bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–09–13
seven papers selected by
Xiong Weng, University of Edinburgh
  1. Exosome trafficking is a key regulator of adipocyte thermogenesis.
  2. ALKBH5 activates creatine-driven thermogenesis by stabilizing CKB mRNA in response to cold.
  3. Rab4b controls hepatic glucose production during fasting through glycophagy.
  4. Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
  5. Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing.
  6. Family-based analyses show how children's genetics shape key traits.
  7. Paediatric proteomic signatures of cardiometabolic disease-associated traits predict adult disease outcomes.
  1. Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2621342123
    Exosome trafficking is a key regulator of adipocyte thermogenesis.
    Devesh Kesharwani, Michele Karolak, Chad Doucette, Rachelle Mendola, Summer Pray, Raghu Bhardwaj, Su Su, Anne Harrington, Victoria DeMambro, Clifford Rosen, Lucy Liaw, Aaron C Brown.
      Activation of beige adipocytes enhances energy expenditure and promotes metabolic health, presenting a promising approach for combating obesity and diabetes. As part of this process, thermogenesis, fueled by uncoupled mitochondrial respiration, plays a central role in converting calories into thermal energy, thereby preventing their storage as fat. Here, we identify exosome trafficking as an intrinsic regulator of thermogenic adipocyte function. Exosomes are small extracellular vesicles that mediate cell-cell and intracellular communication by transporting regulatory cargo, including microRNAs, proteins, and lipids. Using both human cells and mouse models, we show that thermogenic activation of beige adipocytes promotes the rapid release of exosomes enriched in microRNAs known to suppress thermogenic programs. Consistent with a functional role for exosome trafficking, genetic or pharmacological disruption of this pathway attenuated thermogenesis, whereas enhancing exosome release amplified thermogenic output. Mice deficient in the exosome trafficking regulator Rab27a exhibit reduced energy expenditure in response to both cold exposure and β3-adrenergic stimulation, while enhancement of exosome release promotes thermogenic activity in vitro and in vivo. These findings establish exosome trafficking as a key contributor to thermogenic adipocyte function and thermogenic remodeling, highlighting an intracellular mechanism that may be leveraged to enhance energy expenditure and treat obesity-related metabolic diseases.
    Keywords:  Rab27a; beige adipocytes; exosomes; metabolic disease; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2621342123
  2. Nat Metab. 2026 Sep 10.
    ALKBH5 activates creatine-driven thermogenesis by stabilizing CKB mRNA in response to cold.
    Yinliang Zhang, Chunyuan Du, Wei Qiao, Ping Qiu, Chaofan Xu, Xiaohan Yang, Jingran Hao, Dong Zhao, Xiaochen Gai, Yongsheng Chang.
      Non-shivering thermogenesis contributes to increased energy expenditure and can be a potential therapy to combat obesity. Here we show that the adipose tissue N6-methyladenosine (m6A) demethylase ALKBH5 responds to cold and adrenergic stimulation to induce non-shivering thermogenesis independent of UCP1. Fat-specific Alkbh5 knockout reduces thermogenic capacity, increases susceptibility to obesity and disrupts glucose homoeostasis in both male and female mice. Conversely, Alkbh5 overexpression in thermogenic fat increases energy expenditure and improves systemic metabolism. Furthermore, fat ALKBH5 expression inversely correlates with obesity in humans. Mechanistically, ALKBH5 is transcriptionally induced by the cAMP/PKA/CREB pathway in response to thermogenic stimuli. ALKBH5 demethylates m6A on CKB mRNA and prevents its degradation mediated by YTHDF2, thereby enhancing creatine metabolism-mediated thermogenesis in both wild-type and Ucp1-knockout mice. These findings suggest that ALKBH5 transduces thermogenic signalling towards creatine-driven thermogenesis, serving as a potential target for the treatment of obesity.
    DOI:  https://doi.org/10.1038/s42255-026-01592-y
  3. Nat Commun. 2026 Aug 10. pii: 9587. [Epub ahead of print]17(1):
    Rab4b controls hepatic glucose production during fasting through glycophagy.
    Marion Dussot, Lucie Le Parc, Sihame Sabbane, Alycia Zedda, Abderrahman Chafik, Alexandre Gallerand, Karine Dumas, Stéphanie Bonnafous, Yun Kwon, Sandra Lacas-Gervais, Charlotte Hinault Boyer, Giulia Chinetti, Sophie Giorgetti-Peraldi, Philippe Gual, Stoyan Ivanov, Anja Zeigerer, Jean-François Tanti, Mireille Cormont, Jerome Gilleron.
      Hepatic glucose production, essential for maintaining glycemia, is often altered in metabolic-associated fatty liver and glycogen storage diseases. Therefore, understanding the mechanisms that regulate the glucose production by hepatocyte is pivotal. Recent studies have identified endocytic trafficking as a key modulator of liver glucose production. Particularly, its role in directing protein trafficking toward lysosomal degradation influences gluconeogenesis. However, the contribution of endocytic recycling to liver glucose production remains yet poorly understood. Here, we demonstrate that hepatocyte-specific disruption of endocytic recycling, achieved through Rab4b knockout in male, leads to fasting hyperglycemia. Mechanistically, hepatocytes lacking Rab4b exhibit an increased capacity to produce glucose independently of gluconeogenesis by depleting their glycogen stores. This is driven by enhanced glycophagy, leading to excessive glucose release and fasting hyperglycemia. Notably, liver Rab4b expression also correlates with glycemia in both mice and human, highlighting a critical role of Rab4b-dependent endocytic recycling in regulating blood glucose homeostasis during fasting.
    DOI:  https://doi.org/10.1038/s41467-026-76218-8
  4. Sci Adv. 2026 Sep 11. 12(37): eaee4935
    Acetyl-CoA-dependent processes are preferentially supported by local metabolite synthesis.
    Julianna G Supplee, Pedro Costa-Pinheiro, Karl Wessendorf-Rodriguez, Stephanie Stransky, Qihua Yang, Christina Demetriadou, Nivitha Murali, Joy Li, Jennifer L Pennise, Mariola M Marcinkiewicz, Simone Sidoli, Nathaniel W Snyder, Christian M Metallo, Ronen Marmorstein, Kathryn E Wellen.
      The cell nucleus is an active metabolic site. Numerous enzymes best known for their roles in cytosolic or mitochondrial pathways also function in the nucleus, where they contribute to gene regulation and DNA replication and repair. Although metabolites can diffuse through nuclear pores, it remains unclear the extent to which the nucleus and cytosol operate as continuous versus distinct metabolic spaces. Both compartments require acetyl-CoA-for example, for histone acetylation and lipid synthesis-and the acetyl-CoA generating enzyme ATP-citrate lyase (ACLY) resides in both locations, but the significance of its dual localization is incompletely understood. Using cell lines in which ACLY is localized to either compartment, we find that ACLY in either location supports fatty acid synthesis and histone acetylation, yet compartment-localized ACLY enables finer control. Nuclear ACLY preserves histone H3K23 acetylation under glucose limitation and modulates specific transcriptional programs, whereas cytosolic ACLY most efficiently supports lipid biosynthetic fluxes. Thus, local synthesis defines a preferential metabolic fate, providing more precise regulation.
    DOI:  https://doi.org/10.1126/sciadv.aee4935
  5. Sci Transl Med. 2026 Sep 09. 18(866): eaeb1331
    Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing.
    Julia Carrasco-Zanini, Jorge Andrade, Maik Pietzner, Athanasios Kousathanas, Julius O B Jacobsen, Jenny Lord, Narasimha Telugu, Sebastian Diecke, Michael Mülleder, Dominik Bierbaum, Letizia Vestito, Peter N Robinson, Markus Ralser, Diana Baralle, Nicholas J Wareham, Greg Elgar, Michael Potente, Matthew A Brown, Mark Caulfield, Damian Smedley, Claudia Langenberg.
      Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis. Serum proteomic profiling was performed using the Olink Explore 1536 assay (N = 1463 proteins). For 13 patients without genetic diagnoses, detection of lower serum protein "outliers" (z-score < -2) led to confirmed genetic diagnoses by resolving variants of uncertain significance or prioritizing genes for targeted GS reanalysis. For 23 additional patients without genetic diagnoses (64% of findings), we identified candidate gene-disease links and variants through convergent evidence from lower protein outliers and variants ranked through the variant prioritization tool Exomiser. For example, we identified a candidate heterozygous missense variant [Genome Aggregation Database (gnomAD) minor allele frequency = 0.006%] in tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains 1 (TIE1) that was only present in a patient with lower TIE1 serum abundance (z-score = -5.12) and their father, both of whom were affected by the same monogenic cardiac disorder, but in no other individuals from the 100kGP. Missense (52.5%) and splice region (27.5%) variants accounted for most diagnostic or candidate variants prioritized. This proof-of-principle study demonstrated that serum proteomics can support rare disease diagnosis and identify disease-causing genes in patients undiagnosed after GS, although successful implementation will likely depend on tissue specificity of protein expression, detectability in blood, proteomic platform coverage, and sensitivity.
    DOI:  https://doi.org/10.1126/scitranslmed.aeb1331
  6. Nature. 2026 Sep 09.
    Family-based analyses show how children's genetics shape key traits.
      
    Keywords:  Depression; Genetics
    DOI:  https://doi.org/10.1038/d41586-026-02689-w
  7. Nat Metab. 2026 Sep 11.
    Paediatric proteomic signatures of cardiometabolic disease-associated traits predict adult disease outcomes.
    Joshua M Landman, Heather M Highland, Andrew S Perry, Annie G Howard, Quanhu Sheng, Anna Lorenz, Alexandra B Palmer, Shilin Zhao, Wanying Zhu, Xinruo Zhang, Victoria L Buchanan, Elizabeth G Frankel, Rashedeh Roshani, Alyssa Scartozzi, Eric H Farber-Eger, Mohammad Y Anwar, Jessica K Sprinkles, Ash Breidenbach, Ting-Chen Wang, Christine A Ballard, Matthew Nayor, Jaclyn Tamaroff, Absalon Gutierrez, Lauren E Petty, Alexander S Petty, Benjamin Lippi, Lindsay Fernandez-Rhodes, Hung-Hsin Chen, Mohanraj Krishnan, Mariaelisa Graff, Katie A Meyer, Miryoung Lee, Kristin L Young, Quinn Wells, Kahraman Tanriverdi, Jane E Freedman, Eric R Gamazon, Joseph B McCormick, Susan P Fisher-Hoch, Penny Gordon-Larsen, Jennifer E Below, Kari E North, Ravi V Shah.
      While the earliest pathological signs of cardiovascular-kidney-metabolic disease (CKMD) emerge before age 20, current adult-based risk thresholds fail to identify a substantial fraction of children at high risk. With increasing childhood obesity, early, sensitive detection of CKMD risk is critical to timely intervention. We linked 25 CKMD phenotypes spanning liver, adipose, vascular and dysglycaemia traits to the circulating proteome in 273 Hispanic or Latino children and adolescents (13.1 ± 2.7 years; 53% female). Here we show that proteome signatures of CKMD in children are strongly associated with clinical CKMD outcomes in adults. In 685 adults from the same community and 28,256 adults from UK Biobank, we observe high concordance between the paediatric and adult CKMD phenotype-proteome relationships, related to pancreatic beta-cell health and insulin sensitivity, liver homeostasis, inflammation and cholesterol metabolism. Many proteins linked to paediatric CKMD were modifiable with glucagon-like peptide-1 receptor agonist therapy in adults and are linked to genetic liability to CKMD. These findings support an early origin of CKMD disease liability embedded in the human proteome in children, underscoring the value of precision prevention to forestall metabolic disease long before its clinical manifestation.
    DOI:  https://doi.org/10.1038/s42255-026-01589-7
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