bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023–07–23
eleven papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Comprehensive analysis of intercellular communication in the thermogenic adipose niche.
  2. Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
  3. Brown Adipose Tissue and BMP3b Decrease Injury in Cardiac Ischemia-Reperfusion.
  4. The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice.
  5. Resting membrane state as an interplay of electrogenic transporters with various pumps.
  6. Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans.
  7. Mammalian maxilloturbinal evolution does not reflect thermal biology.
  8. Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2.
  9. The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel.
  10. Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
  11. Colony size buffers interactions between neonicotinoid exposure and cold stress in bumblebees.
  1. Commun Biol. 2023 Jul 21. 6(1): 761
    Comprehensive analysis of intercellular communication in the thermogenic adipose niche.
    Farnaz Shamsi, Rongbin Zheng, Li-Lun Ho, Kaifu Chen, Yu-Hua Tseng.
      Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the composition and function of immune cells. Such synergistic adaptation requires extensive crosstalk between individual cells in the tissue to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we apply the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We construct an integrative network of the ligand-receptor interactome in BAT and identify the major signaling inputs and outputs of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we show that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated and non-myelinated Schwann cells, and immune cells. These interactions are predicted to regulate the remodeling of the extracellular matrix, the inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures provides a new understanding of the mechanisms underlying BAT thermogenesis. The resources presented in this study offer a valuable platform for future investigations of BAT development and thermogenesis.
    DOI:  https://doi.org/10.1038/s42003-023-05140-2
  2. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2210599120
    Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
    Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Xiaonan Liu, Sundar Baral, Kaneez Fatima, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa.
      Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here, we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from the GRPEL2 locus on a tightly regulated low level. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling and immunoprecipitation analysis suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. Furthermore, NERCLIN is responsive to heat stress ensuring OPA1 processing and cell survival. Thus, we propose that NERCLIN contributes to the stress-induced adaptation of mitochondrial dynamics. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.
    Keywords:  NERCLIN; OPA1; cardiolipin; prohibitins; small mitochondrial proteins
    DOI:  https://doi.org/10.1073/pnas.2210599120
  3. Circ Res. 2023 Jul 18.
    Brown Adipose Tissue and BMP3b Decrease Injury in Cardiac Ischemia-Reperfusion.
    Íngrid Martí-Pàmies, Robrecht Thoonen, Michael Morley, Lauren Graves, Jesus Tamez, Alex Caplan, Kendra McDaid, Vincent Yao, Allyson Hindle, Robert E Gerszten, Laurie A Farrell, Li Li, Yu-Hua Tseng, Gerson Profeta, Emmanuel S Buys, Donald B Bloch, Marielle Scherrer-Crosbie.
       BACKGROUND: Despite advances in treatment, myocardial infarction (MI) is a leading cause of heart failure and death worldwide, with both ischemia and reperfusion (I/R) causing cardiac injury. A previous study using a mouse model of nonreperfused MI showed activation of brown adipose tissue (BAT). Recent studies showed that molecules secreted by BAT target the heart. We investigated whether BAT attenuates cardiac injury in I/R and sought to identify potential cardioprotective proteins secreted by BAT.
    METHODS: Myocardial I/R surgery with or without BAT transplantation was performed in wild-type (WT) mice and in mice with impaired BAT function (uncoupling protein 1 [Ucp1]-deficient mice). To identify potential cardioprotective factors produced by BAT, RNA-seq was performed in BAT from WT and Ucp1-/- mice. Subsequently, myocardial I/R surgery with or without BAT transplantation was performed in Bmp3b (bone morphogenetic protein 3b)-deficient mice, and WT mice subjected to myocardial I/R were treated using BMP3b.
    RESULTS: Dysfunction of BAT in mice was associated with larger MI size after I/R; conversely, augmenting BAT by transplantation decreased MI size. We identified Bmp3b as a protein secreted by BAT after I/R. Compared with WT mice, Bmp3b-deficient mice developed larger MIs. Increasing functional BAT by transplanting BAT from WT mice to Bmp3b-deficient mice reduced I/R injury whereas transplanting BAT from Bmp3b-deficient mice did not. Treatment of WT mice with BMP3b before reperfusion decreased MI size. The cardioprotective effect of BMP3b was mediated through SMAD1/5/8. In humans, the plasma level of BMP3b increased after MI and was positively correlated with the extent of cardiac injury.
    CONCLUSIONS: The results of this study suggest a cardioprotective role of BAT and BMP3b, a protein secreted by BAT, in a model of I/R injury. Interventions increasing BMP3b levels or targeting Smad 1/5 may represent novel therapeutic approaches to decrease myocardial damage in I/R injury.
    Keywords:  heart failure; mice; myocardium; reperfusion; uncoupling protein 1
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.322337
  4. Nat Commun. 2023 07 19. 14(1): 4257
    The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice.
    Lu Jin, Shuang Han, Xue Lv, Xiaofei Li, Ziyin Zhang, Henry Kuang, Zhimin Chen, Cheng-An Lv, Wei Peng, Zhuoying Yang, Miqi Yang, Lin Mi, Tongyu Liu, Shengshan Ma, Xinyuan Qiu, Qintao Wang, Xiaowen Pan, Pengfei Shan, Yu Feng, Jin Li, Fudi Wang, Liwei Xie, Xuyun Zhao, Jun-Fen Fu, Jiandie D Lin, Zhuo-Xian Meng.
      Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.
    DOI:  https://doi.org/10.1038/s41467-023-39710-z
  5. Pflugers Arch. 2023 Jul 19.
    Resting membrane state as an interplay of electrogenic transporters with various pumps.
    A G Dimitrov.
      In this study, a new idea that electrogenic transporters determine cell resting state is presented. The previous assumption was that pumps, especially the sodium one, determine it. The latter meets difficulties, because it violates the law of conservation of energy; also a significant deficit of pump activity is reported. The amount of energy carried by a single ATP molecule reflects the potential of the inner mitochondrial membrane, which is about -200 mV. If pumps enforce a resting membrane potential that is more than twice smaller, then the majority of energy stored in ATP would be dissipated by each pump turning. However, this problem could be solved if control is transferred from pumps to something else, e.g., electrogenic transporters. Then pumps would transfer the energy to the ionic gradient without losses, while the cell surface membrane potential would be associated with the reversal potential of some electrogenic transporters. A minimal scheme of this type would include a sodium-calcium exchanger as well as sodium and calcium pumps. However, note that calcium channels and pumps are positioned along both intracellular organelles and the surface membrane. Therefore, the above-mentioned scheme would involve them as well as possible intercellular communications. Such schemes where various kinds of pumps are assumed to work in parallel may explain, to a great extent, the slow turning rate of the individual members. Interaction of pumps and transporters positioned at distant biological membranes with various forms of energy transfer between them may thus result in hypoxic/reperfusion injury, different kinds of muscle fatigue, and nerve-glia interactions.
    Keywords:  Hypoxia; Na/K-ATPase; Reperfusion; Sodium-calcium exchanger; Sodium-driven transporter
    DOI:  https://doi.org/10.1007/s00424-023-02838-4
  6. J Appl Physiol (1985). 2023 Jul 20.
    Nitrous oxide consistently attenuates thermogenic and thermoperceptual responses to repetitive cold stress in humans.
    Maaike I Moes, Antonis Elia, Mikael Gennser, Ola Eiken, Michail E Keramidas.
      Divers are at enhanced risk of hypothermia, due to the independent action of the inspired inert gases on thermoregulation. Thus, narcosis induced by acute (≤2h) exposure to either hyperbaric nitrogen, or normobaric nitrous oxide (N2O) impairs shivering thermogenesis and accelerates body core cooling. Animal-based studies, however, have indicated that repeated and sustained N2O administration may prevent the N2O-evoked hypometabolism. We therefore examined the effects of prolonged intermittent exposure to 30% N2O on human thermoeffector plasticity in response to moderate cold. Fourteen men participated in two ~12-h sessions, during which they performed sequentially three 120-min immersions (CWI) in 20˚C water, separated by 120-min rewarming. During CWIs, subjects were breathing either normal air, or a normoxic gas mixture containing 30% N2O. Rectal and skin temperatures, metabolic heat production (via indirect calorimetry), finger and forearm cutaneous vascular conductance (CVC; laser-Doppler fluxmetry/mean arterial pressure), and thermal sensation and comfort were monitored. N2O aggravated the drop in rectal temperature (P = 0.01), especially during the first (by ~0.3°C) and third (by ~0.4°C) CWIs. N2O invariably blunted the cold-induced elevation of metabolic heat production by ~22-25% (P < 0.001). During the initial ~30 min of the first and second CWIs, N2O attenuated the cold-induced drop in finger (P ≤ 0.001), but not in forearm CVC. N2O alleviated the sensation of coldness and thermal discomfort throughout (P < 0.001). Thus, present results demonstrate that, regardless of the cumulative duration of gas exposure, a subanasthetic dose of N2O depresses human thermoregulatory functions, and precipitates the development of hypothermia.
    Keywords:  Hypothermia; Inert gas narcosis; Shivering thermogenesis; Thermoeffector plasticity; Thermoregulation
    DOI:  https://doi.org/10.1152/japplphysiol.00309.2023
  7. Nat Commun. 2023 Jul 21. 14(1): 4425
    Mammalian maxilloturbinal evolution does not reflect thermal biology.
    Quentin Martinez, Jan Okrouhlík, Radim Šumbera, Mark Wright, Ricardo Araújo, Stan Braude, Thomas B Hildebrandt, Susanne Holtze, Irina Ruf, Pierre-Henri Fabre.
      The evolution of endothermy in vertebrates is a major research topic in recent decades that has been tackled by a myriad of research disciplines including paleontology, anatomy, physiology, evolutionary and developmental biology. The ability of most mammals to maintain a relatively constant and high body temperature is considered a key adaptation, enabling them to successfully colonize new habitats and harsh environments. It has been proposed that in mammals the anterior nasal cavity, which houses the maxilloturbinal, plays a pivotal role in body temperature maintenance, via a bony system supporting an epithelium involved in heat and moisture conservation. The presence and the relative size of the maxilloturbinal has been proposed to reflect the endothermic conditions and basal metabolic rate in extinct vertebrates. We show that there is no evidence to relate the origin of endothermy and the development of some turbinal bones by using a comprehensive dataset of µCT-derived maxilloturbinals spanning most mammalian orders. Indeed, we demonstrate that neither corrected basal metabolic rate nor body temperature significantly correlate with the relative surface area of the maxilloturbinal. Instead, we identify important variations in the relative surface area, morpho-anatomy, and complexity of the maxilloturbinal across the mammalian phylogeny and species ecology.
    DOI:  https://doi.org/10.1038/s41467-023-39994-1
  8. Elife. 2023 Jul 19. pii: e80447. [Epub ahead of print]12
    Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2.
    Pragnya Chakraborty, Bipan Kumar Deb, Vikas Arige, Thasneem Musthafa, Sundeep Malik, David I Yule, Colin W Taylor, Gaiti Hasan.
      Loss of endoplasmic reticular (ER) Ca2+ activates store-operated Ca2+ entry (SOCE) by causing the ER localized Ca2+ sensor STIM to unfurl domains that activate Orai channels in the plasma membrane at membrane contact sites (MCS). Here we demonstrate a novel mechanism by which the inositol 1,4,5 trisphosphate receptor (IP3R), an ER-localized IP3-gated Ca2+ channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca2+ is attenuated by loss of IP3Rs, and restored by expression of IP3Rs even when they cannot release Ca2+, but only if the IP3Rs can bind IP3. Imaging studies demonstrate that IP3Rs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP3-binding site, but not a pore. Convergent regulation by IP3Rs, may tune neuronal SOCE to respond selectively to receptors that generate IP3.
    Keywords:  cell biology; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.80447
  9. Nat Commun. 2023 Jul 15. 14(1): 4236
    The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel.
    Katsumasa Irie, Yoshinori Oda, Takashi Sumikama, Atsunori Oshima, Yoshinori Fujiyoshi.
      Divalent cation block is observed in various tetrameric ion channels. For blocking, a divalent cation is thought to bind in the ion pathway of the channel, but such block has not yet been directly observed. So, the behaviour of these blocking divalent cations remains still uncertain. Here, we elucidated the mechanism of the divalent cation block by reproducing the blocking effect into NavAb, a well-studied tetrameric sodium channel. Our crystal structures of NavAb mutants show that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack on the ion pathway. Furthermore, non-equilibrium molecular dynamics simulation showed that the stacking calcium ion repel sodium ion at the bottom of the selectivity filter. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels.
    DOI:  https://doi.org/10.1038/s41467-023-39987-0
  10. Immunity. 2023 Jul 14. pii: S1074-7613(23)00278-9. [Epub ahead of print]
    Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
    Pulavendran Sivasami, Cody Elkins, Pamela P Diaz-Saldana, Kyndal Goss, Amy Peng, Michael Hamersky, Jennifer Bae, Miaoer Xu, Brian P Pollack, Edwin M Horwitz, Christopher D Scharer, Lindsey Seldin, Chaoran Li.
      Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4+Foxp3+ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A+ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ+ skin Treg cells and a corresponding loss of control over IL-17A+ γδ T cell-mediated inflammation. Mechanistically, PPARγ+ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ+ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.
    Keywords:  IL-17A; PPARγ; Treg; free fatty acid; high-fat diet; immunometabolism; obesity; psoriasis; skin; γδ T cell
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.021
  11. Proc Biol Sci. 2023 07 26. 290(2003): 20230555
    Colony size buffers interactions between neonicotinoid exposure and cold stress in bumblebees.
    August C Easton-Calabria, Jessie A Thuma, Kayleigh Cronin, Gigi Melone, Madalyn Laskowski, Matthew A Y Smith, Cassandra L Pasadyn, Benjamin L de Bivort, James D Crall.
      Social bees are critical for supporting biodiversity, ecosystem function and crop yields globally. Colony size is a key ecological trait predicted to drive sensitivity to environmental stressors and may be especially important for species with annual cycles of sociality, such as bumblebees. However, there is limited empirical evidence assessing the effect of colony size on sensitivity to environmental stressors or the mechanisms underlying these effects. Here, we examine the relationship between colony size and sensitivity to environmental stressors in bumblebees. We exposed colonies at different developmental stages briefly (2 days) to a common neonicotinoid (imidacloprid) and cold stress, while quantifying behaviour of individuals. Combined imidacloprid and cold exposure had stronger effects on both thermoregulatory behaviour and long-term colony growth in small colonies. We find that imidacloprid's effects on behaviour are mediated by body temperature and spatial location within the nest, suggesting that social thermoregulation provides a buffering effect in large colonies. Finally, we demonstrate qualitatively similar effects in size-manipulated microcolonies, suggesting that group size per se, rather than colony age, drives these patterns. Our results provide evidence that colony size is critical in driving sensitivity to stressors and may help elucidate mechanisms underlying the complex and context-specific impacts of pesticide exposure.
    Keywords:  automated tracking; bees; neonicotinoid; social behaviour; temperature
    DOI:  https://doi.org/10.1098/rspb.2023.0555
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