bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–06–01
eight papers selected by
José Carlos de Lima-Júnior, Washington University
  1. CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
  2. Reverse electron transport drives metabolic changes in obesity.
  3. Preoptic EP3R neurons constitute a two-way switch for fever and torpor.
  4. The Evaluation of Significance of Uncoupling Protein Genes UCP1, UCP2, UCP3, UCP4, UCP5, and UCP6 in Human Adaptation to Cold Climates.
  5. Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
  6. DNA methyltransferase inhibition by 5-azacytidine promotes thermogenic programming in beige adipocytes.
  7. Personalized molecular signatures of insulin resistance and type 2 diabetes.
  8. Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
  1. Nature. 2025 May 28.
    CoQ imbalance drives reverse electron transport to disrupt liver metabolism.
    Renata L S Goncalves, Zeqiu Branden Wang, Jillian K Riveros, Güneş Parlakgül, Karen E Inouye, Grace Yankun Lee, Xiaorong Fu, Jani Saksi, Clement Rosique, Sheng Tony Hui, Mar Coll, Ana Paula Arruda, Shawn C Burgess, Isabel Graupera, Gökhan S Hotamışlıgil.
      Mitochondrial reactive oxygen species (mROS) are central to physiology1,2. Excess mROS production has been associated with several disease states2,3; however, the precise sources, regulation and mechanism of generation in vivo remain unclear, which limits translational efforts. Here we show that in obesity, hepatic coenzyme Q (CoQ) synthesis is impaired, which increases the CoQH2 to CoQ (CoQH2/CoQ) ratio and drives excessive mROS production through reverse electron transport (RET) from site IQ in complex I. Using multiple complementary genetic and pharmacological models in vivo, we demonstrate that RET is crucial for metabolic health. In patients with steatosis, the hepatic CoQ biosynthetic program is also suppressed, and the CoQH2/CoQ ratio positively correlates with disease severity. Our data identify a highly selective mechanism for pathological mROS production in obesity, which can be targeted to protect metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09072-1
  2. Nature. 2025 May 28.
    Reverse electron transport drives metabolic changes in obesity.
      
    Keywords:  Metabolism; Obesity; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01621-y
  3. Nature. 2025 May 28.
    Preoptic EP3R neurons constitute a two-way switch for fever and torpor.
    Natalia L S Machado, Nicole Lynch, Luis H A Costa, David Melville, Hakan Kucukdereli, Satvinder Kaur, Alexander S Banks, Francesca Raffin, Oscar D Ramirez-Plascencia, Sydney Aten, Janayna D Lima, Sathyajit S Bandaru, Richard D Palmiter, Clifford B Saper.
      Many species use a temporary decrease in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity in a cool environment. Torpor is caused by preoptic neurons that express a variety of peptides and receptors1-7, but no single genetic marker has been found for this population. Here we report that expression of the prostaglandin EP3 receptor (EP3R) marks a unique population of median preoptic nucleus (MnPO) neurons that are required for both torpor and lipopolysaccharide-induced fever8. The MnPO-EP3R neurons produce persistent fever responses when inhibited and prolonged hypothermic responses when activated either chemogenetically or optogenetically, even for brief periods of time. The mechanism for these prolonged responses appears to involve increases in intracellular levels of cAMP and calcium that may persist for many minutes up to hours beyond the termination of a stimulus. These properties endow the population of MnPO-EP3R neurons with the ability to act as a two-way switch for the hypothermic and hyperthermic responses that are required for survival.
    DOI:  https://doi.org/10.1038/s41586-025-09056-1
  4. Biology (Basel). 2025 Apr 23. pii: 454. [Epub ahead of print]14(5):
    The Evaluation of Significance of Uncoupling Protein Genes UCP1, UCP2, UCP3, UCP4, UCP5, and UCP6 in Human Adaptation to Cold Climates.
    Alena A Nikanorova, Nikolay A Barashkov, Vera G Pshennikova, Sergey S Nakhodkin, Georgii P Romanov, Aisen V Solovyev, Sardana A Fedorova.
      Six isoforms of uncoupling proteins (UCPs) exist, spanning from UCP1 to UCP6. A precise physiological function has only been established for UCP1, which is involved in non-shivering thermogenesis, but the functions of other UCPs are still not fully defined. Therefore, the purpose of the present study is to search for indications of the involvement of nine polymorphic variants of UCP1-6 genes in human adaptation to cold climates using four criteria: (1) the presence of associations of polymorphic variants of UCP genes with levels of thyroid-stimulating hormone, free triiodothyronine, and free thyroxine; (2) the presence of associations of polymorphic variants of UCP genes with changes in thyroid homeostasis (SPINA); (3) the presence of associations of polymorphic variants of UCP genes with body surface area; (4) the presence of signals of directional selection to cold climate for polymorphic variants of UCP genes. As a result of the evaluation, the highest scores for cold adaptation traits were recorded for polymorphic variants rs3811787 of the UCP1 gene and rs1800849 of the UCP3 gene. We suggest that the results obtained indicate the importance of uncoupling proteins UCP1 and UCP3 in human adaptation to cold through processes of non-shivering and shivering thermogenesis.
    Keywords:  UCP1; UCP3; adaptation; cold climate; free triiodothyronine (FT3); non-shivering thermogenesis; shivering thermogenesis; uncoupling proteins
    DOI:  https://doi.org/10.3390/biology14050454
  5. Nat Cell Biol. 2025 May 28.
    Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport.
    Zizhen Xu, Ying Meng, Jonathan St-Germain, Arezoo Afshari, Charneal L Dixon, Saskia Heybrock, Qiang Zhao, Xialian Weng, Jishun Chen, Richard Collins, Hu Hu, Quan Zhou, Qiming Sun, Pinglong Xu, Wei Liu, Paul Saftig, Brian Raught, Gregory D Fairn, Dante Neculai.
      Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER-PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER-PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.
    DOI:  https://doi.org/10.1038/s41556-025-01665-2
  6. Biochem Biophys Res Commun. 2025 May 26. pii: S0006-291X(25)00808-3. [Epub ahead of print]774 152094
    DNA methyltransferase inhibition by 5-azacytidine promotes thermogenic programming in beige adipocytes.
    Masashi Kuroda, Kazuhiro Nomura, Rin Chamoto, Yuna Izumi-Mishima, Sonoko Yasui-Yamada, Yasuo M Tsutsumi, Rie Tsutsumi, Hiroshi Sakaue.
      Beige adipocytes play a critical role in energy metabolism by promoting thermogenesis, a process largely influenced by epigenetic modifications such as DNA methylation. This study investigates the effect of DNA demethylation on beige adipocyte differentiation and function using 5-azacytidine (5-AzaC), a DNA methyltransferase inhibitor. We evaluated changes in adipogenic and thermogenic gene expression, mitochondrial activity, and fatty acid uptake following 5-AzaC treatment in 3T3-L1-derived beige adipocytes. Our findings indicate that 5-AzaC does not significantly affect adipocyte differentiation but enhances thermogenic gene expression, including Ucp1 and Cox7a1, and increases mitochondrial function and fatty acid uptake. These results suggest that DNA demethylation modulates beige adipocyte function and may have implications for metabolic disorders such as obesity and type 2 diabetes.
    Keywords:  5-Azacytidine; Beige adipocyte; DNA methylation; Thermogenic gene expression
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152094
  7. Cell. 2025 May 21. pii: S0092-8674(25)00515-X. [Epub ahead of print]
    Personalized molecular signatures of insulin resistance and type 2 diabetes.
    Jeppe Kjærgaard, Ben Stocks, John Henderson, Jordana B Freemantle, David Rizo-Roca, Michele Puglia, Maria Madrazo Montoya, Daniel Andersson, Jesper Bäckdahl, Daniel Eriksson-Hogling, Jacob V Stidsen, Michael Wierer, Simon Rasmussen, Kei Sakamoto, Kurt Højlund, Mikael Rydén, Juleen R Zierath, Anna Krook, Atul S Deshmukh.
      Insulin resistance is a hallmark of type 2 diabetes, which is a highly heterogeneous disease with diverse pathology. Understanding the molecular signatures of insulin resistance and its association with individual phenotypic traits is crucial for advancing precision medicine in type 2 diabetes. Utilizing cutting-edge proteomics technology, we mapped the proteome and phosphoproteome of skeletal muscle from >120 men and women with normal glucose tolerance or type 2 diabetes, with varying degrees of insulin sensitivity. Leveraging deep in vivo phenotyping, we reveal that fasting proteome and phosphoproteome signatures strongly predict insulin sensitivity. Furthermore, the insulin-stimulated phosphoproteome revealed both dysregulated and preserved signaling nodes-even in individuals with severe insulin resistance. While substantial sex-specific differences in the proteome and phosphoproteome were identified, molecular signatures of insulin resistance remained largely similar between men and women. These findings emphasize the necessity of incorporating disease heterogeneity into type 2 diabetes care strategies.
    Keywords:  disease heterogeneity; glucose metabolism; phosphoproteomics; sex differences; signaling; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cell.2025.05.005
  8. Mol Cell. 2025 May 21. pii: S1097-2765(25)00412-5. [Epub ahead of print]
    Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.
    Tigist Y Tamir, Shreya Chaudhary, Annie X Li, Sonia E Trojan, Cameron T Flower, Paula Vo, Yufei Cui, Jeffrey C Davis, Rachit Mukkamala, Francesca N Venditti, Alissandra L Hillis, Alex Toker, Matthew G Vander Heiden, Jessica B Spinelli, Norman J Kennedy, Roger J Davis, Forest M White.
      Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.
    Keywords:  GSTP1; IDH1; UMPS; cell signaling; computational modelling; metabolism; metabolomics; obesity; oxidative stress response; phosphoproteomics
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.007
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