bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–06–01
seventeen papers selected by
Xiong Weng, University of Edinburgh



  1. Nucleic Acids Res. 2025 May 22. pii: gkaf435. [Epub ahead of print]53(10):
      DNA methylation plays a fundamental role in regulating transcription during development and differentiation. However, its functional role in the regulation of endothelial cell (EC) transcription during state transition, meaning the switch from an angiogenic to a quiescent cell state, has not been systematically studied. Here, we report the longitudinal changes of the DNA methylome over the lifetime of the murine pulmonary vasculature. We identified prominent alterations in hyper- and hypomethylation during the transition from angiogenic to quiescent ECs. Once a quiescent state was established, DNA methylation marks remained stable throughout EC aging. These longitudinal differentially methylated regions correlated with endothelial gene expression and highlighted the recruitment of de novo DNA methyltransferase 3a (DNMT3A), evidenced by its motif enrichment at transcriptional start sites of genes with methylation-dependent expression patterns. Loss-of-function studies in mice revealed that the absence of DNMT3A-dependent DNA methylation led to the loss of active enhancers, resulting in mild transcriptional changes, likely due to loss of active enhancer integrity. These results underline the importance of DNA methylation as a key epigenetic mechanism of EC function during state transition. Furthermore, we show that DNMT3A-dependent DNA methylation appears to be involved in establishing the histone landscape required for accurate transcriptome regulation.
    DOI:  https://doi.org/10.1093/nar/gkaf435
  2. Cell. 2025 May 21. pii: S0092-8674(25)00515-X. [Epub ahead of print]
      Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.
    Keywords:  disease heterogeneity; glucose metabolism; phosphoproteomics; sex differences; signaling; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cell.2025.05.005
  3. Metabolites. 2025 May 14. pii: 324. [Epub ahead of print]15(5):
      Background: Whether intestinal epithelial cells can regulate distant adipose tissue remains a mystery. Methods: Cold-stimulated intestinal epithelial cell-derived exosomes (Cold IEC-Exo) play a pivotal role in enhancing adipose thermogenesis and metabolic homeostasis, as demonstrated in this study. Results: IEC-Exo can accumulate in adipose tissue. Compared with IEC-Exo derived from room temperature mice (RT IEC-Exo), Cold IEC-Exo significantly enhanced the thermogenesis of adipose. In vitro, Cold IEC-Exo directly stimulated thermogenesis in primary adipocytes by elevating oxygen consumption rate, proton leak, and fatty acid uptake, with no effect on glucose uptake. Small RNA sequencing identified miR-674-3p as a key mediator enriched in Cold IEC-Exo. miR-674-3p mimicry replicated Cold IEC-Exo effects, augmenting Ucp1 expression, mitochondrial uncoupling, and fatty acid utilization in adipocytes. Local overexpression of miR-674-3p in BAT and sWAT via AAV in vivo enhanced thermogenesis and attenuated diet-induced glucose intolerance. Conclusions: These findings establish that Cold IEC-Exo, via miR-674-3p transfer, drive adipose thermogenic activation and mitigate metabolic dysfunction, highlighting their therapeutic potential in obesity-related disorders.
    Keywords:  adipose; exosomes; intestinal epithelial cell; miRNA; thermogenesis
    DOI:  https://doi.org/10.3390/metabo15050324
  4. Mol Cell. 2025 May 21. pii: S1097-2765(25)00412-5. [Epub ahead of print]
      Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.
    Keywords:  GSTP1; IDH1; UMPS; cell signaling; computational modelling; metabolism; metabolomics; obesity; oxidative stress response; phosphoproteomics
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.007
  5. Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2505263122
      Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Fgf21 gene promoter. The stimulation of Fgf21 gene transcription by ethanol also requires its metabolism to acetyl-CoA and correlates with histone acetylation. Accordingly, a p300/CBP histone acetyltransferase inhibitor blocks histone acetylation, ChREBP recruitment, and transcriptional activation at the Fgf21 promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol's robust stimulatory effect on Fgf21 and possibly other ChREBP target genes in the liver.
    Keywords:  ChREBP; FGF21; alcohol; liver; transcription
    DOI:  https://doi.org/10.1073/pnas.2505263122
  6. Nat Biomed Eng. 2025 May 30.
      Somatic genome editing in mouse models has increased our understanding of the in vivo effects of genetic alterations. However, existing models have a limited ability to create multiple targeted edits, hindering our understanding of complex genetic interactions. Here we generate transgenic mice with Cre-regulated and constitutive expression of enhanced Acidaminococcus sp. Cas12a (enAsCas12a), which robustly generates compound genotypes, including diverse cancers driven by inactivation of trios of tumour suppressor genes or an oncogenic translocation. We integrate these modular CRISPR RNA (crRNA) arrays with clonal barcoding to quantify the size and number of tumours with each array, as well as the impact of varying the guide number and position within a four-guide array. Finally, we generate tumours with inactivation of all combinations of nine tumour suppressor genes and find that the fitness of triple-knockout genotypes is largely explainable by one- and two-gene effects. These Cas12a alleles will enable further rapid creation of disease models and high-throughput investigation of coincident genomic alterations in vivo.
    DOI:  https://doi.org/10.1038/s41551-025-01407-7
  7. Obesity (Silver Spring). 2025 Jun;33(6): 1184-1194
       OBJECTIVE: Effective solutions to obesity remain elusive, partly owing to its root in a positive energy balance (EB), which stems from the interplay of numerous traits spanning body size and composition, diet, physical activity, and metabolic profile. Nevertheless, EB-contributing traits are typically studied in isolation. We integrate numerous EB-related traits measured in the UK Biobank to uncover the underlying patterns of EB and associated genes in study participants.
    METHODS: We used sparse factor analysis to integrate traits and performed genome-wide association analyses on the integrated phenotypes to elucidate EB-related genes and metabolic pathways. We performed pleiotropy analyses on candidate single-nucleotide polymorphisms to uncover the genetic basis of EB.
    RESULTS: We identified multiple genes and genomic regions associated with EB, including many that have previously not been directly associated with obesity measures (e.g., MIR5591, FNDC3B, ANAPC10, SULT1A1, AXIN1, SKIDA1, ERLIN1, DOCK7), which we validated using an independent subset of the UK Biobank dataset along with data from the Atherosclerosis Risk in Communities cohort. We found that the covariances in EB traits are primarily driven by genome-wide pleiotropic associations.
    CONCLUSIONS: We offer new insight into EB patterns and the genetic basis of EB.
    DOI:  https://doi.org/10.1002/oby.24291
  8. Biochem Biophys Res Commun. 2025 May 26. pii: S0006-291X(25)00808-3. [Epub ahead of print]774 152094
      Beige adipocytes play a critical role in energy metabolism by promoting thermogenesis, a process largely influenced by epigenetic modifications such as DNA methylation. This study investigates the effect of DNA demethylation on beige adipocyte differentiation and function using 5-azacytidine (5-AzaC), a DNA methyltransferase inhibitor. We evaluated changes in adipogenic and thermogenic gene expression, mitochondrial activity, and fatty acid uptake following 5-AzaC treatment in 3T3-L1-derived beige adipocytes. Our findings indicate that 5-AzaC does not significantly affect adipocyte differentiation but enhances thermogenic gene expression, including Ucp1 and Cox7a1, and increases mitochondrial function and fatty acid uptake. These results suggest that DNA demethylation modulates beige adipocyte function and may have implications for metabolic disorders such as obesity and type 2 diabetes.
    Keywords:  5-Azacytidine; Beige adipocyte; DNA methylation; Thermogenic gene expression
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152094
  9. Cell. 2025 May 22. pii: S0092-8674(25)00560-4. [Epub ahead of print]
      Recently, microbial amino-acid-conjugated bile acids (MABAs) have been found to be prevalent in human samples. However, their physiological significance is still unclear. Here, we identify tryptophan-conjugated cholic acid (Trp-CA) as the most significantly decreased MABA in patients with type 2 diabetes (T2D), and its abundance is negatively correlated with clinical glycemic markers. We further demonstrate that Trp-CA improves glucose tolerance in diabetic mice. Mechanistically, we find that Trp-CA is a ligand of the orphan G protein-coupled receptor (GPCR) Mas-related G protein-coupled receptor family member E (MRGPRE) and determine the binding mode between the two. Both MRGPRE-Gs-cyclic AMP (cAMP) and MRGPRE-β-arrestin-1-aldolase A (ALDOA) signaling pathways contribute to the metabolic benefits of Trp-CA. Additionally, we find that the bacterial bile salt hydrolase/transferase of Bifidobacterium is responsible for the production of Trp-CA. Together, our findings pave the way for further research on MABAs and offer additional therapeutic targets for the treatment of T2D.
    Keywords:  GPCR; bile acids; microbiota; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cell.2025.05.010
  10. Methods Mol Biol. 2025 ;2938 69-79
      Western blotting (WB) is an end-point technique that is used to analyze the expression of target proteins in cells and tissues. It involves the separation of proteins using SDS-PAGE followed by an electrophoretic transfer of the proteins from the gel to a hydrophobic membrane where they will be immunodetected and captured on a film or by an imager. The peroxisome proliferator-activated receptor gamma (PPARγ) is a type of nuclear receptor protein that plays a crucial role in regulating gene expression and various cellular functions. In this chapter, the western blot procedure is demonstrated for the detection and quantification of the PPARγ nuclear protein from either adipocyte cell lines or adipose tissue.
    Keywords:  Chemiluminescence; Lipid metabolism; PPARγ; SDS-PAGE; Western blot
    DOI:  https://doi.org/10.1007/978-1-0716-4607-6_8
  11. Nat Commun. 2025 May 26. 16(1): 4871
    MULTI consortium
      Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25<r < 0.42). Crucially, including composite metabolites (e.g. sums or ratios of raw metabolites) results in poor generalizability to independent test data due to multicollinearity. Genome-wide associations identify 405 MetBAG-locus pairs (P < 5 × 10-8/5). Using SBayesS, we estimate the SNP-based heritability (0.09< hSNP2  < 0.18), negative selection signatures (-0.93 < S < -0.76), and polygenicity (0.001<Pi < 0.003) for the 5 MetBAGs. Genetic correlation and Mendelian randomization analyses reveal potential causal links between the 5 MetBAGs and cardiometabolic conditions (e.g., metabolic disorders and hypertension). Integrating multi-organ and multi-omics features improves disease category and mortality predictions. The 5 MetBAGs extend existing biological aging clocks to study human aging and disease across multiple biological scales. All results are publicly available at https://labs-laboratory.com/medicine/ .
    DOI:  https://doi.org/10.1038/s41467-025-59964-z
  12. Mol Med. 2025 May 26. 31(1): 206
      Osteoporosis is a prevalent systemic metabolic disease, and an imbalance in the adipogenic and osteogenic differentiation of mesenchymal stem cells (MSCs) plays a crucial role in its pathogenesis. Thus, elucidating the mechanisms that regulate MSC lineage allocation is urgently needed. METTL9 was recently characterized as a novel N1-histidine methyltransferase that performs a wide range of functions. however, the role of METTL9 in the imbalance of MSC differentiation in osteoporosis remains unclear. In this study, we found that METTL9 expression was downregulated in osteoporosis, and further adipogenic functional experiments revealed that METTL9 negatively regulated the adipogenic differentiation of MSCs both in vitro and in vivo. Mechanistically, METTL9 mediated methylation of SLC39A7 at the His45 and His49 residues suppressed ferroptosis through the endoplasmic reticulum (ER) stress regulatory protein kinase R-like endoplasmic reticulum kinase (PERK)/ATF4 signaling pathway and the downstream protein SLC7A11. Moreover, SLC7A11 transported cystine for intracellular glutathione synthesis, eliminating intracellular reactive oxygen species (ROS) and inhibiting MSC adipogenic differentiation. Additionally, METTL9 overexpression significantly alleviated bone loss in ovariectomy (OVX) model mice. In summary, our results suggest that the METTL9/SLC39A7 axis may be a promising diagnostic and therapeutic target for osteoporosis.
    Keywords:  Adipogenic differentiation; Ferroptosis; METTL9; Mesenchymal stem cells; Osteoporosis; SLC39A7
    DOI:  https://doi.org/10.1186/s10020-025-01271-w
  13. Cell Host Microbe. 2025 May 21. pii: S1931-3128(25)00182-9. [Epub ahead of print]
      Alcohol-associated liver disease poses a global health burden with high mortality. Imbalances in the gut microbiota are important for disease progression. Using metagenomic sequencing of fecal samples from a multicenter, international cohort of patients with alcohol-associated hepatitis, we found that the presence of virulence factor KpsM, encoded in the genome of Escherichia coli (E. coli), correlated with patient mortality. Functional studies using gnotobiotic mouse models and genetic manipulation of bacteria demonstrated that kpsM-positive E. coli exacerbate ethanol-induced liver disease. The kpsM gene mediates the translocation of capsular polysaccharides to the cell surface. This enables kpsM-positive E. coli to evade phagocytosis by the scavenger receptor Marco on Kupffer cells in the liver, leading to bacterial spread. Importantly, inhibiting kpsM-dependent capsules with the small molecule 2-(4-phenylphenyl)benzo[g]quinoline-4-carboxylic acid (C7) attenuated ethanol-induced liver disease in mice. We show that precision targeting of the virulence factor KpsM is a promising approach to improve outcomes of patients with alcohol-associated hepatitis.
    Keywords:  alcoholic liver disease; gut-liver axis; metagenomics; microbiome; microbiota; virulence factor
    DOI:  https://doi.org/10.1016/j.chom.2025.05.003
  14. Science. 2025 May 29. eadq7408
      The maintenance of H3K9me3 involves the recognition of pre-existing modifications by HP1, which recruits methyltransferase SUV39H1 to methylate the adjacent newly incorporated histones, thereby establishing a positive feedback loop. However, how this positive feedback is restricted to maintain H3K9me3 homeostasis remains largely unknown. Here, we performed an unbiased genome-scale CRISPR-Cas9 screen and identified CUL5ASB7 E3 ubiquitin ligase as a negative regulator of H3K9me3. ASB7 is recruited to heterochromatin by HP1 and promotes SUV39H1 degradation. During mitosis, CDK1 phosphorylates ASB7, preventing its interaction with SUV39H1, leading to SUV39H1 stabilization and H3K9me3 restoration. Our findings reveal a dynamic circuit involving HP1, SUV39H1, and ASB7 that governs H3K9me3 homeostasis, thereby ensuring faithful epigenetic inheritance and preventing excessive heterochromatin formation.
    DOI:  https://doi.org/10.1126/science.adq7408
  15. Nat Aging. 2025 May 27.
      Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s43587-025-00890-6
  16. Aging Cell. 2025 May 27. e70113
      Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6-methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well-established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5-methyltetrahydrofolate-homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S-adenosylmethionine (SAM), a critical metabolite in the one-carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.
    Keywords:  MTR; antiaging; dietary restriction; m6A; metformin; methionine metabolism; rotifer
    DOI:  https://doi.org/10.1111/acel.70113
  17. Science. 2025 May 29. eads7373
      Only a minority of patients with rare genetic diseases are currently diagnosed by exome sequencing, suggesting that additional unrecognized pathogenic variants may reside in non-coding sequence. Here, we describe PromoterAI, a deep neural network that accurately identifies non-coding promoter variants which dysregulate gene expression. We show that promoter variants with predicted expression-altering consequences produce outlier expression at both RNA and protein levels in thousands of individuals, and that these variants experience strong negative selection in human populations. We observe that clinically relevant genes in rare disease patients are enriched for such variants and validate their functional impact through reporter assays. Our estimates suggest that promoter variation accounts for 6% of the genetic burden associated with rare diseases.
    DOI:  https://doi.org/10.1126/science.ads7373