bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–05–03
nine papers selected by
Xiong Weng, University of Edinburgh
  1. GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
  2. Hepatic FGF21 is not required for fasting metabolism but guides protein appetite post energy depletion.
  3. ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
  4. Cellular Feimin promotes cold-induced thermogenesis.
  5. Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
  6. Early and late RNA eQTL are driven by different genetic mechanisms.
  7. Epithelial SLC39A1 prevents acute lung injury through zinc-mediated transcriptional activation of autophagy in male mice.
  8. Circulating FGF21 levels reflect liver disease risk and metabolic stress in the UK Biobank.
  9. Mapping functional non-coding variation in individual human genomes through haplotyping, multiomics, and deep learning.
  1. Nature. 2026 Apr 29.
    GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
    Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil, Seun Akindehin, Jonathan E Campbell, Pietra Candela, Russell L Castelino, Callum Coupland, Maxime Culot, W Scott Dodson, Jonathan D Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina Garcia-Caceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M Gutgesell, Daniel T Haas, Martin Jastroch, Ezgi Karaoglu, Pamela Kakimoto, Anna Cristina Kaltenbach, Michaela Keuper, Christine M Kusminski, Danielle C Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez Martinez, Stephanie A Mowery, Ruben Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia S S Petersen, Paul T Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Christian Weber, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L Horvath, Philipp E Scherer, Randy J Seeley, Richard D DiMarchi, Matthias H Tschöp, Natalie Krahmer, Patrick J Knerr, Timo D Müller.
      There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.
    DOI:  https://doi.org/10.1038/s41586-026-10427-5
  2. EMBO Rep. 2026 Apr 27.
    Hepatic FGF21 is not required for fasting metabolism but guides protein appetite post energy depletion.
    Justine Bruse, Clothilde Marbach, Arnaud Polizzi, Tatiana Landre, Juliette Salvi, Valérie Alquier-Bacquie, Shiou-Ping Chen, Marine Huillet, Clémence Rives, Céline M P Martin, Prunelle Perrier, Fadila Benhamed, Marion Régnier, Stefan Weger, Claire Naylies, Yannick Lippi, Caroline Sommer, Mikael Albin, Frédéric Lasserre, Thierry Levade, Michael Schupp, Laurence Gamet-Payrastre, Léon Kautz, Nicolas Loiseau, Walter Wahli, Sandrine Ellero-Simatos, Céline Cruciani-Guglielmacci, Alexandra Montagner, Alexandre Benani, Catherine Postic, Hervé Guillou, Anne Fougerat.
      Fasting initiates a coordinated metabolic response to preserve energy balance. As glycogen stores are depleted, the body transitions to mobilizing fatty acids from adipose tissue and generating ketone bodies in the liver to sustain the function of vital organs. A network of hormonal signals and transcriptional programs coordinate these adaptations. Among these, the hepatokine fibroblast growth factor 21 (FGF21) is strongly upregulated during fasting and has been proposed as a key mediator of the fasting response. To investigate the physiological functions of FGF21, we study mice with hepatocyte-specific deletion of Fgf21. Although the liver is the primary source of circulating FGF21 during fasting, its absence in hepatocytes does not alter typical fasting-induced gene expression or key metabolic pathways such as hepatic gluconeogenesis, adipose tissue lipolysis, or ketone production. Instead, we uncover a distinct role for FGF21 in promoting protein appetite following a fast. These findings challenge the conventional view of hepatocyte-produced FGF21 as a fasting-acting hormone and reveal a more specialized function in guiding nutrient selection after energy depletion.
    DOI:  https://doi.org/10.1038/s44319-026-00790-9
  3. bioRxiv. 2026 Apr 14. pii: 2026.04.12.718013. [Epub ahead of print]
    ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
    Songnan Wang, Yingjie Guo, Weidong An, Michelle Lee, Yu Li, Valentino Sudaryo, Gabriel Grenot, Gemini Skariah, Saranya C Reghupaty, Sonny Young, Xiaochen Bai, Katrin J Svensson, Lingyin Li.
      The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has long been linked with metabolic diseases, with the common ENPP1 K173Q (historically K121Q) variant conferring increased risk for type 2 diabetes (T2D). However, the mechanistic basis of this association has remained unclear. Here, we demonstrate that the K173Q variant has decreased cGAMP hydrolysis activity, suggesting that this loss of enzymatic function could contribute to its pathogenesis. Using a cGAMP-hydrolysis-deficient knock-in mouse ( Enpp1 H362A ), we show that selective loss of this activity leads to a primary defect in energy expenditure and exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An unbiased in vivo glucose-uptake screen reveals brown adipose tissue (BAT) as a focal site of metabolic impairment, characterized by profound extracellular cGAMP accumulation and a selective failure of insulin-stimulated glucose uptake. Mechanistically, we demonstrate that nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP production and export. Excess cGAMP directly propagates STING-dependent suppression of glucose uptake and lipogenesis in brown adipocytes. Additionally, when ENPP1-mediated clearance is compromised, extracellular cGAMP acts as a paracrine immunotransmitter that remodels the BAT microenvironment by recruiting and polarizing macrophages toward an M1-like phenotype. Together, our findings nominate the impaired ENPP1-dependent buffering of extracellular cGAMP as one mechanism by which ENPP1 variants influence metabolic homeostasis.
    DOI:  https://doi.org/10.64898/2026.04.12.718013
  4. Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2534599123
    Cellular Feimin promotes cold-induced thermogenesis.
    Ying Peng, Xiaoliu Shi, Yazhuo Wang, Liangjie Jia, Tiantian Li, Zixin Cai, Hao Li, Jingjing Zhang, Yiguo Wang.
      Adaptive thermogenesis is a fundamental defense against obesity through energy dissipation, yet the molecular mechanisms that couple energy sensing to transcriptional control remain incompletely understood. Here, we identify Feimin as a key activator of adaptive thermogenesis that connects AMP-activated protein kinase (AMPK) signaling to nuclear transcriptional regulation in adipose tissue. Upon cold exposure, AMPK phosphorylates Feimin, promoting translocation of Feimin into the nucleus, where it directly interacts with PGC1α to drive thermogenic gene expression. Conversely, obesity attenuates Feimin phosphorylation and nuclear localization, leading to impaired thermogenic capacity. Adipose-specific Feimin knockout abolishes cold-induced thermogenesis and exacerbates diet-induced obesity, phenotypes that cannot be rescued by a nuclear localization-defective Feimin mutant. Together, these findings delineate an AMPK-Feimin-PGC1α signaling axis essential for thermogenic regulation and identify Feimin as a promising therapeutic target for obesity and metabolic disorders.
    Keywords:  AMPK; Feimin; PGC1α; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2534599123
  5. Nat Commun. 2026 Apr 27.
    Dietary intake and BCAA metabolism regulate pulmonary fibrosis through KDM4A-mediated epigenetic remodeling in male mice.
    Jie Yao, Su Fang, Miao Lei, Zexian Ou, Chuanfei Zeng, Wanli Peng, Na He, Lian Yang, Bingpeng Guo, Mingmeng Fang, Cuihua Wang, Jie Lv, Shuang Wu, Wei Kevin Zhang, Huimin Huang, Yang Peng, Wei Rao, Zhili Rong, Penghui Yang, Chaoqun Wang, Qian Han, Wenxiang Hu.
      Idiopathic pulmonary fibrosis is a progressive and fatal disorder characterized by abnormal activation of alveolar fibroblasts. However, the metabolic reprogramming of alveolar fibroblasts during lung injury remains unclear. Here we show that uptake of branched-chain amino acids is increased, whereas their catabolism is significantly impaired in fibrotic lung fibroblasts and mouse lung tissues. Branched-chain amino acids promote lung fibroblast activation and bleomycin-induced lung fibrosis. Genetic inactivation of branched-chain amino acid transaminase 2 exacerbates fibrosis, whereas inhibition of the corresponding transporter SLC7A5 or enhancement of catabolism attenuates pulmonary fibrosis in male mice. Mechanistically, ATF4 and PPARγ regulate the expression of SLC7A5 and BCAA catabolic genes, respectively. We identify KDM4A as a key mediator of the epigenetic regulation of fibrotic genes. Notably, dysregulated BCAA metabolism is associated with disease severity in patients, suggesting that targeting BCAA metabolism may serve as a promising therapeutic strategy for idiopathic pulmonary fibrosis.
    DOI:  https://doi.org/10.1038/s41467-026-72273-3
  6. Nat Commun. 2026 Apr 25.
    Early and late RNA eQTL are driven by different genetic mechanisms.
    Accelerating Medicines Partnership®: RA/SLE Network
      Understanding the genetic regulation of RNA abundance is essential for defining disease mechanisms. Conventional expression quantitative trait locus (eQTL) studies measure steady-state RNA and capture effects across the entire transcript lifecycle. While most eQTL likely affect transcription by altering promoter or enhancer function within the nucleus, others may act post-transcriptionally through RNA modification or stability in the cytosol. To distinguish these mechanisms, we compare eQTL from mature cellular RNA and recently transcribed nuclear RNA in brain and kidney. We identify distinct causal variants underlying cellular and nuclear eQTL at the same eGenes. Cellular eQTL are enriched in transcribed regions (P = 3.3×10⁻¹²⁶), suggesting post-transcriptional regulation, whereas nuclear eQTL are enriched in distal regulatory elements (P = 7.0×10⁻³²), consistent with transcriptional control. For example, stop-gain variants likely acting through nonsense-mediated decay appear only in cellular eQTL. Conversely, nuclear eQTL variants (e.g., TUBGCP4) within enhancers sometimes uniquely colocalize with disease loci (schizophrenia), revealing distinct regulatory mechanisms.
    DOI:  https://doi.org/10.1038/s41467-026-72139-8
  7. Nat Commun. 2026 Apr 27.
    Epithelial SLC39A1 prevents acute lung injury through zinc-mediated transcriptional activation of autophagy in male mice.
    Jun Zhang, Kun Zhang, Yishi Li, Lejiao Mao, Ge Xu, Yinzhen Fan, Hong Ling, Na Li, Zhihui Liu, Shuliang Guo, Chengzhi Chen, Zhen Zou.
      Zinc transporters regulate intracellular zinc homeostasis, but their role in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remains underexplored. Here, we show that the zinc transporter SLC39A1 is highly upregulated in alveolar type II (AT2) cells from male murine ALI models and patients with ARDS. AT2-specific Slc39a1 deletion or zinc chelation exacerbates lung injury, whereas overexpression or zinc supplementation attenuates it. Notably, zinc supplementation fails to rescue Slc39a1-deficient mice, indicating SLC39A1 governs zinc uptake to control ALI. Zinc likely directly binds to and activates TFEB, TFE3, and MITF, inducing transcriptional activation of autophagy to eliminate damaged mitochondria and suppress apoptosis/pyroptosis in AT2 cells. Lc3b- or Tfe3-deficient mice show heightened lung injury, which remain unmitigated by zinc supplementation. Importantly, administration of AAV-shLc3b to AT2 Slc39a1-deficient mice did not further aggravate lung injury beyond that caused by either intervention alone. This epistatic relationship places SLC39A1 upstream of autophagy activation within a linear pathway. Collectively, we define an essential role for epithelial SLC39A1 in host defense against ALI/ARDS, which is mediated by a protective zinc-autophagy axis.
    DOI:  https://doi.org/10.1038/s41467-026-72403-x
  8. J Hepatol. 2026 Apr 29. pii: S0168-8278(26)00223-0. [Epub ahead of print]
    Circulating FGF21 levels reflect liver disease risk and metabolic stress in the UK Biobank.
    Shaoyang Yan, Boda Zhou.
      
    DOI:  https://doi.org/10.1016/j.jhep.2026.04.020
  9. Nat Commun. 2026 Apr 29.
    Mapping functional non-coding variation in individual human genomes through haplotyping, multiomics, and deep learning.
    Mikhail D Magnitov, Robin H van der Weide, Aster F Witvliet, Miguel Hernández-Quiles, Moreno Martinović, Hans Teunissen, Luca Braccioli, Michiel Vermeulen, Elzo de Wit.
      Most genetic variants in the human genome reside in non-coding regions, where they can perturb regulatory element activity to influence gene expression, thereby contributing to various phenotypes and diseases. However, identifying functionally relevant non-coding genetic variation remains challenging. Here we integrate personal genomics, allele-specific gene regulation, and deep learning predictions to map the impact of non-coding variation in its native allelic and regulatory context. Leveraging whole-chromosome haplotypes and allele-specific analyses, we establish regulatory links within individual human genomes, enabling us to evaluate functional consequences of both common and rare variants. We identify and validate hundreds of cell-type-specific transcription factor binding events disrupted by genetic variants, revealing known and novel mechanisms that underlie allele-specific chromatin accessibility and gene expression. Using this framework, we discovered a rare variant that disrupted an OCT2 binding site within a distal enhancer, thereby modulating the expression of PIK3R5 gene. Our study establishes a generalisable strategy for interpreting non-coding regulatory variation, enabling systematic dissection of variant effects across diverse biological systems and offering a framework to investigate disease mechanisms.
    DOI:  https://doi.org/10.1038/s41467-026-72392-x
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