bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–04–12
eight papers selected by
Xiong Weng, University of Edinburgh
  1. Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.
  2. SRC-mediated phosphorylation of UBC9 regulates inflammatory and metabolic signaling in alcohol-associated liver disease.
  3. Metabolomics across scales: from single cells to population studies.
  4. ATGL-catalyzed lipid catabolism promotes DNA repair.
  5. The exonic SNP rs11676272-C risk allele mediates diet-induced obesity and reduces enhancer activation.
  6. Deletion of miR-130b/301b cluster promotes macrophage efferocytosis and resolution of adipose tissue inflammation.
  7. Why obesity drugs work better for some people: these genes hold clues.
  8. Mutation-specific impairment of TET2 and DNMT3A enzymatic activity predicts clonal hematopoiesis disease risk.
  1. Nat Commun. 2026 Apr 10.
    Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.
    Haizhou Jiang, Shihong Ni, Zi Li, Shanghai Chen, Xiaoying Li, Huijie Zhang, Wei L Shen, Xiaoxue Jiang, Peixiang Luo, Yousheng Shu, Feixiang Yuan, Kexin Tong, Fei Xiao, Feifan Guo.
      A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ.
    DOI:  https://doi.org/10.1038/s41467-026-71581-y
  2. Sci Adv. 2026 Apr 10. 12(15): eaec0138
    SRC-mediated phosphorylation of UBC9 regulates inflammatory and metabolic signaling in alcohol-associated liver disease.
    Swati Chandla, Youngyi Lim, Andrea Floris, Michael Mazarei, Xi Yang, Takashi Tsuchiya, Manisha Dagar, Alfonso Darmawan, Monica Justo, Ramachandran Murali, Alexandra Gangi, Ivan Tomasi, Nirmala Mavila, Komal Ramani, Maria Lauda Tomasi.
      Alcohol-associated liver disease (ALD) remains a major public health challenge with limited treatment options. NF-κB-driven inflammation in Kupffer cells (KCs) plays a central role in ALD, but the upstream regulators remain poorly understood. Here, we identify the tyrosine kinase SRC as a key mediator of ALD. Chronic ethanol exposure activates SRC in KCs, which directly phosphorylates ubiquitin-conjugating enzyme 9 (UBC9), the only E2 SUMO enzyme, at tyrosine-68 (Y68). This modification enhances NF-κB signaling and increases proinflammatory cytokines (TNF-α, IL-6, and IL-1β). These cytokines then promote hepatic lipogenesis through SREBP1c- and CEBPβ-dependent induction of FASN and ACC. Inhibition of UBC9 phosphorylation by gene editing or SRC inhibitor reduces NF-κB-dependent inflammation and lessens ethanol-induced liver injury in mouse models. These findings uncover a previously unrecognized SRC-UBC9-NF-κB axis that drives inflammation in ALD and highlight it as a potential therapeutic target in liver disease.
    DOI:  https://doi.org/10.1126/sciadv.aec0138
  3. Nature. 2026 04;652(8109): 313-320
    Metabolomics across scales: from single cells to population studies.
    Theodore Alexandrov, Nicola Zamboni.
      Metabolomics has matured into a powerful approach for probing metabolism, offering readouts that closely reflect cellular and organismal function in health and disease. Here we highlight two rapidly advancing frontiers: single-cell metabolomics and population-scale metabolomics. Single-cell metabolomics resolves the metabolic states of individual cells, uncovering cell-to-cell heterogeneity and spatial organization within tissues. Population-scale profiling profiles metabolites across large cohorts, enabling the discovery of markers of disease, environmental exposures and genetic variation. Although these approaches operate at different scales, they face shared challenges-including metabolite identification, quantification and multimodal data integration-and offer common advantages, such as the ability to capture non-genetic influences on phenotype and to scale to high throughput. We propose that continued advances in scalability will bring these domains together, enabling the construction of comprehensive metabolic atlases that chart cellular and interindividual variation and provide training data for foundation models of metabolism. By integrating cellular and population-level insights, single-cell and population-scale metabolomics promise to advance our understanding of metabolism across biology, medicine and pharmacology.
    DOI:  https://doi.org/10.1038/s41586-026-10277-1
  4. bioRxiv. 2026 Apr 04. pii: 2026.04.03.716381. [Epub ahead of print]
    ATGL-catalyzed lipid catabolism promotes DNA repair.
    Mahima Devarajan, Rachel K Meyer, Gavin Fredrickson, William A Hofstadter, Mara T Mashek, Mari V Reid, Evan W Kerr, Anna Bartelt, Peter Gutenberger, Simone Intriago, Linshan Laux, Emma Petta, Hai Dang Nguyen, Douglas G Mashek.
      An imbalance of DNA damage over DNA repair contributes to the genomic instability that drives aging and numerous age-related diseases. While numerous DNA repair mechanisms have been elucidated over decades of study, little is known about the contribution of metabolism to genomic stability. We report that adipose triglyceride lipase (ATGL), a primary lipolytic enzyme, promotes DNA repair. We show that lipid droplets (LDs) accumulate in response to DNA damage and that inhibition of LD biogenesis before genotoxic stress increases the persistence of DNA damage. Overexpression of ATGL (increasing lipolysis) enhances DNA repair in response to etoposide and ionizing radiation, thus reducing DNA damage burden. Mechanistically, ATGL promotes bulk acetylation of chromatin-bound proteins and blockade of the histone acetyltransferase p300 negates these effects. Further, ATGL-induced DNA repair attenuates the long-term consequences of DNA damage, and reducing senescence and enhancing viability. Overall, these studies reveal a novel role for LDs and LD proteins in DNA damage and repair, thus unveiling a mechanism through which lipid metabolism contributes to genomic stability.
    DOI:  https://doi.org/10.64898/2026.04.03.716381
  5. EMBO Rep. 2026 Apr 06.
    The exonic SNP rs11676272-C risk allele mediates diet-induced obesity and reduces enhancer activation.
    Weina Wang, Yue Li, Sheng Dong, Yuwei Liu, Chenghang Guo, Yuzhe Su, Wei Tian, Xiaoyu Hu, Zhenshan Wang.
      Genome-wide association studies (GWASs) have identified hundreds of obesity-associated SNPs, but establishing their causality remains challenging. Here, we demonstrate that rs11676272, located in the ADCY3 gene, is a functional causal variant for obesity susceptibility. Bioinformatic analyses and dual-luciferase reporter assays indicate that the rs11676272 region may act as a human-gained enhancer regulating ADCY3 expression. In HEK293T cells, CRISPR-Cas9-mediated single-nucleotide editing of rs11676272 (T > C) reduces ADCY3 expression. Moreover, the rs11676272-T allele is preferentially bound by the transcription factor E2F3 to upregulate ADCY3 expression, whereas the rs11676272-C risk allele loses this binding. In vivo, the rs11676272 T > C variant in human ADCY3 (hADCY3) knock-in mice accelerates weight gain under high-fat diet conditions and shortens primary cilia in the ventromedial hypothalamus (VMH). CRISPRa-mediated activation of the hADCY3 promoter region rescues ciliary length in both the VMH and hypothalamic arcuate nucleus of Mut-hADCY3 mice. Our data reveal a causal role for rs11676272 in obesity, offering insight into potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s44319-026-00758-9
  6. iScience. 2026 Apr 17. 29(4): 115307
    Deletion of miR-130b/301b cluster promotes macrophage efferocytosis and resolution of adipose tissue inflammation.
    Lei Yang, Tuerdiguli Abuduyimiti, Yibo Xi, Gianfilippo Coppola, Chen Liu, Shaoning Jiang.
      Macrophage efferocytosis, the clearance of apoptotic cells, is essential for tissue homeostasis and preventing inflammation. Impaired efferocytosis contributes to chronic inflammatory conditions, including obesity. However, its key regulators remain unclear. MicroRNA-130b (miR-130b) is increased in adipose tissue macrophages of individuals with obesity. Here, we found that miR-130b was enriched in bone marrow of mice, and its expression in bone marrow-derived macrophages was suppressed by IL-4 and by apoptotic cell uptake. Deletion of the miR-130b and its cluster member miR-301b enhanced macrophage efferocytosis in vitro and apoptotic cell clearance in vivo, accompanied by increased mitochondrial respiration and anti-inflammatory polarization. In high fat diet-fed mice, global deletion of miR-130b/301b reduced inflammatory gene expression in adipose tissues. Mechanistically, miR-130b suppressed PPARγ and PGC-1α, regulators of mitochondrial metabolism and inflammation, and miR-130b/301b deletion increased CX3CR1, a receptor for apoptotic cell "find me" signals. Together, miR-130b/301b deletion promotes macrophage efferocytosis and resolves adipose tissue inflammation.
    Keywords:  cell biology; immunology; molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115307
  7. Nature. 2026 Apr 08.
    Why obesity drugs work better for some people: these genes hold clues.
    Mariana Lenharo.
      
    Keywords:  Genetics; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-026-01107-5
  8. medRxiv. 2026 Apr 05. pii: 2026.04.03.26350108. [Epub ahead of print]
    Mutation-specific impairment of TET2 and DNMT3A enzymatic activity predicts clonal hematopoiesis disease risk.
    Yash Pershad, Kun Zhao, Joseph C Van Amburg, Robert W Corty, Alyssa C Parker, Alexander J Silver, Yara Almadani, Ashwin Kishtagari, Emily Hodges, Michael R Savona, J Brett Heimlich, Alexander G Bick.
      Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in TET2 and DNMT3A is present in >10% of adults over 60 and confers substantial risk for hematologic malignancy and cardiovascular disease, yet the majority of patients with CHIP do not progress to disease. Analyzing 1,020,538 individuals across three biobanks (UK Biobank, All of Us, BioVU), we show that a discrete subset of enzymatically disruptive mutations - TET2 loss-of-function variants and the DNMT3A R882 hotspot - account for the majority of clinical risk in these genes and exhibit the strongest clonal fitness advantage. Because DNMT3A and TET2 encode enzymes that modulate DNA methylation, we reasoned that peripheral blood methylation patterns should reflect the functional impact of individual mutations, enabling a direct readout of enzymatic dysfunction in CHIP patients. We developed and validated methylation-based activity scores for TET2 and DNMT3A as patient specific biomarkers that quantify enzymatic activity. These scores capture functional heterogeneity across mutation subtypes, predict disease risk comparably to clinical risk scores such as the Clonal Hematopoiesis Risk Score and the AHA PREVENT cardiovascular risk model. Integrating the activity score with the clinical models substantially improves prediction of incident cytopenia, myeloid neoplasm, and major adverse cardiovascular events. These findings establish that TET2 and DNMT3A CHIP pathogenicity is proportional to the degree of enzymatic disruption conferred by specific variants, and nominate methylation-based activity scores as a functional biomarker for individualized CHIP risk stratification and monitoring therapeutic response.
    DOI:  https://doi.org/10.64898/2026.04.03.26350108
This page is being maintained by Thomas Krichel. It was last updated on 2026‒04‒12 at 21:05.