bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–08–03
twelve papers selected by
Xiong Weng, University of Edinburgh



  1. Sci Immunol. 2025 Jul 25. 10(109): eads0478
      Whereas visceral adipose tissue (VAT) primarily stores excess energy, brown adipose tissue (BAT) dissipates it in a process termed nonshivering thermogenesis. Several key VAT features, particularly murine epidydimal VAT, are regulated by a distinct population of regulatory T (Treg) cells, raising the question of whether BAT hosts an analogous population. Although Treg cells have been observed in BAT, their properties and mechanisms of action require elucidation. We found BAT Treg cells to be heterogeneous in subtissular localization and subtype composition. Punctual depletion of Treg cells unleashed interferon-γ (IFN-γ)-producing lymphocytes in BAT, but not in subcutaneous or visceral fat depots, leading to IFN-γ-dependent mitochondrial dysfunction and metabolic dysregulation, thereby impeding nonshivering thermogenesis. Cold challenge selectively expanded the IL-18R1+ Treg subtype in BAT; stripping this receptor specifically from Treg cells unleashed IFN-γ-producing lymphocytes and compromised temperature control. Thus, control of local IFN-γ production is a core feature of Treg cell control of tissue homeostasis.
    DOI:  https://doi.org/10.1126/sciimmunol.ads0478
  2. Nat Microbiol. 2025 Aug;10(8): 1918-1939
      The human gut microbiota has the potential to synthesize proteins that may influence host metabolism. Here we report two polypeptides, RUMTOR-derived peptide (RORDEP) 1 and RORDEP2, circulating in human blood and synthesized by specific strains of gut commensal Ruminococcus torques that correlate inversely with adiposity in humans. Oral gavage with RORDEP-expressing strains improved glucose tolerance, increased bone density and reduced fat mass with an enhanced expression of genes and proteins involved in thermogenesis and lipolysis in lean mice on a high-fat diet and diet-induced obese mice. Recombinant RORDEP1 given to rats intraperitoneally decreased plasma gastric inhibitory polypeptide but increased glucagon-like peptide 1, peptide YY and insulin. Intestinal delivery of recombinant RORDEP1 to rats potentiated insulin-mediated inhibition of hepatic glucose production by downregulating genes and proteins controlling liver gluconeogenesis, glycogenolysis and lipogenesis but upregulating those involved in insulin signalling, glycogenesis and glycolysis. These preclinical findings warrant the exploration of RORDEPs for the prevention and treatment of human metabolic disorders.
    DOI:  https://doi.org/10.1038/s41564-025-02064-x
  3. Liver Int. 2025 Sep;45(9): e70240
      Steatotic liver disease (SLD), caused by excess lipid accumulation in hepatocytes, is now a leading global liver condition triggered by metabolic dysfunction, alcohol, toxins and heritable factors. The main genetic determinant is the common PNPLA3 p.I148M variant, which explains a substantial portion of SLD interindividual and interethnic variability, up to a quarter of liability to cirrhosis and liver cancer in the general population. Discovered in 2008 through genome-wide association studies, this variant increases the risk of liver steatosis, inflammation, fibrosis and the risk of complications as hepatocellular carcinoma. Carriers, particularly homozygotes, show higher susceptibility to liver damage, with the variant interacting with environmental factors such as increased adiposity, diet, insulin resistance and female sex. Experimental models indicate a complex mechanistic impact, involving lipid transfer and retinoid metabolism. Phase 1 clinical trials exploring PNPLA3 inhibitors, such as siRNA and antisense oligonucleotides, are promising, demonstrating up to 40% reductions in hepatic fat and inflammation in homozygous carriers. These advances suggest that targeting PNPLA3 can pave the way for precision medicine in hepatology. Overall, the discovery of PNPLA3's role has significantly enhanced understanding of liver steatosis, steatohepatitis and potential therapeutic interventions, highlighting its importance as a therapeutic target for SLD.
    Keywords:  MASLD; PNPLA3; genetics; steatosis
    DOI:  https://doi.org/10.1111/liv.70240
  4. Cell Metab. 2025 Jul 23. pii: S1550-4131(25)00328-6. [Epub ahead of print]
      L-lactate participates in metabolism, including the Cori cycle, but less is known about D-lactate. We found that circulating D-lactate was higher in humans and mice with obesity. D-lactate increased hepatic glycogen, triglycerides, and blood glucose more than equimolar L-lactate in mice. Stable isotope analyses showed that D-lactate is metabolized in mice and in hepatocytes to pyruvate, TCA intermediates, lipids, and glucose. The gut microbiota is the main source of blood D-lactate. Colonization of mice with a bacterial strain that produced D-lactate elevated blood glucose more than an L-lactate producer. Oral delivery of a biocompatible polymer that traps gut D-lactate, forcing fecal excretion, lowered blood glucose and insulin resistance in obese mice in a polymer length- and dose-dependent manner. This D-lactate trap lowered hepatic inflammation and fibrosis in mice with metabolic dysfunction-associated fatty liver disease (MAFLD)/metabolic dysfunction-associated steatohepatitis (MASH). Therefore, microbial-derived D-lactate contributes to host glucose and lipid metabolism and can be trapped to improve metabolic disease during obesity.
    Keywords:  diabetes; fibrosis; gut; inflammation; liver; metabolic dysfunction-associated steatotic liver disease; microbiome; obesity; polymer; postbiotics
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.001
  5. Cell Stem Cell. 2025 Jul 28. pii: S1934-5909(25)00261-9. [Epub ahead of print]
      White adipose tissue supports essential physiological functions through adipocyte precursor cells (APCs), comprising progenitors and preadipocytes, which generate mature adipocytes during depot expansion. Using single-cell RNA sequencing-based lineage tracing, we characterize APCs in skin adipose tissue-a depot uniquely capable of rapid adipogenesis compared with other sites, such as inguinal adipose. We identify a previously uncharacterized population of immature preadipocytes and reveal distinct differentiation potentials among APCs. Contrary to traditional stepwise differentiation models, progenitors predominantly generate committed preadipocytes, whereas preexisting preadipocytes accumulate in immature states with divergent potential. Leveraging this refined APC hierarchy, we uncover Sox9 as a crucial regulator of progenitor proliferation and adipogenic differentiation. Cross-depot transplantation further demonstrates how intrinsic and extrinsic factors differentially regulate skin progenitor behavior, highlighting distinct adipogenic dynamics between skin and inguinal depots. Together, these insights redefine the cellular hierarchy and molecular mechanisms underpinning rapid adipogenesis in skin adipose tissue.
    Keywords:  Sox9; adipocyte precursors; adipogenesis; cell proliferation; single-cell lineage tracing; skin adipose hierarchy
    DOI:  https://doi.org/10.1016/j.stem.2025.07.004
  6. Genome Res. 2025 Aug 01. pii: gr.280155.124. [Epub ahead of print]
      Epigenetic drift refers to the gradual and stochastic accumulation of epigenetic changes, such as DNA methylation variability, with advancing age. Although increasingly recognized for its potential role in aging biology, its extent, biological significance, and population specificity remain insufficiently characterized. Here, we present the first comprehensive epigenome-wide drift study (EWDS) in a large Chinese cohort (n = 3,538), with replication in two independent Chinese (total n = 1,467) and two European cohorts (total n = 956), to investigate the scale and relevance of epigenetic drift across populations. Through simulation, we identified White's test as the most powerful method among four alternatives for detecting age-associated methylation variability. Our EWDS revealed that 10.8% (50,385 CpGs) of sites on the 850K EPIC array exhibited epigenome-wide significant drift, with 99% showing increased interindividual variability (positive drift) and 1% showing decreased variability (negative drift). Integration with single-cell RNA-seq data demonstrated that positive drift-CpGs are associated with increased transcriptional variability and upregulation in specific cell types, while negative drift-CpGs exhibit the opposite effect. We developed epigenetic drift scores (EDSs) to quantify individual drift burden; these scores are strongly age-associated and correlate with lipidomic profiles and clinical aging indicators. Longitudinal data confirm within-individual accumulation of drift over time. Finally, a GWAS of EDS identified genetic determinants of drift magnitude, including heritable loci (e.g., ASTN2, SOCS5). Collectively, these findings establish epigenetic drift as a pervasive, directional, and biologically meaningful feature of human aging.
    DOI:  https://doi.org/10.1101/gr.280155.124
  7. Cell Rep. 2025 Jul 29. pii: S2211-1247(25)00836-8. [Epub ahead of print]44(8): 116065
      Genome-wide association studies (GWASs) have identified over 100 signals associated with type 1 diabetes (T1D). However, it has been challenging to translate any given T1D GWAS signal into mechanistic insights, such as causal variants, their target genes, and the specific cell types involved. Here, we present a comprehensive multi-omic integrative analysis of single-cell/nucleus resolution profiles of gene expression and chromatin accessibility in human pancreatic islets under baseline and T1D-stimulating conditions. We nominate effector cell types for all T1D GWAS signals and the regulatory elements and genes for three independent T1D signals acting through β cells at the DLK1/MEG3, RASGRP1, and TOX loci. Subsequently, we validated the functional impact of these genes and regulatory regions using isogenic human embryonic stem cells (hESCs). We found that loss of RASGRP1 or DLK1, as well as disruption of their corresponding regulatory regions, led to increased β cell apoptosis. Furthermore, β cells derived from isogenic hESCs carrying the T1D risk allele of rs3783355 associated with DLK1 showed elevated β cell death. Through additional RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses, we identified five genes upregulated in both RASGRP1-/- and DLK1-/- β-like cells, four of which are near T1D GWAS signals. This integrative approach combining single-cell multi-omics, GWASs, and isogenic human pluripotent stem cell (hPSC)-derived β-like cells illuminates cell type context, genes, single nucleotide polymorphisms (SNPs), and regulatory elements underlying T1D-associated signals, providing insights into the biological functions and molecular mechanisms involved.
    Keywords:  CP: Genomics; CP: Metabolism; GWAS; T1D-associated signals; apoptosis; cytokine; differentiation; hPSCs; human pancreatic islets; multi-omics profiling; type 1 diabetes; β cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.116065
  8. Nat Metab. 2025 Jul 25.
      Obesity increases the risk of many cancers and impairs the anti-tumour immune response. However, little is known about whether the source or composition of dietary fat affects tumour growth or anti-tumour immunity in obesity. Here, we show that high-fat diets (HFDs) derived from lard, beef tallow or butter accelerate tumour growth in a syngeneic model of melanoma, but HFDs based on coconut oil, palm oil or olive oil do not, despite equivalent obesity. Using butter-based and palm oil-based HFDs as examples, we find that these dietary fat sources differentially regulate natural killer and CD8 T cell infiltration and function within the tumour microenvironment, governed by distinct effects on the plasma metabolome and intracellular metabolism. We identify diet-related lipid intermediates, namely long-chain acylcarnitine species, as immunosuppressive metabolites enriched in mice fed butter compared to palm oil HFD. Together, these results highlight the significance of diet in maintaining a healthy immune system and suggest that modifying dietary fat may improve cancer outcomes in obesity.
    DOI:  https://doi.org/10.1038/s42255-025-01330-w
  9. Cell Rep. 2025 Jul 26. pii: S2211-1247(25)00831-9. [Epub ahead of print]44(8): 116060
      Adipose tissue remodels via hypertrophy or hyperplasia in response to nutrient status, but the mechanisms governing these expansion modes remain unclear. Here, we identify a nutrient-sensitive epigenetic circuit linking glucose metabolism to chromatin remodeling during adipogenesis. Upon glucose stimulation, α-ketoglutarate (α-KG) accumulates in the nucleus and activates the histone demethylase JMJD1A to remove repressive histone H3 lysine 9 dimethylation (H3K9me2) marks at glycolytic and adipogenic gene loci, including Pparg. JMJD1A is recruited to pre-marked promoter chromatin via nuclear factor IC (NFIC), enabling carbohydrate-responsive element-binding protein (ChREBP) binding and transcriptional activation. This feedforward mechanism couples nutrient flux to chromatin accessibility and gene expression. In vivo, JMJD1A is essential for de novo adipogenesis and hyperplastic expansion in visceral fat under nutrient excess. JMJD1A deficiency impairs hyperplasia, exacerbates adipocyte hypertrophy, and induces local inflammation. These findings define a glucose-α-KG-JMJD1A-ChREBP axis regulating depot-specific adipogenesis and uncover a chromatin-based mechanism by which glucose metabolism governs adaptive adipose tissue remodeling.
    Keywords:  Adipogenesis; CP: Metabolism; adipose hyperplasia; adipose hypertrophy; glycolysis; histone H3 lysine 9 di-methylation; histone demethylation; obesity; peroxisome proliferator-activated receptor; visceral fat; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2025.116060
  10. EMBO J. 2025 Jul 25.
      DNA N6-methyladenine (6mA) is an emerging epigenetic mark in the mammalian genome. ALKBH1 preferentially exhibits 6mA demethylase activity for single-stranded DNA (ssDNA) or bubbled/bulged DNA, but not for double-stranded DNA (dsDNA). Nevertheless, ALKBH1 significantly decreases the cellular 6mA level in genomic DNA, whose prevailing DNA conformation in living mammalian cells is dsDNA. Therefore, the demethylase activity of ALKBH1 toward 6mA in genomic DNA, especially dsDNA, remains largely debated. Here, we found that YTHDF3 increases the 6mA demethylase activity of ALKBH1 in genomic DNA with different conformations, including dsDNA. Compared with ALKBH1, YTHDF3 preferentially recognizes and binds to 6mA-modified DNA with different conformations. YTHDF3 recognizes 6mA in genomic DNA, and binds ALKBH1 to recruit it to sites near 6mA in genomic DNA, thereby facilitating the ALKBH1-mediated removal of 6mA in genomic dsDNA. In summary, YTHDF3 is a novel genomic DNA reader and guides ALKBH1 to remove 6mA in human genomic DNA.
    Keywords:  ALKBH1; Genomic 6mA Reader; Genomic DNA 6mA; YTHDF3; dsDNA
    DOI:  https://doi.org/10.1038/s44318-025-00512-2
  11. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00580-5. [Epub ahead of print]
      Ferroptosis, a metabolic cell death process driven by iron-dependent phospholipid peroxidation, is implicated in various pathologies, including cancer. While metabolic factors such as glucose, lipids, and multiple amino acids have all been demonstrated to modulate ferroptosis, the role of oxygen, another fundamental metabolic component, in ferroptosis is not fully understood. Here, we show that cells acclimated to a low oxygen environment develop marked resistance to ferroptosis, and this resistance is independent of canonical oxygen-sensing pathway mediated by prolyl hydroxylases (PHDs) and HIF transcription factors. Instead, hypoxia suppresses ferroptosis by inhibiting KDM6A, a tumor suppressor and oxygen-dependent histone demethylase, leading to reduced expression of its transcriptional targets, including lipid metabolic enzymes ACSL4 and ETNK1, thus rewiring cellular phospholipid profile to a ferroptosis-resistant state. Relevant to cancer, pharmacological inhibition of the oncogenic histone methyltransferase EZH2, which opposes KDM6A activity, restored ferroptosis sensitivity of xenograft bladder tumor tissues harboring KDM6A mutation.
    Keywords:  ACSL4; ETNK1; KDM6A; KMT2D; bladder cancer; cancer therapy; ferroptosis; hypoxia; lipid metabolism; oxygen sensing
    DOI:  https://doi.org/10.1016/j.molcel.2025.07.001
  12. Nat Metab. 2025 Aug 01.
      Mitochondria have a crucial role in regulating cellular homeostasis in response to intrinsic and extrinsic cues by changing cellular metabolism to meet these challenges. However, the molecular underpinnings of this regulation and the complete spectrum of these physiological outcomes remain largely unexplored. In this study, we elucidate the mechanisms driving the whitening phenotype in brown adipose tissue (BAT) deficient in the mitochondrial matrix protease CLPP. Here we show that CLPP-deficient BAT shows aberrant accumulation of lipid droplets, which occurs independently of defects in oxygen consumption and fatty acid oxidation. Our results indicate that mitochondrial dysfunction due to CLPP deficiency leads to the build-up of the oncometabolite D-2-hydroxyglutarate (D-2HG), which in turn promotes lipid droplet enlargement. We further demonstrate that D-2HG influences gene expression and decreases nuclear stiffness by modifying epigenetic signatures. We propose that lipid accumulation and altered nuclear stiffness regulated through 2HG are stress responses to mitochondrial dysfunction in BAT.
    DOI:  https://doi.org/10.1038/s42255-025-01332-8