bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2022‒11‒13
seven papers selected by
José Carlos de Lima-Júnior
Washington University
  1. A modest change in housing temperature alters whole body energy expenditure and adipocyte thermogenic capacity in mice.
  2. Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
  3. ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.
  4. Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans.
  5. AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
  6. Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress.
  7. A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience.
  1. Am J Physiol Endocrinol Metab. 2022 Nov 09.
    A modest change in housing temperature alters whole body energy expenditure and adipocyte thermogenic capacity in mice.
    Daniel G Sadler, Lillie Treas, James D Sikes, Craig Porter.
      BACKGROUND: Typical vivarium temperatures (20-26°C) induce facultative thermogenesis in mice, a process attributable in part to uncoupling protein-1 (UCP1). The impact of modest changes in housing temperature on whole body and adipose tissue energetics in mice remains unclear. Here, we determined the effects of transitioning mice from 24°C to 30°C on total energy expenditure and adipose tissue protein signatures.METHODS: C57BL/6J mice were housed at 24°C for two weeks and then either remained at 24°C (n=16 per group, 8M/8F) or were transitioned to 30°C (n=16 per group, 8M/8F) for 4 weeks. Total energy expenditure and its components were determined by indirect calorimetry. Interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) proteins were quantified by western blot and quantitative proteomics.
    RESULTS: Transitioning from 24°C to 30°C reduced total energy expenditure in both male (-25%) and female (-16%) mice, which was attributable to 36% and 40% decreases in basal energy expenditure in males and females, respectively. Total iBAT UCP1 protein content was 50% lower at 30°C compared to 24°C, whereas iWAT UCP1 protein content was similar between conditions. iBAT UCP1 protein content remained 20-fold greater than iWAT at 30°C. 183 and 41 proteins were differentially expressed between 24°C and 30°C in iBAT and iWAT, respectively. 257 iWAT proteins differentially expressed between sexes at 30°C were not differentially expressed at 24°C.
    SUMMARY: 30°C housing lowers total energy expenditure of mice when compared to an ambient temperature (24°C) that falls within the National Research Council's guidelines for housing laboratory mice. Lower iBAT UCP1 content accompanied chronic housing at 30°C. Further, housing temperature influences sexual dimorphism in the iWAT proteome. These data have implications regarding the optimization of preclinical models of human disease.
    Keywords:  adipose tissue; ambient temperature; proteomics; thermogenesis; thermoneutral
    DOI:  https://doi.org/10.1152/ajpendo.00079.2022
  2. Cell. 2022 Nov 02. pii: S0092-8674(22)01318-6. [Epub ahead of print]
    Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.
    Haopeng Xiao, Luiz H M Bozi, Yizhi Sun, Christopher L Riley, Vivek M Philip, Mandy Chen, Jiaming Li, Tian Zhang, Evanna L Mills, Margo P Emont, Wenfei Sun, Anita Reddy, Ryan Garrity, Jiani Long, Tobias Becher, Laura Potano Vitas, Dina Laznik-Bogoslavski, Martha Ordonez, Xinyue Liu, Xiong Chen, Yun Wang, Weihai Liu, Nhien Tran, Yitong Liu, Yang Zhang, Aaron M Cypess, Andrew P White, Yuchen He, Rebecca Deng, Heiko Schöder, Joao A Paulo, Mark P Jedrychowski, Alexander S Banks, Yu-Hua Tseng, Paul Cohen, Linus T Tsai, Evan D Rosen, Samuel Klein, Maria Chondronikola, Fiona E McAllister, Nick Van Bruggen, Edward L Huttlin, Bruce M Spiegelman, Gary A Churchill, Steven P Gygi, Edward T Chouchani.
      Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.
    DOI:  https://doi.org/10.1016/j.cell.2022.10.003
  3. Nat Metab. 2022 Nov 07.
    ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.
    Janane F Rahbani, Charlotte Scholtes, Damien M Lagarde, Mohammed F Hussain, Anna Roesler, Christien B Dykstra, Jakub Bunk, Bozena Samborska, Shannon L O'Brien, Emma Tripp, Alain Pacis, Anthony R Angueira, Olivia S Johansen, Jessica Cinkornpumin, Ishtiaque Hossain, Matthew D Lynes, Yang Zhang, Andrew P White, William A Pastor, Maria Chondronikola, Labros Sidossis, Samuel Klein, Anastasia Kralli, Aaron M Cypess, Steen B Pedersen, Niels Jessen, Yu-Hua Tseng, Zachary Gerhart-Hines, Patrick Seale, Davide Calebiro, Vincent Giguère, Lawrence Kazak.
      Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.
    DOI:  https://doi.org/10.1038/s42255-022-00667-w
  4. Sci Rep. 2022 Nov 05. 12(1): 18753
    Association of apolipoprotein M and sphingosine-1-phosphate with brown adipose tissue after cold exposure in humans.
    Anna Borup, Ida Donkin, Mariëtte R Boon, Martin Frydland, Borja Martinez-Tellez, Annika Loft, Sune H Keller, Andreas Kjaer, Jesper Kjaergaard, Christian Hassager, Romain Barrès, Patrick C N Rensen, Christina Christoffersen.
      The HDL-associated apolipoprotein M (apoM) and its ligand sphingosine-1-phosphate (S1P) may control energy metabolism. ApoM deficiency in mice is associated with increased vascular permeability, brown adipose tissue (BAT) mass and activity, and protection against obesity. In the current study, we explored the connection between plasma apoM/S1P levels and parameters of BAT as measured via 18F-FDG PET/CT after cold exposure in humans. Fixed (n = 15) vs personalized (n = 20) short-term cooling protocols decreased and increased apoM (- 8.4%, P = 0.032 vs 15.7%, P < 0.0005) and S1P (- 41.0%, P < 0.0005 vs 19.1%, P < 0.005) plasma levels, respectively. Long-term cooling (n = 44) did not affect plasma apoM or S1P levels. Plasma apoM and S1P did not correlate significantly to BAT volume and activity in the individual studies. However, short-term studies combined, showed that increased changes in plasma apoM correlated with BAT metabolic activity (β: 0.44, 95% CI [0.06-0.81], P = 0.024) after adjusting for study design but not BAT volume (β: 0.39, 95% CI [- 0.01-0.78], P = 0.054). In conclusion, plasma apoM and S1P levels are altered in response to cold exposure and may be linked to changes in BAT metabolic activity but not BAT volume in humans. This contrasts partly with observations in animals and highlights the need for further studies to understand the biological role of apoM/S1P complex in human adipose tissue and lipid metabolism.
    DOI:  https://doi.org/10.1038/s41598-022-21938-2
  5. Sci Adv. 2022 Nov 11. 8(45): eabo7956
    AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.
    Lisa Tilokani, Fiona M Russell, Stevie Hamilton, Daniel M Virga, Mayuko Segawa, Vincent Paupe, Anja V Gruszczyk, Margherita Protasoni, Luis-Carlos Tabara, Mark Johnson, Hanish Anand, Michael P Murphy, D Grahame Hardie, Franck Polleux, Julien Prudent.
      Mitochondria are dynamic organelles that undergo membrane remodeling events in response to metabolic alterations to generate an adequate mitochondrial network. Here, we investigated the function of mitochondrial fission regulator 1-like protein (MTFR1L), an uncharacterized protein that has been identified in phosphoproteomic screens as a potential AMP-activated protein kinase (AMPK) substrate. We showed that MTFR1L is an outer mitochondrial membrane-localized protein modulating mitochondrial morphology. Loss of MTFR1L led to mitochondrial elongation associated with increased mitochondrial fusion events and levels of the mitochondrial fusion protein, optic atrophy 1. Mechanistically, we show that MTFR1L is phosphorylated by AMPK, which thereby controls the function of MTFR1L in regulating mitochondrial morphology both in mammalian cell lines and in murine cortical neurons in vivo. Furthermore, we demonstrate that MTFR1L is required for stress-induced AMPK-dependent mitochondrial fragmentation. Together, these findings identify MTFR1L as a critical mitochondrial protein transducing AMPK-dependent metabolic changes through regulation of mitochondrial dynamics.
    DOI:  https://doi.org/10.1126/sciadv.abo7956
  6. Elife. 2022 Nov 08. pii: e82206. [Epub ahead of print]11
    Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress.
    Jingruo Zhang, Manuel A Riquelme, Rui Hua, Francisca M Acosta, Sumin Gu, Jean X Jiang.
      Oxidative stress is a major risk factor that causes osteocyte cell death and bone loss. Prior studies primarily focus on the function of cell surface expressed Cx43 channels. Here, we reported a new role of mitochondrial Cx43 (mtCx43) and hemichannels (HCs) in modulating mitochondria homeostasis and function in bone osteocytes under oxidative stress. In murine long bone osteocyte-Y4 cells, the translocation of Cx43 to mitochondria was increased under H2O2-induced oxidative stress. H2O2 increased the mtCx43 level accompanied by elevated mtCx43 HC activity, determined by dye uptake assay. Cx43 knockdown (KD) by the CRISPR-Cas9 lentivirus system resulted in impairment of mitochondrial function, primarily manifested as decreased ATP production. Cx43 KD had reduced intracellular reactive oxidative species levels and mitochondrial membrane potential. Additionally, live-cell imaging results demonstrated that the proton flux was dependent on mtCx43 HCs because its activity was specifically inhibited by an antibody targeting Cx43 C-terminus. The co-localization and interaction of mtCx43 and ATP synthase subunit F (ATP5J2) were confirmed by Förster resonance energy transfer and a protein pull-down assay. Together, our study suggests that mtCx43 HCs regulate mitochondrial ATP generation by mediating K+, H+, and ATP transfer across the mitochondrial inner membrane and the interaction with mitochondrial ATP synthase, contributing to the maintenance of mitochondrial redox levels in response to oxidative stress.
    Keywords:  ATP synthase; cell biology; connexin 43; mouse; osteocytes; oxidative stress; proton
    DOI:  https://doi.org/10.7554/eLife.82206
  7. Nat Commun. 2022 Nov 10. 13(1): 6805
    A conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience.
    Changnan Wang, Bingying Wang, Taruna Pandey, Yong Long, Jianxiu Zhang, Fiona Oh, Jessica Sima, Ruyin Guo, Yun Liu, Chao Zhang, Shaeri Mukherjee, Michael Bassik, Weichun Lin, Huichao Deng, Goncalo Vale, Jeffrey G McDonald, Kang Shen, Dengke K Ma.
      Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through conserved homeostatic mechanisms. Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that mediates lipid trafficking to confer cold resilience. We identify lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7. LPD-3 bridges the endoplasmic reticulum (ER) and plasma membranes (PM), forming a structurally predicted hydrophobic tunnel for lipid trafficking. lpd-3 mutants exhibit abnormal phospholipid distribution, diminished FAT-7 abundance, organismic vulnerability to cold, and are rescued by Lecithin comprising unsaturated phospholipids. Deficient lpd-3 homologues in Zebrafish and mammalian cells cause defects similar to those observed in C. elegans. As mutations in BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, LPD-3 family proteins may serve as evolutionarily conserved highway bridges critical for ER-associated non-vesicular lipid trafficking and resilience to cold stress in eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41467-022-34450-y
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