bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–07–19
seven papers selected by
Xiong Weng, University of Edinburgh
  1. Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
  2. Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
  3. FGF21 synergizes with leptin to counteract obesity-related metabolic comorbidities by reversing hepatic leptin resistance.
  4. Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs.
  5. Lysosomes and lysosomal dysfunction in ageing biology.
  6. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
  7. WWP1 modulates metabolic adaptation in white adipose tissue but does not significantly modify caloric restriction-induced longevity in mice.
  1. Nat Metab. 2026 Jul 14.
    Macrophage-derived itaconate is a negative regulator of adipose tissue thermogenesis.
    Jiayin Tang, Gerard Pernes, Brenda Nakagaki, Nhien Tran, Laura Bokor, Fran Prenen, Mingyang Yi, Avery E Robertson, Rachel Cronin, Mohamad Sarmini, Jacob Pierscianowski, Victoria Roberts, Birgitta A Ryback, Carl D Novina, Karine Auclair, Haopeng Xiao, Evanna L Mills.
      Thermogenic brown and beige adipose tissues are important in maintaining metabolic health because of their distinct ability to catabolize stored fat and circulating glucose in futile cycles1,2. Macrophages, present in brown adipose tissue, have been reported to both positively and negatively regulate thermogenic adipocyte function through mechanisms that are incompletely understood3-14. Here we show that the macrophage-derived metabolite, itaconate, acts as a paracrine signal to repress adipose tissue thermogenesis in mice. Mechanistically, itaconate inhibits thermogenesis by antagonizing uptake of the pro-thermogenic metabolite, succinate, into brown adipose tissue. These findings reveal an unexpected mechanism for local control of thermogenesis in vivo that relies on paracrine itaconate signalling and demonstrate that the important signalling roles of itaconate extend beyond immunological processes to the regulation of energy balance.
    DOI:  https://doi.org/10.1038/s42255-026-01572-2
  2. Cell Metab. 2026 Jul 14. pii: S1550-4131(26)00246-9. [Epub ahead of print]
    Brown fat protects against hepatic oxidative stress by remodeling the circulating metabolome.
    Dandan Wang, Mark Li, Tian Lu, Mami Matsushita, Juro Sakai, Masayuki Saito, Takeshi Yoneshiro, Shingo Kajimura.
      Brown adipose tissue (BAT) regulates systemic metabolism beyond thermogenesis, yet the circulating mediators through which BAT communicates with other organs remain less explored. Here, we performed comprehensive serum metabolomics and lipidomics in BAT-ablated mice and human cohorts with varying BAT activity to delineate how BAT activity shapes the circulating metabolome. By integrating datasets across serum, tissues, extracellular fluids, and conditioned media, we assembled BAT-linked circulating molecular signatures. The analyses support a critical role for BAT in the clearance of circulating branched-chain amino acids and triglycerides. We also identified a cold-inducible metabolite, 3-hydroxystearic acid (3-OHSA), produced primarily by BAT and released into circulation. 3-OHSA serves as a circulating readout of cold-activated BAT and acts on the liver to reduce mitochondrial membrane potential and reactive oxygen species production, thereby limiting oxidative stress. This work provides a framework for identifying BAT-derived mediators and uncovers a BAT-liver axis that coordinates adaptation to metabolic stress.
    Keywords:  bioenergetics; brown adipose tissue; inter-organ communication; metabolic health; oxidative stress
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.020
  3. Cell Metab. 2026 Jul 16. pii: S1550-4131(26)00247-0. [Epub ahead of print]
    FGF21 synergizes with leptin to counteract obesity-related metabolic comorbidities by reversing hepatic leptin resistance.
    Qing Shen, Hailan Zou, Leigang Jin, Jiaxin Liu, Shixiang Wang, Na Li, Runhong Zhou, Ming Yue, Baile Wang, Ranyao Yang, Erfei Song, Yifen Lin, Songyan Liao, Zhiwei Chen, Yang Xiao, Yun-Shen Chan, Hung-Fat Tse, Aimin Xu.
      Leptin resistance hinders its therapeutic potential for obesity-related metabolic comorbidities. Here, we show that fibroblast growth factor 21 (FGF21) synergizes with leptin in metabolic regulation by reversing obesity-induced peripheral leptin resistance. FGF21 acts in adipocytes to promote the secretion of adiponectin, which in turn induces the expression of leptin receptors by phosphorylation and activation of the signal transducer and activator of transcription 1 (STAT1) in hepatocytes. Intraperitoneal injection of a long-acting FGF21/leptin dual agonist achieves much more robust pharmacological effects than FGF21 or leptin mono-agonists in protecting mice from diet-induced weight gain, insulin resistance, hyperglycemia, dyslipidemia, and metabolic dysfunction-associated steatotic liver disease without affecting food intake. In human primary hepatocytes and liver organoids, adiponectin but not FGF21 counteracts palmitate/oleate-induced downregulation of leptin receptor b, thereby restoring the effects of leptin in suppressing gluconeogenesis and hepatic steatosis. Thus, FGF21 and leptin dual agonism may represent a promising therapeutic approach for obesity-related multimorbidity through their synergistic and complementary actions in peripheral tissues.
    Keywords:  MASLD; interorgan crosstalk; leptin resistance; metabolic multimorbidity; obesity; peptide hormones
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.021
  4. Nat Metab. 2026 Jul 16.
    Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs.
    Marsel Lino, Gabriel Palermo-Ruiz, Vissarion Efthymiou, Alice Rodrigues, Shraddha Bhonsle, Allah Nawaz, Anindya Ghosh, Bruna Brasil Brandão, Yoshiyuki Watanabe, Rafael Barrera Salgueiro, Yingying Yu, C Ronald Kahn.
      Extracellular microRNAs (miRNAs) are emerging as key regulators of organismal homeostasis. Here, using tissue-specific RNA labelling based on uracil phosphoribosyltransferase-mediated incorporation of 4-thiouracil in male mice, we develop a roadmap of miRNA transfer from brown adipose tissue (BAT) to other tissues, where they can act to regulate energy metabolism. We show that BAT secretes miRNAs in both small extracellular vesicles and is associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in the liver, muscle and hypothalamus. Disruption of Dicer in BAT leads to a significant depletion of multiple miRNAs in both BAT and distal tissues, including 80-90% decreases in the most abundant miRNAs in muscle. Target analyses, in vitro modelling and PAR-CLIP analysis in muscle in vivo confirm that these BAT-secreted miRNAs directly interact with target mRNAs and alter mitochondrial function in recipient tissues. These findings provide a framework for understanding the role of BAT-secreted miRNAs in inter-organ communication.
    DOI:  https://doi.org/10.1038/s42255-026-01558-0
  5. Nat Cell Biol. 2026 Jul 15.
    Lysosomes and lysosomal dysfunction in ageing biology.
    Matthew L Steinhauser, Yuan Liu, Stacey J Sukoff Rizzo, Bill B Chen, Toren Finkel, Jay Xiaojun Tan.
      Lysosomes are essential regulators of cellular homeostasis. Emerging evidence positions lysosomes as both vulnerable targets and active drivers of ageing biology. During ageing, lysosomes exhibit impaired biogenesis, defective acidification, reduced hydrolytic activity and compromised membrane integrity. These defects impair the clearance of damaged organelles and macromolecules and promote cellular stress responses, inflammageing and senescence, causing age-dependent functional decline across tissues. Lysosomal dysfunction has been increasingly linked to age-related diseases, including neurodegeneration, cardiometabolic disorders and increased susceptibility to infection, among others. Thus, lysosomal dysfunction is a hallmark of ageing that drives age-related pathology. Here we review recent progress in lysosomal biogenesis and quality control, discuss how lysosomes intersect with fundamental ageing mechanisms and evaluate emerging therapeutic strategies that target lysosomes to promote healthy ageing and potentially ameliorate age-associated pathologies.
    DOI:  https://doi.org/10.1038/s41556-026-02007-6
  6. Science. 2026 Jul 16. 393(6808): eadx8675
    A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin.
    Alex C Sternisha, Haocheng Li, Kumar Gajendra, Yi Xiao, Xin Zhao, Jeffrey I Traylor, Lei Guo, Ji Hyung Jun, Morgan Fleishman, Tracey Shipman, Vinesh T Puliyappadamba, Pranita Kaphle, Qing Ouyang, Michael Schmidt, Diana D Shi, Milan R Savani, Alexander C-Y Tsai, Joyce H Lee, Ruth Gordillo, Javier Garcia-Bermudez, Yoon Jung Kim, Shih-Chia Tso, Chad A Brautigam, Lauren G Zacharias, Thomas P Mathews, Lin Xu, John G Doench, Vidyasagar Koduri, Kalil G Abdullah, Michalis Agathocleous, Laura A Banaszynski, Ralph J DeBerardinis, Eric M Morrow, Samuel K McBrayer.
      The metabolite α-ketoglutarate (αKG) is required for chromatin demethylation, but mechanisms that control αKG abundance in the nucleus are poorly defined. We designed a biosensor to monitor this metabolite pool in human cells using an αKG-responsive cyanobacterial transcription factor, NtcA, and used it to identify genes that regulate αKG in the nucleus. We defined an interorganelle pathway in which sequential mitochondrial activities of glutamic-pyruvic transaminase 2 (GPT2) and the SLC25A11 transporter supply nuclear αKG. In a mouse model of GPT2 deficiency, an inborn error of metabolism, Gpt2 loss caused histone hypermethylation in the brain and dysregulated neurodevelopmental genes. Restoring αKG counteracted these changes and promoted mouse fitness. Our work provides a tool to directly monitor nuclear αKG and reveals nuclear αKG depletion as a key pathogenic mechanism underlying GPT2 deficiency.
    DOI:  https://doi.org/10.1126/science.adx8675
  7. Front Nutr. 2026 ;13 1846488
    WWP1 modulates metabolic adaptation in white adipose tissue but does not significantly modify caloric restriction-induced longevity in mice.
    Yuka Nozaki, Kumi Miura, Kenta Yajima, Shunsuke Hoshino, Shoma Tamori, Yuhei Mizunoe, Masaki Kobayashi, Yoshikazu Higami.
      Caloric restriction (CR) extends lifespan across diverse species. While the WW domain-containing E3 ubiquitin ligase1 (WWP1) is an essential mediator of dietary restriction-induced longevity in Caenorhabditis elegans, its role in mammalian CR remains unclear. In this study, we investigated the role of WWP1 in CR-mediated longevity and metabolic adaptation using systemic Wwp1 knockout (KO) mice. Male wild-type (WT) and Wwp1 KO mice were subjected to either ad libitum (AL) feeding or long-term CR (70% of AL intake) and monitored throughout their natural lifespan. As a result, Wwp1 deficiency did not markedly modify the CR-associated survival response in mice. Despite comparable food intake, CR-Wwp1 KO mice after middle age exhibited a modest increase in body weight compared with CR WT mice. WWP1 deficiency selectively enhanced CR-induced, Srebp-1c-dependent expression of proteins involved in de novo fatty acid synthesis in epididymal WAT, whereas hepatic lipid metabolism was unaffected. Collectively, our results demonstrated that, unlike in C. elegans, WWP1 is not required for CR-induced longevity in mammals; rather, it acts as a partial suppressor of CR-driven de novo fatty acid metabolism, limits energy storage and lipid retention in WAT.
    Keywords:  WWP1; caloric restriction; de novo fatty acid synthesis; longevity; mice
    DOI:  https://doi.org/10.3389/fnut.2026.1846488
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