCas9), which introduces methylated DNA binding domain into dCas9-mediated proximity labeling system to enable in situ protein capture at repetitive elements with 5-methylcytosine (5mC) modifications. SelectID is demonstrated as feasible as dCas9-TurboID system at specific DNA methylation regions, such as the chromosome 9 satellite. Using SelectID, we successfully identify CHD4 as potential repressors of methylated long interspersed nuclear element-1 (LINE-1) retrotransposon through direct binding at the 5' untranslated region (5'UTR) of young LINE-1 elements. Overall, our SelectID approach has opened up avenues for uncovering potential regulators of specific DNA regions with DNA methylation, which will greatly facilitate future studies on epigenetic regulation.
    DOI:  https://doi.org/10.1038/s41467-025-59002-y
  13. Nature. 2025 Apr 16.
    Multi-zonal liver organoids from human pluripotent stem cells.
    Hasan Al Reza, Connie Santangelo, Kentaro Iwasawa, Abid Al Reza, Sachiko Sekiya, Kathryn Glaser, Alexander Bondoc, Jonathan Merola, Takanori Takebe.
      Distinct hepatocyte subpopulations are spatially segregated along the portal-central axis and are critical to understanding metabolic homeostasis and injury in the liver1. Although several bioactive molecules, including ascorbate and bilirubin, have been described as having a role in directing zonal fates, zonal liver architecture has not yet been replicated in vitro2,3. Here, to evaluate hepatic zonal polarity, we developed a self-assembling zone-specific liver organoid by co-culturing ascorbate- and bilirubin-enriched hepatic progenitors derived from human induced pluripotent stem cells. We found that preconditioned hepatocyte-like cells exhibited zone-specific functions associated with the urea cycle, glutathione synthesis and glutamate synthesis. Single-nucleus RNA-sequencing analysis of these zonally patterned organoids identifies a hepatoblast differentiation trajectory that dictates periportal, interzonal and pericentral human hepatocytes. Epigenetic and transcriptomic analysis showed that zonal identity is orchestrated by ascorbate- or bilirubin-dependent binding of EP300 to TET1 or HIF1α. Transplantation of the self-assembled zonally patterned human organoids improved survival of immunodeficient rats who underwent bile duct ligation by ameliorating the hyperammonaemia and hyperbilirubinaemia. Overall, this multi-zonal organoid system serves as an in vitro human model to better recapitulate hepatic architecture relevant to liver development and disease.
    DOI:  https://doi.org/10.1038/s41586-025-08850-1
  14. Nat Commun. 2025 Apr 15. 16(1): 3580
    Crystal structure of Isthmin-1 and reassessment of its functional role in pre-adipocyte signaling.
    Tongqing Li, Steven E Stayrook, Wenxue Li, Yueyue Wang, Hengyi Li, Jianan Zhang, Yansheng Liu, Daryl E Klein.
      Isthmin-1 (ISM1) is a recently described adipokine with insulin-like properties that can control hyperglycemia and liver steatosis. Additionally, ISM1 is proposed to play critical roles in patterning, angiogenesis, vascular permeability, and apoptosis. A key feature of ISM1 is its AMOP (adhesion-associated domain in MUC4 (Mucin-4) and other proteins) domain which is essential for many of its functions. However, the molecular details of AMOP domains remain elusive as there are no descriptions of their structure. Here we determined the crystal structure of ISM1 including its thrombospondin type I repeat (TSR) and AMOP domain. Interestingly, ISM1's AMOP domain exhibits a distinct fold with similarities to bacterial streptavidin. When comparing our structure to predicted structures of other AMOP domains, we observed that while the core streptavidin-like barrel is conserved, the surface helices and loops vary greatly. Thus, the AMOP domain fold allows for structural plasticity that may underpin its diverse functions. Furthermore, and contrary to prior studies, we show that highly purified ISM1 does not stimulate AKT phosphorylation on 3T3-F442A pre-adipocytes. Rather, we find that co-purifying growth factors are responsible for this activity. Together, our data reveal the structure and clarify functional studies of this enigmatic protein.
    DOI:  https://doi.org/10.1038/s41467-025-58828-w
  15. Nature. 2025 Apr 15.
    Twenty years of genome-wide association studies.
    Lorraine Southam, Eleftheria Zeggini.
      
    Keywords:  Diseases; Genetics; Genomics; Technology
    DOI:  https://doi.org/10.1038/d41586-025-01128-6
  16. Bone Res. 2025 Apr 14. 13(1): 47
    SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis.
    Xiangyu Zu, Shenghong Chen, Zhengyuan Li, Lin Hao, Wenhan Fu, Hui Zhang, Zongsheng Yin, Yin Wang, Jun Wang.
      Chondrocyte senescence is a critical pathological hallmark of osteoarthritis (OA). Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging; however, the precise underlying mechanism remains elusive. Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression. SPI1 binds to the PERK promoter, thereby promoting its transcriptional activity. Importantly, PERK, rather than GCN2, facilitates eIF2α phosphorylation, activating the mitochondrial unfolded protein response (UPRmt) and impeding chondrocyte senescence. Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression. Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration. In summary, our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK, which may present a novel therapeutic target for treating OA. SPI1 alleviates the progression of OA by inhibiting mechanical stress-induced chondrocyte senescence through mitochondrial UPR signaling.
    DOI:  https://doi.org/10.1038/s41413-025-00421-4
  17. Nat Commun. 2025 Apr 14. 16(1): 3525
    Gene clusters linked to insulin resistance identified in a genome-wide study of the Taiwan Biobank population.
    Eugene Lin, Yu-Ting Yan, Mu-Hong Chen, Albert C Yang, Po-Hsiu Kuo, Shih-Jen Tsai.
      This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research.
    DOI:  https://doi.org/10.1038/s41467-025-58506-x
  18. Nat Commun. 2025 Apr 16. 16(1): 3306
    Elevated mitochondrial membrane potential is a therapeutic vulnerability in Dnmt3a-mutant clonal hematopoiesis.
    Kira A Young, Mohsen Hosseini, Jayna J Mistry, Claudia Morganti, Taylor S Mills, Xiurong Cai, Brandon T James, Griffin J Nye, Natalie R Fournier, Veronique Voisin, Ali Chegini, Aaron D Schimmer, Gary D Bader, Grace Egan, Marc R Mansour, Grant A Challen, Eric M Pietras, Kelsey H Fisher-Wellman, Keisuke Ito, Steven M Chan, Jennifer J Trowbridge.
      The competitive advantage of mutant hematopoietic stem and progenitor cells (HSPCs) underlies clonal hematopoiesis (CH). Drivers of CH include aging and inflammation; however, how CH-mutant cells gain a selective advantage in these contexts is an unresolved question. Using a murine model of CH (Dnmt3aR878H/+), we discover that mutant HSPCs sustain elevated mitochondrial respiration which is associated with their resistance to aging-related changes in the bone marrow microenvironment. Mutant HSPCs have DNA hypomethylation and increased expression of oxidative phosphorylation gene signatures, increased functional oxidative phosphorylation capacity, high mitochondrial membrane potential (Δψm), and greater dependence on mitochondrial respiration compared to wild-type HSPCs. Exploiting the elevated Δψm of mutant HSPCs, long-chain alkyl-TPP molecules (MitoQ, d-TPP) selectively accumulate in the mitochondria and cause reduced mitochondrial respiration, mitochondrial-driven apoptosis and ablate the competitive advantage of HSPCs ex vivo and in vivo in aged recipient mice. Further, MitoQ targets elevated mitochondrial respiration and the selective advantage of human DNMT3A-knockdown HSPCs, supporting species conservation. These data suggest that mitochondrial activity is a targetable mechanism by which CH-mutant HSPCs gain a selective advantage over wild-type HSPCs.
    DOI:  https://doi.org/10.1038/s41467-025-57238-2
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