bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–10–04
eight papers selected by
Xiong Weng, University of Edinburgh
  1. Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
  2. ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
  3. Advancing aging biomarkers and intervention discovery at the TimePie Longevity Forum.
  4. ETS-2 deficiency impairs brown adipose tissue function through Prdm16 repression.
  5. Distinct multi-omics signatures of clinical subgroups of type 2 diabetes define heterogeneous responses to an insulin sensitizer.
  6. Decoding mitochondrial proteomes of diverse eukaryotes.
  7. PI(3,5)P2 controls the signaling activity of class I PI3K.
  8. Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.
  1. Science. 2026 Oct;394(6819): eadz4797
    Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of adipocyte lipid cycling.
    Iuliia Karavaeva, Astrid Linde Basse, Samuel A J Trammell, Mohammed Faiz Hussain, Lasse Kruse Markussen, Jesper F Havelund, Marie Sophie Isidor, Adam Chatoff, Andrea Andress Huacachino, Hannah J Richter, Meghna Birla, Sabina Chubanava, Yann Deleye, Rini Arianti, David Tandio, Sarah E Utzon, Zafir Kaiser, Yachen Shen, Ditte Neess, Hannes Embring, Dilip Menon, Olivia J Conway, Frederike Sass, Fabian Finger, Lidia Argemi-Muntadas, Tao Ma, Elahu G Sustarsic, Cecilie Kynding Kristensen, Rebecca L McIntyre, Genesee J Martinez, Anna Sofie Husted, Matthew J Emmett, Zachary A Kipp, Mikkel Frost, Mark P Jedrychowski, Michel van Weeghel, Homa Majd, Ekaterina Zhuravleva, Robert W McGarrah, Kaja Plucińska, Mohit K Midha, Andreas Prokesch, Paul Cohen, James G Granneman, Patrick Seale, Riekelt H Houtkooper, Jacob B Hansen, Steven P Gygi, Thue W Schwartz, Matthew P Gillum, Terry D Hinds, Raymond E Soccio, Phillip J White, Edmund R S Kunji, Thomas Moritz, Jonas T Treebak, Endre Kristóf, Susanne Mandrup, Brice Emanuelli, Nathaniel W Snyder, Daniel J Fazakerley, Lawrence Kazak, Nils J Færgeman, Mitchell A Lazar, Zachary Gerhart-Hines.
      Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature, but how these diverse signals are molecularly integrated remains unknown. We showed that these cues converge on the orphan mitochondrial transporter SLC25A34 to orchestrate lipid cycling. During the sleep phase, the adipocyte clock suppresses Slc25a34 expression through the REV-ERB transcriptional repressors. Entering the active phase, consuming lipid-rich diets, or exposure to cold abolishes REV-ERB repression, and lipolytic signals stimulate Slc25a34 transcription through the peroxisome proliferator-activated receptors. SLC25A34 is proposed to import oxaloacetate into mitochondria, dually supporting the tricarboxylic acid cycle and cytosolic acetyl-coenzyme A (acetyl-CoA) production. Elevated cytosolic acetyl-CoA then fuels the synthesis of lipids and promotes the transcription of genes enhancing mitochondrial oxidation. Thus, SLC25A34 confers circadian, dietary, and temperature control of adipocyte lipid metabolism.
    DOI:  https://doi.org/10.1126/science.adz4797
  2. Nat Commun. 2026 Aug 27. pii: 10297. [Epub ahead of print]17(1):
    ALKBH5-mediated microglia-neuron crosstalk inhibits sympathetic innervation and adipocyte browning in male mice.
    Yong-Feng Yang, Yan Li, Mei-Hua Chen, Xi-De Hu, Yi-Jie Hua, Xiao-Dong Shi, Dong-Hua Hu, Ting Meng, Cheng-Yu Sheng, Tao Zhuang, Cheng-Chao Ruan, Xiang-Rong Zuo, Yu Lei, Ruo-Gu Li.
      Interactions between nervous system and adipose tissue are involved in the regulation of adipocyte browning. However, whether microglial activation participates in the regulation of cold exposure-induced sympathetic innervation and adipocyte browning is unclear. Here, we demonstrate that RNA m6A demethylase ALKBH5 in the microglia nucleus of hypothalamus (PVH) region inhibits cold exposure-induced adipocyte browning in the subcutaneous white adipose tissue (sWAT) of male mice. The single nuclear-RNA sequencing, brain slice electrophysiological assay and pathological analyses show that microglia-specific ALKBH5 knockout (MCKO) enhances sympathetic activation and adipocyte browning in the sWAT during cold exposure. Mechanistically, MCKO enhances m6A methylation of Ntf5 mRNA and upregulates Ntf5 expression in the microglia. Ntf5 then activates PVH-TrkB neurons and downstream sympathetic innervation in the sWAT. During aging, MCKO prevents brown adipocyte decline in the sWAT, and promotes metabolic activity. These findings fill a gap in the research of microglia in neuron-mediated adipocyte browning, and suggest that microglia may be a potential therapeutic target for the treatment of individuals with metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-77050-w
  3. Nat Aging. 2026 Sep 30.
    Advancing aging biomarkers and intervention discovery at the TimePie Longevity Forum.
    Kejun Ying, Juntao Bie, Guobing Chen, Ana Maria Cuervo, Haiteng Deng, Lu Dong, David Furman, Vera Gorbunova, Jing-Dong J Han, Steve Horvath, Guangju Ji, Ning Jiang, Raul Mostoslavsky, Susanna Rosi, Andrei Seluanov, Vincenzo Sorrentino, Yuhan Tang, Jan Vijg, Qingling Yang.
      
    DOI:  https://doi.org/10.1038/s43587-026-01226-8
  4. Metabolism. 2026 Sep 26. pii: S0026-0495(26)00301-X. [Epub ahead of print]185 156788
    ETS-2 deficiency impairs brown adipose tissue function through Prdm16 repression.
    Hongjin Chen, Xinrong Zhai, Youjun Zhang, Kun Chen, Lei Fu, Donghua Hu, Zhiyuan Zheng, Shaofeng Guan, Xinkai Qu, Maoqing Ye.
       BACKGROUND: Brown adipose tissue (BAT) and beige adipocytes regulate adaptive thermogenesis and systemic energy balance, whereas BAT dysfunction contributes to obesity and metabolic disease. Although ETS transcription factors participate in adipocyte biology, the role of ETS-2 in BAT remains unclear.
    METHODS: Adipocyte-specific Ets-2 knockout mice were generated using the Adipoq-Cre system. BAT morphology, thermogenic responses, energy expenditure, and mitochondrial structure and function were assessed under basal conditions, cold exposure, β3-adrenergic stimulation, and mTOR activation. Primary adipocytes were used for gain- and loss-of-function analyses. RNA-seq, CUT&Tag, luciferase reporter assays, Seahorse respirometry, rescue experiments, and public human adipose single-nucleus RNA-seq analyses were performed.
    RESULTS: ETS-2 was enriched in BAT and dynamically regulated during adipocyte differentiation. Adipocyte-specific Ets-2 deletion induced BAT whitening, reduced UCP-1 expression, impaired cold tolerance and β3-adrenergic responsiveness, and decreased oxygen consumption and energy expenditure. ETS-2 deficiency also disrupted mitochondrial ultrastructure and reduced respiratory capacity in brown adipocytes. Mechanistically, integrated RNA-seq and CUT&Tag identified Prdm16 as a direct ETS-2 target. ETS-2 loss repressed PRDM16, suppressed the PRDM16-PGC-1α-UCP-1 thermogenic program, and attenuated IRS-1-PI3K/Akt-mTOR signaling. PRDM16 overexpression and mTOR activation partially rescued ETS-2-deficient phenotypes. Human single-nucleus data further supported conservation of this regulatory axis.
    CONCLUSION: ETS-2 is a critical transcriptional regulator of BAT thermogenic function. By directly activating Prdm16 and maintaining both the PRDM16-PGC-1α-UCP-1 axis and IRS-1-PI3K/Akt-mTOR signaling, ETS-2 preserves mitochondrial integrity and adaptive thermogenesis. These findings identify the ETS-2-PRDM16 axis as a potential therapeutic target for metabolic diseases associated with BAT dysfunction.
    Keywords:  Adipocyte browning; Adipose thermogenesis; ETS-2; Mitochondria; PI3K/Akt/mTOR signaling; PRDM16
    DOI:  https://doi.org/10.1016/j.metabol.2026.156788
  5. Nat Commun. 2026 Aug 29. pii: 10311. [Epub ahead of print]17(1):
    Distinct multi-omics signatures of clinical subgroups of type 2 diabetes define heterogeneous responses to an insulin sensitizer.
    Zehui Cao, Ruolan Zhang, Haonan Chen, Naixin Zhang, Qiaochu Chen, Yuanbang Mai, Xintong Yao, Qingwang Chen, Jiaqi Li, Desi Pan, Linong Ji, Weiping Jia, Xianping Lu, Antonio Vidal-Puig, Leming Shi, Yan Zheng, Yuanting Zheng.
      Type 2 diabetes (T2D) subgroups defined by clinical variables differ in disease progression and treatment response. To uncover potential molecular drivers of this heterogeneity, we performed a multi-omics analysis of 826 drug-naïve T2D patients from two phase 3 trials of the insulin sensitizer chiglitazar. Here we show that severe insulin-resistant diabetes (SIRD) is characterized by distinct miRNA profiles (e.g., miR-122-5p) correlated with liver injury, and metabolic shifts in amino acids and primary bile acids. Mild obesity-related diabetes (MOD) showed the lowest level of phenylacetylglutamine, a metabolite known to promote cardiovascular disease. Severe insulin-deficient diabetes (SIDD) exhibited high pancreas-specific miR-7-5p, while mild age-related diabetes (MARD) presented the mildest abnormalities. Finally, integrating these multi-omics signatures into machine learning models enhanced prediction of insulin sensitizer efficacy over clinical data alone. Our findings define the distinct molecular signatures of T2D subgroups, facilitating the prediction of heterogeneous treatment responses and supporting personalized clinical management.
    DOI:  https://doi.org/10.1038/s41467-026-77187-8
  6. Cell. 2026 Oct 01. pii: S0092-8674(26)01076-7. [Epub ahead of print]189(20): 6243-6245
    Decoding mitochondrial proteomes of diverse eukaryotes.
    Vamsi K Mootha, Sarah E Calvo.
      Our textbook view of mitochondria, which has been shaped by studies in animals and yeast, fails to do justice to the organelle's broader eukaryotic diversity. While most mitochondria retain a tiny genome, the overwhelming majority of their proteins are nuclear-encoded and vary extensively across lineages. To map this diversity, the MitoCarta Tree of Life Consortium developed experimental and computational workflows to generate high-accuracy mitochondrial proteomes across diverse eukaryotes-helping to lay a foundation for comparative mitochondrial biology with broad implications for physiology, evolution, and disease.
    DOI:  https://doi.org/10.1016/j.cell.2026.09.007
  7. Sci Adv. 2026 Oct 02. 12(40): eaeh8582
    PI(3,5)P2 controls the signaling activity of class I PI3K.
    Jiachen Sun, Julian Zalejski, Seohyeon Song, Ashutosh Sharma, Wei Wang, Yusi Hu, Wen-Ting Lo, Philipp Alexander Koch, Duy-Viet Vo, Jagriti Singh, Indira Singaram, Baoshu An, Hirushi Gunasekara, Jean J Zhao, Liang-Wei Gong, Ying S Hu, Volker Haucke, Ruixuan Gao, Wonhwa Cho.
      3-Phosphoinositides are essential cellular lipids regulating health and disease. Among them, phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2] remains the least understood. Using a newly developed ratiometric PI(3,5)P2 sensor that enables spatiotemporally resolved PI(3,5)P2 quantification, we demonstrate that growth factor stimulation generates a distinct PI(3,5)P2 pool on lysosomes and late endosomes. Formed sequentially by class II PI3KC2β and PIKfyve, this PI(3,5)P2 pool terminates growth factor-stimulated class I phosphatidylinositol 3-kinase (PI3K) activity through a specific interaction with its regulatory p85 subunit. Disrupting this p85-PI(3,5)P2 interaction via a small-molecule inhibitor or cancer-causing mutations blocks feedback inhibition, driving sustained class I PI3K activation and promoting neurite growth. Our findings uncover a spatiotemporally specific regulatory function of PI(3,5)P2 that links class I and II PI3Ks to tune growth factor signaling. This mechanism offers therapeutic strategies for treating p85-mutant cancers and advancing tissue regeneration.
    DOI:  https://doi.org/10.1126/sciadv.aeh8582
  8. Mol Genet Genomic Med. 2026 Oct;14(10): e70319
    Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.
    Himanshu Goel, Shuxiang Goh, Luke Stuart.
       BACKGROUND: Epigenomic testing complements sequence-based analysis by detecting downstream changes in epigenomic state associated with genetic variation. Genome-wide DNA methylation episignatures are reproducible molecular phenotypes that can serve as biomarkers of specific Mendelian disorders, particularly those involving chromatin regulators, DNA methylation machinery, and transcriptional regulatory pathways.
    METHODS: We reviewed the biological basis, laboratory methodology, analytical approaches and clinical applications of DNA methylation episignature testing, with emphasis on neurodevelopmental disorders and rare diseases. We also considered current computational tools, limitations of clinical interpretation and emerging epigenomic and epitranscriptomic approaches.
    RESULTS: DNA methylation episignature testing is now used clinically to support molecular diagnosis, assist interpretation of variants of uncertain significance and distinguish overlapping neurodevelopmental and chromatin-related disorders. Interpretation integrates methylation-array data, statistical and machine-learning classification, phenotype, genotype and assay-specific validation. Important limitations include tissue specificity, mosaicism, developmental effects, incomplete disorder coverage and dependence on reference datasets. Emerging approaches include tissue-agnostic classifiers, long-read methylation profiling, additional epigenomic signatures and multi-omic integration.
    CONCLUSION: DNA methylation episignatures provide a clinically useful functional layer of evidence by detecting downstream epigenomic consequences of genomic variation. They should be interpreted as an adjunct to sequence-based diagnosis and clinical assessment rather than as a replacement for either. Continued expansion of reference datasets and integration with other functional genomic approaches should broaden their diagnostic utility.
    Keywords:  DNA methylation; chromatinopathy; clinical epigenomics; episignature; long‐read sequencing; m6A; multi‐omics; neurodevelopmental disorder; rare disease; variant of uncertain significance
    DOI:  https://doi.org/10.1002/mgg3.70319
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒04 at 10:23.