bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–05–17
eight papers selected by
Xiong Weng, University of Edinburgh
  1. Single-cell and spatial omics in liver identify cell-cell communication regulators in aging and insulin resistance.
  2. SIRT6 overexpression counteracts chromatin aging in the male murine liver.
  3. Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes.
  4. Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
  5. Population-scale genomic medicine with the Hong Kong Genome Project.
  6. Microbial dysbiosis in metabolic disorders: linking epigenomic regulation and pathological mechanisms.
  7. Glyceroneogenesis has a new PEP in its step(s).
  8. Framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO): 2026 update.
  1. Metabolism. 2026 May 09. pii: S0026-0495(26)00140-X. [Epub ahead of print] 156630
    Single-cell and spatial omics in liver identify cell-cell communication regulators in aging and insulin resistance.
    Wei Zhao, Xinfeng Jiao, Kang Du, Qiushi Sun, Junyan Duan, Yang Cao, Xiyu Shen, Zaid Said, Satya S Karri, Peter Ellsworth, Wenjing Hu, Ashot Sargsyan, Inna Astapova, So Yeon Kim, John Gonzalez, Albert T Higgins-Chen, Rachel J Perry, Ekihiro Seki, Mark A Herman, Bogi Andersen, Qing Nie, Qin Yang.
      The liver is a major metabolic organ regulating systemic insulin sensitivity, which progressively declines with age. Due to the complexity of cellular components and spatial structures, how the liver regulates insulin resistance during aging remains to be elucidated. Using single-cell RNA-seq, ATAC-seq, and spatial transcriptomics, we studied liver cellular composition and zonation in young, insulin-sensitive mice and old mice with varying degrees of insulin resistance. Aging reduced pericentral zone 3 hepatocyte population but increased mid-zone 2 hepatocytes and hepatic stellate cells (HSCs). The interaction of aging and insulin resistance led to further zone 3 contraction and zone 2 expansion. Cell-cell communication and spatial proximity analysis revealed reduced hepatocyte growth factor (HGF) signaling activity from HSCs to zone 3 hepatocytes in aging and insulin resistance. In HGF activator (HGFAC)-knockout mice, a significant reduction in the zone 3 hepatocyte proportion was observed. Treating insulin-resistant aged mice with HGF reversed zone 3 contraction and improved insulin sensitivity. These findings highlight the significance of liver zonation dynamics in aging-associated insulin resistance.
    Keywords:  Aging; Cell-cell communication; Insulin resistance; Liver zonation; Single-cell analysis
    DOI:  https://doi.org/10.1016/j.metabol.2026.156630
  2. Nat Commun. 2026 May 14.
    SIRT6 overexpression counteracts chromatin aging in the male murine liver.
    Ron Nagar, Zacharia Schwartz, Almog Katz, Noga Touitou, Efrat Sharon, Kobi Tzdaka, Odeya Waner, Noam Shalev, Rotem Clo, Leah Weiss, Benjamin Epstein, Michel Bernier, Roni B Shtark, Nirad Banskota, Kwan-Wood G Lam, Supriyo De, Nathan L Price, Batia Lerrer, Daniel Z Bar, Rafael de Cabo, Haim Y Cohen.
      Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Our multi-omics approach, combining ATAC-seq, methylome and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways. Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.
    DOI:  https://doi.org/10.1038/s41467-026-73115-y
  3. Cell Metab. 2026 May 14. pii: S1550-4131(26)00151-8. [Epub ahead of print]
    Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes.
    Jiadai Liu, Ronghui Gao, Qianqian Kang, Zhihan Wang, Xuemin Peng, Jing Ge, Wenshe Wang, Hongyan Deng, Yuyu Xie, Zengzhe Zhu, Min Yang, Rui He, Huanyu Wang, Yulian Liu, Pema Maretich, Yongsheng Chang, Jichun Yang, Shingo Kajimura, Ruping Pan, Yong Chen.
      Adipocytes exhibit cellular plasticity by secreting pro-inflammatory cytokines in response to an energy excess. Here, we identify that interleukin (IL)-11 is robustly induced and secreted from adipocytes, especially beige adipocytes upon adrenergic stimulation. IL-11 inhibits adipocyte thermogenesis through binding to IL-11 receptor a (IL-11Ra) and serves as a "brake" to maintain energy homeostasis. Adipocyte-specific IL-11Ra-knockout mice exhibit enhanced whole-body energy consumption and improved glucose and lipid metabolism under a high-fat diet (HFD). Inhibition of IL-11/IL-11Ra signaling enhances sphingosine kinase 1 (Sphk1)-driven production of sphingosine-1-phosphate (S1P), thus remodeling intracellular calcium cycling in beige adipocytes. Notably, treatment with a designed peptide against IL-11Ra in obese mice effectively alleviates fat accumulation and obesity-associated disorders. Taken together, our study defines a physiological and noncanonical mechanism of beige adipocyte-derived IL-11 in energy metabolism, which may serve as a promising target for the treatment of obesity.
    Keywords:  adipokine; calcium signaling; obesity; sphingolipid metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.013
  4. Nat Aging. 2026 May 14.
    Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
    David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.
      Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.
    DOI:  https://doi.org/10.1038/s43587-026-01120-3
  5. Nat Med. 2026 May 15.
    Population-scale genomic medicine with the Hong Kong Genome Project.
    Hong Kong Genome Project
      The Hong Kong Genome Project (HKGP) aims to build a foundational resource for precision medicine in the Chinese population through large-scale genome sequencing and integrated analyses. Here we report findings from over 20,000 HKGP participants across two cohorts: a rare disease cohort including 2,227 patients with suspected genetic diseases and a population cohort including 18,261 participants undergoing genomic screening for medically actionable findings. The rare disease cohort achieved a diagnostic rate of 25%. When benchmarked against panels designed for European ancestries, the analysis revealed that 3.7% of the individuals in the population cohort had pathogenic or likely pathogenic variants associated with dominant disorders. While 48% of individuals were found to carry recessive disorder genes in the gene list based upon European ancestries, our analysis revealed that 38 additional clinically important genes would have been overlooked in the Chinese population. Pharmacogenomic analysis demonstrated that nearly all participants harbored at least one actionable phenotype, potentially informing nearly one million annual prescriptions in Hong Kong. The ongoing HKGP establishes a curated Hong Kong Chinese reference for clinically relevant genetic variation and serves as a blueprint for the implementation of precision medicine in underrepresented populations.
    DOI:  https://doi.org/10.1038/s41591-026-04410-w
  6. Drug Discov Today. 2026 May 13. pii: S1359-6446(26)00103-0. [Epub ahead of print] 104698
    Microbial dysbiosis in metabolic disorders: linking epigenomic regulation and pathological mechanisms.
    Arun K Sharma, Md Sayeed Akhtar, Khalid Orayj, Sadaf Farooqui, Abida Khan, Gunjan Sharma.
      Microbial dysbiosis critically contributes to metabolic disorders by altering host-microbiome interactions and disrupting metabolic homeostasis. This review highlights how dysbiosis-derived metabolites, including short-chain fatty acids (SCFA) and trimethylamine-N-oxide (TMAO), modulate epigenetic mechanisms such as DNA methylation, histone modification, and non-coding RNA expression in key metabolic tissues. These epigenomic changes impair insulin signaling, lipid metabolism, and inflammatory responses. We further explore the potential of microbial-epigenetic biomarkers for early diagnosis of metabolic disease. Moreover, we assess emerging microbiome-based therapies including prebiotics, SCFA supplementation, and fecal microbiota transplantation for their ability to reverse epigenetic dysregulation. Understanding the microbiome-epigenome-metabolism axis may enable precision diagnostics and targeted interventions for obesity, type 2 diabetes, and related disorders.
    Keywords:  Dysbiosis; Epigenetic biomarkers; Epigenomic regulators; Metabolic disorders; Metabolic pathology; Multi-omics integration
    DOI:  https://doi.org/10.1016/j.drudis.2026.104698
  7. Cell. 2026 May 14. pii: S0092-8674(26)00470-8. [Epub ahead of print]189(10): 2788-2790
    Glyceroneogenesis has a new PEP in its step(s).
    Alexandra E Jerrett, Nicolai R Hathiramani, Jessica B Spinelli.
      Mitochondria generate phosphoenolpyruvate (PEP), although its export mechanism and physiological roles were unknown. In this issue of Cell, Kajimura and colleagues identify SLC25A35 as the mitochondrial PEP exporter and uncover a previously unrecognized role for mitochondrial PEP synthesis in glyceroneogenesis in adipose tissue and upon development of fatty liver disease.
    DOI:  https://doi.org/10.1016/j.cell.2026.04.035
  8. Nat Med. 2026 May 13.
    Framework for the pharmacological treatment of obesity and its complications from the European Association for the Study of Obesity (EASO): 2026 update.
    Andreea Ciudin, Jennifer L Baker, Andrej Belančić, Luca Busetto, Dror Dicker, Ľubomíra Fábryová, Gema Frühbeck, Gijs H Goossens, Jason Gordon, Matteo Monami, Paolo Sbraccia, Borja Martinez-Tellez, Volkan Yumuk, Barbara McGowan.
      
    DOI:  https://doi.org/10.1038/s41591-026-04397-4
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