bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–06–15
nine papers selected by
Xiong Weng, University of Edinburgh
  1. Disruption of YY1‑mediated super‑enhancer-promoter looping drives transcriptomic changes during mammalian stem‑cell aging.
  2. Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.
  3. Ligand-specific regulation of a binary enhancer code dictating cellular senescence.
  4. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
  5. Metabolic adaptations direct cell fate during tissue regeneration.
  6. Genetic and physiological insights into satiation variability predict responses to obesity treatment.
  7. Neonatal diabetes-associated missense PDX1 variant disrupts chromatin association and protein-protein interaction.
  8. Genome-wide identification and analysis of recurring patterns of epigenetic variation across individuals.
  9. Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance.
  1. Res Sq. 2025 Jun 06. pii: rs.3.rs-6531164. [Epub ahead of print]
    Disruption of YY1‑mediated super‑enhancer-promoter looping drives transcriptomic changes during mammalian stem‑cell aging.
    Weiwei Dang, Luyang Sun, Brenna McCauley, Haiying Liu, Xueqian Chen.
      Stem‑cell aging leads to a progressive decline in self‑renewal and differentiation. How changes in chromatin architecture shape the gene‑expression program underlying this loss of function remains incompletely understood. Here, we integrate transcriptomic, epigenomic, and Hi‑C data from young and in‑vitro‑aged human mesenchymal stem cells (MSCs) to map super‑enhancer-promoter (SE-promoter) loops and trace how they rewire during aging. SE target genes are enriched for Gene Ontology terms central to MSC identity and are disproportionately represented among age‑regulated transcripts, suggesting that altered SE activity contributes to functional decline. YY1 is highly enriched at both promoters and SEs in young cells but is depleted from these loci in old cells. Loss of YY1 coincides with weakened Hi‑C contacts, and YY1 knockdown in young MSCs recapitulates age‑associated expression changes, especially among SE targets. Together, our results highlight YY1 as a key stabilizer of SE-promoter looping and gene‑expression homeostasis during stem‑cell aging.
    DOI:  https://doi.org/10.21203/rs.3.rs-6531164/v1
  2. Cell Rep Med. 2025 May 29. pii: S2666-3791(25)00236-8. [Epub ahead of print] 102163
    Insulin- and exercise-induced phosphoproteomics of human skeletal muscle identify REPS1 as a regulator of muscle glucose uptake.
    Jeppe Kjærgaard, Cecilie B Lindqvist, Júlia Prats Quesada, Søren Jessen, Farina Schlabs, Amy M Ehrlich, Caio Y Yonamine, Mario García-Ureña, Johann H Schmalbruch, Lewin Small, Martin Thomassen, Anders Krogh Lemminger, Kasper Eibye, Alba Gonzalez-Franquesa, Jacob V Stidsen, Kurt Højlund, Juleen R Zierath, Tuomas O Kilpeläinen, Jens Bangsbo, Jonas T Treebak, Morten Hostrup, Atul S Deshmukh.
      Skeletal muscle glucose uptake, essential for metabolic health, is regulated by both insulin and exercise. Using phosphoproteomics, we analyze skeletal muscle from healthy individuals following acute exercise or insulin stimulation, generating a valuable dataset. We identify 71 phosphosites on 55 proteins regulated by both stimuli in the same direction, suggesting a convergence of exercise and insulin signaling pathways. Among these, the vesicle-associated protein, REPS1, is highly phosphorylated at Ser709 in response to both stimuli. We identify p90 ribosomal S6 kinase (RSK) to be a key upstream kinase of REPS1 S709 phosphorylation and that the RSK-REPS1 signaling axis is involved in insulin-stimulated glucose uptake. Insulin-induced REPS1 Ser709 phosphorylation is closely linked to muscle and whole-body insulin sensitivity and is impaired in insulin-resistant mice and humans. These findings highlight REPS1 as a convergence point for insulin and exercise signaling, presenting a potential therapeutic target for treating individuals with insulin resistance.
    Keywords:  REPS1; RSK; exercise; glucose metabolism; insulin; phosphoproteomics; skeletal muscle signaling
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102163
  3. Proc Natl Acad Sci U S A. 2025 Jun 17. 122(24): e2506321122
    Ligand-specific regulation of a binary enhancer code dictating cellular senescence.
    Thomas Suter, Meyer J Friedman, Cagdas Tazearslan, Daria Merkurjev, Kenny Ohgi, Dario Meluzzi, Michael G Rosenfeld, Yousin Suh.
      Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 (TGFB2) and Activin A (INHBA) transcription units, both of which are significantly up-regulated in replicative senescence. The characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.
    Keywords:  NFI; SMAD2/3; cellular senescence; enhancers; p65
    DOI:  https://doi.org/10.1073/pnas.2506321122
  4. Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]
    AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
    Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.
      Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.
    Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
  5. Nature. 2025 Jun 11.
    Metabolic adaptations direct cell fate during tissue regeneration.
    Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.
      Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09097-6
  6. Cell Metab. 2025 Jun 03. pii: S1550-4131(25)00264-5. [Epub ahead of print]
    Genetic and physiological insights into satiation variability predict responses to obesity treatment.
    Lizeth Cifuentes, Diego Anazco, Timothy O'Connor, Maria Daniela Hurtado, Wissam Ghusn, Alejandro Campos, Sima Fansa, Alison McRae, Sunil Madhusudhan, Elle Kolkin, Michael Ryks, William S Harmsen, Serban Ciotlos, Barham K Abu Dayyeh, Donald D Hensrud, Michael Camilleri, Andres Acosta.
      Satiation, the process that regulates meal size and termination, varies widely among adults with obesity. To better understand and leverage this variability, we assessed calories to satiation (CTS) through an ad libitum meal, combined with physiological and behavioral evaluations, including calorimetry, imaging, blood sampling, and gastric emptying tests. Although factors like baseline characteristics, body composition, and hormone levels partially explain CTS variability, they leave substantial variability unaccounted for. To address this gap, we developed a machine-learning-assisted genetic risk score (CTSGRS) to predict high CTS. In a randomized clinical trial, participants with high CTS or CTSGRS achieved greater weight loss with phentermine-topiramate over 52 weeks, whereas those with low CTS or CTSGRS responded better to liraglutide at 16 weeks in a separate trial. These findings highlight the potential of combining satiation measurements with genetic modeling to predict treatment outcomes and inform personalized strategies for obesity management.
    Keywords:  calories to satiation; genetic risk score; liraglutide; machine learning; obesity treatment; personalized obesity management; phentermine-topiramate; precision medicine; satiation; satiety; weight loss outcomes
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.008
  7. JCI Insight. 2025 Jun 09. pii: e189343. [Epub ahead of print]10(11):
    Neonatal diabetes-associated missense PDX1 variant disrupts chromatin association and protein-protein interaction.
    Xiaodun Yang, Angela Zanfardino, Riccardo Schiaffini, Jeff Ishibashi, Bareket Daniel, Matthew W Haemmerle, Novella Rapini, Alessia Piscopo, Emanuele Miraglia Del Giudice, Maria Cristina Digilio, Raffaele Iorio, Mafalda Mucciolo, Stefano Cianfarani, Dario Iafusco, Fabrizio Barbetti, Doris A Stoffers.
      PDX1 mutations are associated with multiple forms of diabetes, including syndromic, neonatal, mature onset diabetes of the young (MODY), and type 2 diabetes. Two PDX1 missense mutations (Thr151Met and Asn196Thr) were identified in a pediatric female patient that cause permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder. We found that the mouse Pdx1 Asn197Thr variant (homologous to human PDX1 Asn196Thr), but not Pdx1 Thr152Met (homologous to human PDX1 Thr151Met), altered its nuclear localization and disrupted the PDX1-ONECUT1 interaction. Neither variant substantially affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, the Pdx1 Asn197Thr variant caused pancreas agenesis and reduced enteroendocrine cells in the duodenum in genetically engineered mice, due at least in part to reduced Pdx1 promoter binding and disrupted PDX1-ONECUT1 interaction.
    Keywords:  Development; Diabetes; Endocrinology; Genetic diseases
    DOI:  https://doi.org/10.1172/jci.insight.189343
  8. Commun Biol. 2025 Jun 07. 8(1): 888
    Genome-wide identification and analysis of recurring patterns of epigenetic variation across individuals.
    Jennifer Zou, Emily Maciejewski, Jason Ernst.
      Epigenetic mapping studies across individuals have identified many positions of epigenetic variation across the human genome. However the relationships between these positions, and in particular global patterns that recur in many regions of the genome, remains understudied. In this study, we use a stacked chromatin state model to systematically learn global patterns of epigenetic variation across individuals and annotate the human genome based on them. We apply this framework to histone modification data across individuals in lymphoblastoid cell lines and across autism spectrum disorder cases and controls in prefrontal cortex tissue. We find that global patterns are correlated across multiple histone modifications and with gene expression. We use the global patterns as a framework to predict trans-regulators and study a complex disorder. The frameworks for identifying and analyzing global patterns of epigenetic variation are general and we expect will be useful in other systems.
    DOI:  https://doi.org/10.1038/s42003-025-08179-5
  9. Nat Genet. 2025 Jun 12.
    Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance.
    Elizabeth Dorans, Karthik Jagadeesh, Kushal Dey, Alkes L Price.
      Methods that analyze single-cell paired RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) multiome data have shown promise in linking regulatory elements to genes. However, existing methods exhibit low concordance and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on expression quantitative trait locus (eQTL) data to assign a probabilistic score to each candidate single-nucleotide polymorphism-gene link. pgBoost attained higher enrichment than existing methods for evaluation sets derived from eQTL, activity-by-contact, CRISPR and genome-wide association study (GWAS) data. We further determined that restricting pgBoost to features from a focal cell type improved power to identify links relevant to that cell type. We highlight several examples in which pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies improves power to identify target genes underlying GWAS associations.
    DOI:  https://doi.org/10.1038/s41588-025-02220-3
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