bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2025–03–09
seven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
  2. Constitutively active glucagon receptor drives high blood glucose in birds.
  3. A cellular and molecular basis of leptin resistance.
  4. Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
  5. A cryptic pocket in CB1 drives peripheral and functional selectivity.
  6. Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2.
  7. HCN4 channels sense temperature and determine heart rate responses to heat.
  1. EMBO J. 2025 Feb 28.
    Proton conductance by human uncoupling protein 1 is inhibited by purine and pyrimidine nucleotides.
    Scott A Jones, Alice P Sowton, Denis Lacabanne, Martin S King, Shane M Palmer, Thomas Zögg, Els Pardon, Jan Steyaert, Jonathan J Ruprecht, Edmund R S Kunji.
      Uncoupling protein 1 (UCP1, SLC25A7) is responsible for the thermogenic properties of brown adipose tissue. Upon fatty acid activation, UCP1 facilitates proton leakage, dissipating the mitochondrial proton motive force to release energy as heat. Purine nucleotides are considered to be the only inhibitors of UCP1 activity, binding to its central cavity to lock UCP1 in a proton-impermeable conformation. Here we show that pyrimidine nucleotides can also bind and inhibit its proton-conducting activity. All nucleotides bound in a pH-dependent manner, with the highest binding affinity observed for ATP, followed by dTTP, UTP, GTP and CTP. We also determined the structural basis of UTP binding to UCP1, showing that binding of purine and pyrimidine nucleotides follows the same molecular principles. We find that the closely related mitochondrial dicarboxylate carrier (SLC25A10) and oxoglutarate carrier (SLC25A11) have many cavity residues in common, but do not bind nucleotides. Thus, while UCP1 has evolved from dicarboxylate carriers, no selection for nucleobase specificity has occurred, highlighting the importance of the pH-dependent nucleotide binding mechanism mediated via the phosphate moieties.
    Keywords:  Bioenergetics; Pyrimidine Nucleotides; SLC25; Thermogenesis; Uncoupling Protein
    DOI:  https://doi.org/10.1038/s44318-025-00395-3
  2. Nature. 2025 Mar 03.
    Constitutively active glucagon receptor drives high blood glucose in birds.
    Chang Zhang, Xiangying Xiang, Jian Liu, Yongjie Huang, Jingwen Xue, Qian Sun, Song Leng, Shaobo Liu, Xuefei He, Peng Hu, Xiangjiang Zhan, Qiang Qiu, Shilong Yang, Jürgen Brosius, Cheng Deng.
      As the body's primary source of energy, the maintenance of blood glucose is indispensable for overall health and metabolic homeostasis. It is predominantly regulated by the glucagon receptor family which is highly conserved in vertebrates1-4. Compared to other vertebrates, avian blood glucose levels are relatively high5,6, yet its regulatory mechanisms have remained obscure for more than a century. We show that high hepatic expression of the avian glucagon receptor (GCGR) in association with constitutively active Gs signaling was dependent upon the interaction of different domains. In vivo experiments focusing on the regulation of constitutively active GCGR expression in hepatic cells led to correspondingly high blood glucose, rapid hepatic lipid utilization and high metabolic rates via downstream signaling pathway activation in fish, reptiles, birds, and mammals. Furthermore, we identified a point mutation in chicken at the proximal gene region that resulted in GCGR mRNA reduction and weight increase. Overexpressing a natural human GCGR mutation (hsGCGRH339R) with modest constitutive activity in mice, demonstrated that high level expression of this variant augmented high blood glucose, while reducing body weight. The combination of high expression and constitutive activity of the glucagon receptor may have contributed to the evolution of flight in the ancestors of birds.
    DOI:  https://doi.org/10.1038/s41586-025-08811-8
  3. Cell Metab. 2025 Mar 04. pii: S1550-4131(25)00001-4. [Epub ahead of print]37(3): 723-741.e6
    A cellular and molecular basis of leptin resistance.
    Bowen Tan, Kristina Hedbacker, Leah Kelly, Zhaoyue Zhang, Alexandre Moura-Assis, Ji-Dung Luo, Joshua D Rabinowitz, Jeffrey M Friedman.
      Similar to most humans with obesity, diet-induced obese (DIO) mice have high leptin levels and fail to respond to the exogenous hormone, suggesting that their obesity is caused by leptin resistance, the pathogenesis of which is unknown. We found that leptin treatment reduced plasma levels of leucine and methionine, mTOR-activating ligands, leading us to hypothesize that chronic mTOR activation might reduce leptin signaling. Rapamycin, an mTOR inhibitor, reduced fat mass and increased leptin sensitivity in DIO mice but not in mice with defects in leptin signaling. Rapamycin restored leptin's actions on POMC neurons and failed to reduce the weight of mice with defects in melanocortin signaling. mTOR activation in POMC neurons caused leptin resistance, whereas POMC-specific mutations in mTOR activators decreased weight gain of DIO mice. Thus, increased mTOR activity in POMC neurons is necessary and sufficient for the development of leptin resistance in DIO mice, establishing a key pathogenic mechanism leading to obesity.
    Keywords:  POMC; diet-induced obesity; leptin; leptin resistance; mTOR; rapamycin
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.001
  4. Nature. 2025 Mar 05.
    Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
    Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.
      The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
    DOI:  https://doi.org/10.1038/s41586-025-08667-y
  5. Nature. 2025 Mar 05.
    A cryptic pocket in CB1 drives peripheral and functional selectivity.
    Vipin Ashok Rangari, Evan S O'Brien, Alexander S Powers, Richard A Slivicki, Zachariah Bertels, Kevin Appourchaux, Deniz Aydin, Nokomis Ramos-Gonzalez, Juliet Mwirigi, Li Lin, Elizaveta Mangutov, Briana L Sobecks, Yaseen Awad-Agbaria, Manoj B Uphade, Jhoan Aguilar, Teja Nikhil Peddada, Yuki Shiimura, Xi-Ping Huang, Jakayla Folarin-Hines, Maria Payne, Anirudh Kalathil, Balazs R Varga, Brian K Kobilka, Amynah A Pradhan, Michael D Cameron, Kaavya Krishna Kumar, Ron O Dror, Robert W Gereau, Susruta Majumdar.
      The current opioid overdose epidemic highlights the urgent need to develop safer and more effective treatments for chronic pain1. Cannabinoid receptor type 1 (CB1) is a promising non-opioid target for pain relief, but its clinical use has been limited by centrally mediated psychoactivity and tolerance. We overcame both issues by designing peripherally restricted CB1 agonists that minimize arrestin recruitment. We achieved these goals by computationally designing positively charged derivatives of the potent CB1 agonist MDMB-Fubinaca2. We designed these ligands to occupy a cryptic pocket identified through molecular dynamics simulations-an extended binding pocket that opens rarely and leads to the conserved signalling residue D2.50 (ref. 3). We used structure determination, pharmacological assays and molecular dynamics simulations to verify the binding modes of these ligands and to determine the molecular mechanism by which they achieve this dampening of arrestin recruitment. Our lead ligand, VIP36, is highly peripherally restricted and demonstrates notable efficacy in three mouse pain models, with 100-fold dose separation between analgesic efficacy and centrally mediated side effects. VIP36 exerts analgesic efficacy through peripheral CB1 receptors and shows limited analgesic tolerance. These results show how targeting a cryptic pocket in a G-protein-coupled receptor can lead to enhanced peripheral selectivity, biased signalling, desired in vivo pharmacology and reduced adverse effects. This has substantial implications for chronic pain treatment but could also revolutionize the design of drugs targeting other G-protein-coupled receptors.
    DOI:  https://doi.org/10.1038/s41586-025-08618-7
  6. Diabetes. 2025 Feb 28. pii: db241003. [Epub ahead of print]
    Regulation of Type 1 Diabetes via Brown Adipocyte-Secreted Proteins and the Novel Glucagon Regulator Nidogen-2.
    Jeongmin Lee, Alessandro Ustione, Emily M Wilkerson, Rekha Balakrishnan, Debbie C Thurmond, Dennis Goldfarb, David W Piston.
      Current treatments for type 1 diabetes (T1D) focus on insulin replacement. We demonstrate the therapeutic potential of a secreted protein fraction from embryonic brown adipose tissue (BAT) that mediates insulin receptor-dependent recovery of euglycemia in a T1D model, nonobese diabetic (NOD) mice, by suppressing glucagon secretion. This fraction promotes white adipocyte differentiation and browning, maintains healthy BAT, and enhances glucose uptake in adipose tissue, skeletal muscle, and liver. We identify nidogen-2 as a critical BAT-secreted protein that reverses hyperglycemia in NOD mice, inhibits glucagon secretion from pancreatic α-cells, and mimics other actions of the entire secreted fraction. Secretions from a BAT cell line with siRNA knockdown of nidogen-2 fail to inhibit glucagon secretion and restore euglycemia. These findings demonstrate that BAT-secreted peptides represent a novel therapeutic approach to diabetes management. Furthermore, our research reveals a novel signaling role for nidogen-2, beyond its traditional classification as an extracellular matrix protein.
    DOI:  https://doi.org/10.2337/db24-1003
  7. Nat Commun. 2025 Mar 01. 16(1): 2102
    HCN4 channels sense temperature and determine heart rate responses to heat.
    Yuejin Wu, Qinchuan Wang, Jonathan Granger, Oscar Reyes Gaido, Gabriel Lopez-Cecetaite, Eric Nunez Aguilar, Andreas Ludwig, Anna Moroni, Mario A Bianchet, Mark E Anderson.
      The hyperpolarization-activated cyclic nucleotide-gated ion channel 4 (HCN4) current increases due to cAMP binding and is well-recognized to contribute to adrenergically driven heart rate acceleration. HCN4 current also increases with heat by an unknown mechanism(s). We use thermodynamical and homology computational modeling, site-directed mutagenesis, and mouse models to identify a concise motif on the S4-S5 linker of HCN4 channels (M407/Y409) that determines HCN4 current (If) responses to heat. This motif is required for heat-triggered rate acceleration in cardiac pacemaker cells, isolated hearts and in vivo. Surprisingly, a loss of function M407/Y409 motif mutation prevented not only normal heat but also cAMP responses, suggesting that the heat-sensing machinery within the S4-S5 linker is essential for operating the cAMP allosteric pathway and is central to HCN4 gating modulation. The M407/Y409 motif is conserved across all HCN family members suggesting that HCN channels participate broadly in coupling heat to changes in cell membrane excitability.
    DOI:  https://doi.org/10.1038/s41467-025-57358-9
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