bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒11‒20
thirteen papers selected by
José Carlos de Lima-Júnior
Washington University
  1. Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice.
  2. Endothelial SIRT-1 has a critical role in the maintenance of capillarization in brown adipose tissue.
  3. Cold exposure induces dynamic changes in circulating triacylglycerol species, which is dependent on intracellular lipolysis: A randomized cross-over trial.
  4. Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.
  5. Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice.
  6. The role of Phe150 in human voltage-gated proton channel.
  7. PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53.
  8. Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.
  9. Alternative respiratory oxidases to study the animal electron transport chain.
  10. Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization.
  11. pH-Dependent transport of amino acids across lipid bilayers by simple monotopic anion carriers.
  12. TRPC3 governs the spatiotemporal organization of cellular Ca2+ signatures by functional coupling to IP3 receptors.
  13. "Humanizing" mouse environments: Humidity, diurnal cycles and thermoneutrality.
  1. Elife. 2022 Nov 14. pii: e81996. [Epub ahead of print]11
    Brown adipocytes local response to thyroid hormone is required for adaptive thermogenesis in adult male mice.
    Yanis Zekri, Romain Guyot, Inés Garteizgogeascoa Suñer, Laurence Canaple, Amandine Gautier Stein, Justine Vily Petit, Denise Aubert, Sabine Richard, Frederic Flamant, Karine Gauthier.
      Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3 signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.
    Keywords:  genetics; genomics; mouse
    DOI:  https://doi.org/10.7554/eLife.81996
  2. iScience. 2022 Nov 18. 25(11): 105424
    Endothelial SIRT-1 has a critical role in the maintenance of capillarization in brown adipose tissue.
    Ryo Furuuchi, Ippei Shimizu, Yohko Yoshida, Goro Katsuumi, Masayoshi Suda, Yoshiaki Kubota, Kenneth Walsh, Tohru Minamino.
      Brown adipose tissue (BAT) has critical roles in thermogenesis and systemic metabolism. Capillary rarefaction was reported to develop in BAT with dietary obesity, and previous studies showed that suppression of vascular endothelial growth factor A (VEGF-A) reduced capillary density in BAT, promoting the functional decline of this organ. Capillarization is regulated through the balance between angiogenesis and vasculogenesis on the one hand and apoptosis of endothelial cells (ECs) on the other; however, the role of EC apoptosis in BAT remained to be explored. In studies testing the role of boysenberry polyphenols (BoyP) in BAT, we found that BoyP decreased EC apoptosis, enhanced capillarization in BAT, and ameliorated dietary BAT dysfunction, which was associated with the upregulation of nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin 1 (SIRT-1) in ECs. Our studies suggest that EC SIRT-1 would be one of the potential targets of BoyP that contributes to BAT capillarization and function.
    Keywords:  Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105424
  3. EBioMedicine. 2022 Nov 10. pii: S2352-3964(22)00531-X. [Epub ahead of print]86 104349
    Cold exposure induces dynamic changes in circulating triacylglycerol species, which is dependent on intracellular lipolysis: A randomized cross-over trial.
    Maaike E Straat, Lucas Jurado-Fasoli, Zhixiong Ying, Kimberly J Nahon, Laura G M Janssen, Mariëtte R Boon, Gernot F Grabner, Sander Kooijman, Robert Zimmermann, Martin Giera, Patrick C N Rensen, Borja Martinez-Tellez.
      BACKGROUND: The application of cold exposure has emerged as an approach to enhance whole-body lipid catabolism. The global effect of cold exposure on the lipidome in humans has been reported with mixed results depending on intensity and duration of cold.METHODS: This secondary study was based on data from a previous randomized cross-over trial (ClinicalTrials.gov ID: NCT03012113). We performed sequential lipidomic profiling in serum during 120 min cold exposure of human volunteers. Next, the intracellular lipolysis was blocked in mice (eighteen 10-week-old male wild-type mice C57BL/6J) using a small-molecule inhibitor of adipose triglyceride lipase (ATGL; Atglistatin), and mice were exposed to cold for a similar duration. The quantitative lipidomic profiling was assessed in-depth using the Lipidyzer platform.
    FINDINGS: In humans, cold exposure gradually increased circulating free fatty acids reaching a maximum at 60 min, and transiently decreased total triacylglycerols (TAGs) only at 30 min. A broad range of TAG species was initially decreased, in particular unsaturated and polyunsaturated TAG species with ≤5 double bonds, while after 120 min a significant increase was observed for polyunsaturated TAG species with ≥6 double bonds in humans. The mechanistic study in mice revealed that the cold-induced increase in polyunsaturated TAGs was largely prevented by blocking adipose triglyceride lipase.
    INTERPRETATION: We interpret these findings as that cold exposure feeds thermogenic tissues with TAG-derived fatty acids for combustion, resulting in a decrease of circulating TAG species, followed by increased hepatic production of polyunsaturated TAG species induced by liberation of free fatty acids stemming from adipose tissue.
    FUNDING: This work was supported by the Netherlands CardioVascular Research Initiative: 'the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences' [CVON2017-20 GENIUS-II] to Patrick C.N. Rensen. Borja Martinez-Tellez is supported by individual postdoctoral grant from the Fundación Alfonso Martin Escudero and by a Maria Zambrano fellowship by the Ministerio de Universidades y la Unión Europea - NextGenerationEU (RR_C_2021_04). Lucas Jurado-Fasoli was supported by an individual pre-doctoral grant from the Spanish Ministry of Education (FPU19/01609) and with an Albert Renold Travel Fellowship from the European Foundation for the Study of Diabetes (EFSD). Martin Giera was partially supported by NWO XOmics project #184.034.019.
    Keywords:  Cold; Desaturation; Fatty acid metabolism; Intracellular lipolysis; Long-chain polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.ebiom.2022.104349
  4. Cell Rep Med. 2022 Nov 15. pii: S2666-3791(22)00372-X. [Epub ahead of print]3(11): 100813
    Anti-diabetic effects of GLP1 analogs are mediated by thermogenic interleukin-6 signaling in adipocytes.
    Absalon D Gutierrez, Zhanguo Gao, Vala Hamidi, Liang Zhu, Karla Bermudez Saint Andre, Kayla Riggs, Monika Ruscheinsky, Hongyu Wang, Yongmei Yu, Charles Miller, Hernan Vasquez, Heinrich Taegtmeyer, Mikhail G Kolonin.
      Mechanisms underlying anti-diabetic effects of GLP1 analogs remain incompletely understood. We observed that in prediabetic humans exenatide treatment acutely induces interleukin-6 (IL-6) secretion by monocytes and IL-6 in systemic circulation. We hypothesized that GLP1 analogs signal through IL-6 in adipose tissue (AT) and used the mouse model to test if IL-6 receptor (IL-6R) signaling underlies the effects of the GLP1-IL-6 axis. We show that liraglutide transiently increases IL-6 in mouse circulation and IL-6R signaling in AT. Metronomic liraglutide treatment resulted in AT browning and thermogenesis linked with STAT3 activation. IL-6-blocking antibody treatment inhibited STAT3 activation in AT and suppressed liraglutide-induced increase in thermogenesis and glucose utilization. We show that adipose IL-6R knockout mice still display liraglutide-induced weight loss but lack thermogenic adipocyte browning and metabolism activation. We conclude that the anti-diabetic effects of GLP1 analogs are mediated by transient upregulation of IL-6, which activates canonical IL-6R signaling and thermogenesis.
    Keywords:  GLP1; brown adipocyte; diabetes; exenatide; incretin; interleukin-6; liraglutide
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100813
  5. Nat Metab. 2022 Nov 18.
    Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice.
    Lingfeng Shi, Yixiang Li, Xiaoli Xu, Yangyang Cheng, Biying Meng, Jinling Xu, Lin Xiang, Jiajia Zhang, Kaiyue He, Jiayue Tong, Junxia Zhang, Lingwei Xiang, Guangda Xiang.
      Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)-nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.
    DOI:  https://doi.org/10.1038/s42255-022-00671-0
  6. iScience. 2022 Nov 18. 25(11): 105420
    The role of Phe150 in human voltage-gated proton channel.
    Xin Wu, Lu Zhang, Liang Hong.
      The voltage-gated proton channel Hv1 is a member of voltage-gated ion channels containing voltage-sensing domains (VSDs). The VSDs are made of four membrane-spanning segments (S1 through S4), and their function is to detect changes in membrane potential in the cells. A highly conserved phenylalanine 150 (F150) is located in the S2 segment of human voltage-gated proton channels. We previously discovered that the F150 is a binding site for the open channel blocker 2GBI. Here, we show that the Hv1 VSD voltage-dependent activation requires a hydrophobic group at position F150. We perform double-mutant cycle analysis to probe interactions between F150 and positively charged arginines in the S4 segment of the channel. Our results indicate that F150 interacts with two arginines (R2 and R3) in the S4 segment and catalyzes the transfer of the S4 arginines in the process of voltage-dependent activation.
    Keywords:  Biochemistry; Biological sciences; Cellular physiology; Molecular physiology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.105420
  7. Proc Natl Acad Sci U S A. 2022 Nov 22. 119(47): e2206923119
    PAHSAs reduce cellular senescence and protect pancreatic beta cells from metabolic stress through regulation of Mdm2/p53.
    Maria F Rubin de Celis, Ruben Garcia-Martin, Ismail Syed, Jennifer Lee, Cristina Aguayo-Mazzucato, Susan Bonner-Weir, Barbara B Kahn.
      Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress-induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.
    Keywords:  cellular senescence; diabetes; lipids; metabolic stress; pancreatic islets
    DOI:  https://doi.org/10.1073/pnas.2206923119
  8. Proc Natl Acad Sci U S A. 2022 Nov 22. 119(47): e2210730119
    Mitochondrial nucleoid trafficking regulated by the inner-membrane AAA-ATPase ATAD3A modulates respiratory complex formation.
    Takaya Ishihara, Reiko Ban-Ishihara, Azusa Ota, Naotada Ishihara.
      Mitochondria have their own DNA (mtDNA), which encodes essential respiratory subunits. Under live imaging, mitochondrial nucleoids, composed of several copies of mtDNA and DNA-binding proteins, such as mitochondrial transcription factor A (TFAM), actively move inside mitochondria and change the morphology, in concert with mitochondrial membrane fission. Here we found the mitochondrial inner membrane-anchored AAA-ATPase protein ATAD3A mediates the nucleoid dynamics. Its ATPase domain exposed to the matrix binds directly to TFAM and mediates nucleoid trafficking along mitochondria by ATP hydrolysis. Nucleoid trafficking also required ATAD3A oligomerization via an interaction between the coiled-coil domains in intermembrane space. In ATAD3A deficiency, impaired nucleoid trafficking repressed the clustered and enlarged nucleoids observed in mitochondrial fission-deficient cells resulted in dispersed distribution of small nucleoids observed throughout the mitochondrial network, and this enhanced respiratory complex formation. Thus, mitochondrial fission and nucleoid trafficking cooperatively determine the size, number, and distribution of nucleoids in mitochondrial network, which should modulate respiratory complex formation.
    Keywords:  ATAD3A; Drp1; mitochondrial fission; mtDNA nucleoid; respiratory complex
    DOI:  https://doi.org/10.1073/pnas.2210730119
  9. Biochim Biophys Acta Bioenerg. 2022 Nov 14. pii: S0005-2728(22)00406-6. [Epub ahead of print] 148936
    Alternative respiratory oxidases to study the animal electron transport chain.
    Pablo Hernansanz-Agustín, José Antonio Enríquez.
      Oxidative phosphorylation is a common process to most organisms in which the main function is to generate an electrochemical gradient across the inner mitochondrial membrane (IMM) and to make energy available to the cell. However, plants, many fungi and some animals maintain non-energy conserving oxidases which serve as a bypass to coupled respiration. Namely, the alternative NADH:ubiquinone oxidoreductase NDI1, present in the complex I (CI)-lacking Saccharomyces cerevisiae, and the alternative oxidase, ubiquinol:oxygen oxidoreductase AOX, present in many organisms across different kingdoms. In the last few years, these alternative oxidases have been used to dissect previously indivisible processes in bioenergetics and have helped to discover, understand, and corroborate important processes in mitochondria. Here, we review how the use of alternative oxidases have contributed to the knowledge in CI stability, bioenergetics, redox biology, and the implications of their use in current and future research.
    Keywords:  AOX; Alternative oxidase; CoQ pool; Oxphos; ROS
    DOI:  https://doi.org/10.1016/j.bbabio.2022.148936
  10. iScience. 2022 Nov 18. 25(11): 105447
    Both ANT and ATPase are essential for mitochondrial permeability transition but not depolarization.
    M A Neginskaya, S E Morris, E V Pavlov.
      An increase in permeability of the mitochondrial inner membrane, mitochondrial permeability transition (PT), is the central event responsible for cell death and tissue damage in conditions such as stroke and heart attack. PT is caused by the cyclosporin A (CSA)-dependent calcium-induced pore, the permeability transition pore (PTP). The molecular details of PTP are incompletely understood. We utilized holographic and fluorescent microscopy to assess the contribution of ATP synthase and adenine nucleotide translocator (ANT) toward PTP. In cells lacking either ATP synthase or ANT, we observed CSA-sensitive membrane depolarization, but not high-conductance PTP. In wild-type cells, calcium-induced CSA-sensitive depolarization preceded opening of PTP, which occurred only after nearly complete mitochondrial membrane depolarization. We propose that both ATP synthase and ANT are required for high-conductance PTP but not depolarization, which presumably occurs through activation of the low-conductance PT, which has a molecular nature that is different from both complexes.
    Keywords:  Cell biology; Functional aspects of cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2022.105447
  11. Chem Sci. 2022 Nov 02. 13(42): 12374-12381
    pH-Dependent transport of amino acids across lipid bilayers by simple monotopic anion carriers.
    Krystyna Maslowska-Jarzyna, Krzysztof M Bąk, Bartłomiej Zawada, Michał J Chmielewski.
      The transport of amino acids across lipid membranes is vital for the proper functioning of every living cell. In spite of that, examples of synthetic transporters that can facilitate amino acid transport are rare. This is mainly because at physiological conditions amino acids predominantly exist as highly polar zwitterions and proper shielding of their charged termini, which is necessary for fast diffusion across lipophilic membranes, requires complex and synthetically challenging heteroditopic receptors. Here we report the first simple monotopic anion receptor, dithioamide 1, that efficiently transports a variety of natural amino acids across lipid bilayers at physiological pH. Mechanistic studies revealed that the receptor rapidly transports deprotonated amino acids, even though at pH 7.4 these forms account for less than 3% of the total amino acid concentration. We also describe a new fluorescent assay for the selective measurement of the transport of deprotonated amino acids into liposomes. The new assay allowed us to study the pH-dependence of amino acid transport and elucidate the mechanism of transport by 1, as well as to explain its exceptionally high activity. With the newly developed assay we screened also four other representative examples of monotopic anion transporters, of which two showed promising activity. Our results imply that heteroditopic receptors are not necessary for achieving high amino acid transport activities and that many of the previously reported anionophores might be active amino acid transporters. Based on these findings, we propose a new strategy for the development of artificial amino acid transporters with improved properties.
    DOI:  https://doi.org/10.1039/d2sc04346g
  12. Cell Calcium. 2022 Nov 02. pii: S0143-4160(22)00143-9. [Epub ahead of print]108 102670
    TRPC3 governs the spatiotemporal organization of cellular Ca2+ signatures by functional coupling to IP3 receptors.
    Sanja Curcic, Hazel Erkan-Candag, Johannes Pilic, Roland Malli, Patrick Wiedner, Oleksandra Tiapko, Klaus Groschner.
      Communication between TRPC channels and IP3 receptors (IP3R) is considered pivotal in the generation of spatiotemporal Ca2+signaling patterns. Here we revisited the role of TRPC3-IP3R coupling for local Ca2+ signaling within TRPC3-harbouring micro/nanodomains using R-GECO as a reporter, fused to the channel´s C-terminus. Cytoplasmic Ca2+ changes at TRPC3 originated from both the entry of Ca2+ through the TRPC channel and Ca2+ mobilization via IP3R. Local Ca2+ changes at TRPC3 channels expressed in HEK293 cells were predominantly biphasic with IP3R-dependent initial Ca2+ transients, while exclusively monophasic signals were recorded when all three IP3R isoforms were lacking. Abrogation of Ca2+ entry through TRPC3 by point mutations, which impair Ca2+ permeability (E630Q), cation permeation (E630K), or DAG sensitivity (G652A), promoted microdomain Ca2+ oscillations. Ca2+ signals at E630Q, E630K, and G652A channels featured initial Ca2+ transients along with oscillatory activity. Similarly, when extracellular Ca2+ was omitted, IP3R-mediated Ca2+ transients and Ca2+ oscillations were promoted at the cytoplasmic face of wild-type TRPC3 channels. By contrast, oscillations, as well as initial Ca2+ transients, were virtually lacking, when the TRPC3 channels were sensitized by preexposure to low-level PLC activity. TIRF imaging provided evidence for dynamic colocalization of TRPC3 and IP3R. We suggest that TRPC3-mediated Ca2+ entry controls IP3R activity at ER-PM junctions to determine Ca2+ signaling signatures and enable specificity of downstream signaling.
    Keywords:  ER-PM nanojunction; IP3R; Phospholipase C signaling; TRPC3
    DOI:  https://doi.org/10.1016/j.ceca.2022.102670
  13. Biochimie. 2022 Nov 10. pii: S0300-9084(22)00281-4. [Epub ahead of print]
    "Humanizing" mouse environments: Humidity, diurnal cycles and thermoneutrality.
    Ildiko Kasza, Colleen Cuncannan, Julian Michaud, Dave Nelson, Chi-Liang E Yen, Raghav Jain, Judi Simcox, Ormond A MacDougald, Brian Parks, Caroline M Alexander.
      Thermoneutral housing has been shown to promote more accurate and robust development of several pathologies in mice. Raising animal housing temperatures a few degrees may create a relatively straightforward opportunity to improve translatability of mouse models. In this commentary, we discuss the changes of physiology induced in mice housed at thermoneutrality, and review techniques for measuring systemic thermogenesis, specifically those affecting storage and mobilization of lipids in adipose depots. Environmental cues are a component of the information integrated by the brain to calculate food consumption and calorie deposition. We show that relative humidity is one of those cues, inducing a rapid sensory response that is converted to a more chronic susceptibility to obesity. Given high inter-institutional variability in the regulation of relative humidity, study reproducibility may be improved by consideration of this factor. We evaluate a "humanized" environmental cycling protocol, where mice sleep in warm temperature housing, and are cool during the wake cycle. We show that this protocol suppresses adaptation to cool exposure, with consequence for adipose-associated lipid storage. To evaluate systemic cues in mice housed at thermoneutral temperatures, we characterized the circulating lipidome, and show that sera are highly depleted in some HDL-associated phospholipids, specifically phospholipids containing the essential fatty acid, 18:2 linoleic acid, and its derivative, arachidonic acid (20:4) and related ether-phospholipids. Given the role of these fatty acids in inflammatory responses, we propose they may underlie the differences in disease progression observed at thermoneutrality.
    Keywords:  Diurnal environmental cycling; Essential fatty acids; Relative humidity; Sera lipidome; Thermogenesis
    DOI:  https://doi.org/10.1016/j.biochi.2022.10.015
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