bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2023‒09‒03
thirteen papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Brown adipose tissue but not tibia exhibits a dramatic response to acute reduction in environmental temperature in growing male mice.
  2. Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.
  3. Reconstructing human brown fat developmental trajectory in vitro.
  4. The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
  5. Control of murine brown adipocyte development by GATA6.
  6. Structure and function of the human mitochondrial MRS2 channel.
  7. Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
  8. Unanswered questions about the causes of obesity.
  9. Role of gut microbiota in the postnatal thermoregulation of Brandt's voles.
  10. Identification of an alternative triglyceride biosynthesis pathway.
  11. Malonate induces the browning of white adipose tissue in high-fat diet induced obesity model.
  12. Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.
  13. Prolonged endurance exercise increases macrophage content and mitochondrial respiration in adipose tissue in trained men.
  1. Bone Rep. 2023 Dec;19 101706
    Brown adipose tissue but not tibia exhibits a dramatic response to acute reduction in environmental temperature in growing male mice.
    Carmen P Wong, Urszula T Iwaniec, Russell T Turner.
      Mice are typically housed at room temperature (∼22 °C), which is well below their thermoneutral zone and results in cold stress. Chronic cold stress leads to increased adaptive thermogenesis and reductions in cancellous bone volume and bone marrow adipose tissue mass in long bones of growing mice. There is strong evidence that increased neuronal activity initiates the metabolic response of intrascapular brown adipose tissue (BAT) to cold stress, but it is less clear whether bone is regulated through a similar mechanism. Therefore, we compared the short-term response of BAT and whole tibia to a reduction in environmental temperature. To accomplish this, we transferred a group of 6-week-old male mice from 32 °C to 22 °C housing and sacrificed the mice 24 h later. Age-matched controls were maintained at 32 °C. We then evaluated expression levels of a panel of genes related to adipocyte differentiation and fat metabolism in BAT and tibia, and a panel of genes related to bone metabolism in tibia. The decrease in housing temperature resulted in changes in expression levels for 47/86 genes related to adipocyte differentiation and fat metabolism in BAT, including 9-fold and 17-fold increases in Ucp1 and Dio2, respectively. In contrast, only 1/86 genes related to adipocyte differentiation and fat metabolism and 4/84 genes related to bone metabolism were differentially expressed in tibia. These findings suggest that bone, although innervated with sensory and sympathetic neurons, does not respond as rapidly as BAT to changes in environmental temperature.
    Keywords:  Adipocyte gene expression; Bone; Brown adipose tissue; Cold stress; Mouse
    DOI:  https://doi.org/10.1016/j.bonr.2023.101706
  2. J Lipid Res. 2023 Aug 26. pii: S0022-2275(23)00107-4. [Epub ahead of print] 100434
    Acute activation of adipocyte lipolysis reveals dynamic lipid remodeling of the hepatic lipidome.
    Sicheng Zhang, Kevin J Williams, Amandine Verlande-Ferrero, Alvin P Chan, Gino B Su, Erin E Kershaw, James E Cox, John Alan Maschek, Suzanne N Shapira, Heather R Christofk, Thomas Q de Aguiar Vallim, Selma Masri, Claudio J Villanueva.
      Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte secreted lipidome and show that there is inter-organ crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome, showed that free fatty acids increase within 30 minutes of β3-adrenergic receptor activation, and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of ATGL exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together these data highlight critical role of adipocyte lipolysis in inter-organ crosstalk between adipocytes and liver.
    Keywords:  Adipocytes; Adipose tissue triglyceride lipase; Ceramides; Fasting; Lipase; Lipid droplets; Lipidomics; Lipids; Liver; Triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2023.100434
  3. Dev Cell. 2023 Aug 24. pii: S1534-5807(23)00397-0. [Epub ahead of print]
    Reconstructing human brown fat developmental trajectory in vitro.
    Jyoti Rao, Yannis Djeffal, Jerome Chal, Fabio Marchianò, Chih-Hao Wang, Ziad Al Tanoury, Svetlana Gapon, Alicia Mayeuf-Louchart, Ian Glass, Elizabeth M Sefton, Bianca Habermann, Gabrielle Kardon, Fiona M Watt, Yu-Hua Tseng, Olivier Pourquié.
      Brown adipocytes (BAs) represent a specialized cell type that is able to uncouple nutrient catabolism from ATP generation to dissipate energy as heat. In humans, the brown fat tissue is composed of discrete depots found throughout the neck and trunk region. BAs originate from a precursor common to skeletal muscle, but their developmental trajectory remains poorly understood. Here, we used single-cell RNA sequencing to characterize the development of interscapular brown fat in mice. Our analysis identified a transient stage of BA differentiation characterized by the expression of the transcription factor GATA6. We show that recapitulating the sequence of signaling cues identified in mice can lead to efficient differentiation of BAs in vitro from human pluripotent stem cells. These precursors can in turn be efficiently converted into functional BAs that can respond to signals mimicking adrenergic stimuli by increasing their metabolism, resulting in heat production.
    Keywords:  GATA6; brown adipocytes; brown adipose tissue; directed differentiation; human pluripotent stem cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.001
  4. bioRxiv. 2023 Aug 16. pii: 2023.08.15.553413. [Epub ahead of print]
    The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
    Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.
      Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.
    DOI:  https://doi.org/10.1101/2023.08.15.553413
  5. Dev Cell. 2023 Aug 23. pii: S1534-5807(23)00399-4. [Epub ahead of print]
    Control of murine brown adipocyte development by GATA6.
    Seoyoung Jun, Anthony R Angueira, Ethan C Fein, Josephine M E Tan, Angela H Weller, Lan Cheng, Kirill Batmanov, Jeff Ishibashi, Alexander P Sakers, Rachel R Stine, Patrick Seale.
      Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the identity of embryonic brown fat progenitor cells and regulators of adipogenic commitment are unclear. Here, we performed single-cell gene expression analyses of mesenchymal cells during mouse embryogenesis with a focus on BAT development. We identified cell populations associated with the development of BAT, including Dpp4+ cells that emerge at the onset of adipogenic commitment. Immunostaining and lineage-tracing studies show that Dpp4+ cells constitute the BAT fascia and contribute minorly as adipocyte progenitors. Additionally, we identified the transcription factor GATA6 as a marker of brown adipogenic progenitor cells. Deletion of Gata6 in the brown fat lineage resulted in a striking loss of BAT. Together, these results identify progenitor and transitional cells in the brown adipose lineage and define a crucial role for GATA6 in BAT development.
    Keywords:  DPP4; EBF2; GATA6; UCP1; adipose tissue; brown adipocyte; brown adipocyte development; brown adipogenesis; progenitor
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.003
  6. bioRxiv. 2023 Aug 15. pii: 2023.08.12.553106. [Epub ahead of print]
    Structure and function of the human mitochondrial MRS2 channel.
    Zhihui He, Yung-Chi Tu, Chen-Wei Tsai, Jonathan Mount, Jingying Zhang, Ming-Feng Tsai, Peng Yuan.
      The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg 2+ transport across mitochondrial inner membranes, thus playing an important role in Mg 2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca 2+ -regulated, non-selective channel permeable to Mg 2+ , Ca 2+ , Na + and K + , which contrasts with its prokaryotic ortholog, CorA, operating as a Mg 2+ -gated Mg 2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.
    DOI:  https://doi.org/10.1101/2023.08.12.553106
  7. Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]
    Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
    Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.
      The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.
    Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
  8. Science. 2023 Sep;381(6661): 944-946
    Unanswered questions about the causes of obesity.
    John R Speakman, Thorkild I A Sørensen, Kevin D Hall, David B Allison.
      Obesity is now a global pandemic, but there is little consensus about the causes.
    DOI:  https://doi.org/10.1126/science.adg2718
  9. Cell Rep. 2023 Aug 28. pii: S2211-1247(23)01032-X. [Epub ahead of print]42(9): 113021
    Role of gut microbiota in the postnatal thermoregulation of Brandt's voles.
    Tingbei Bo, Liqiu Tang, Xiaoming Xu, Min Liu, Jing Wen, Jinzhen Lv, Dehua Wang.
      Homeothermy is crucial for mammals. Postnatal growth is the key period for young offspring to acquire gut microbiota. Although gut microbiota may affect mammal thermogenesis, the impact of developmental regulation of gut microbiota on the ability of young pups to produce heat remains unclear. Antibiotics were used to interfere with the establishment of gut microbiota during the development of Brandt's voles, and their thermogenic development and regulatory pathways were determined. Deprivation of microbiota by antibiotics inhibits the development of thermogenesis in pups. Butyric acid and bile acid, as metabolites of gut microbiota, participated in the thermoregulation of pups. We propose that gut microbiota promote the development of thermoregulation through the butyric acid-free fatty acid receptor-2-uncoupling protein-1 or the deoxycholic acid-Takeda-G-protein-receptor-5-uncoupling protein-1 pathway in pups. These results show a relationship between gut microbiota and thermogenesis and expand the mechanism of postnatal development of thermogenesis in small mammals.
    Keywords:  Brandt’s vole; CP: Metabolism; CP: Microbiology; Lasiopodomys brandtii; bile acids; brown adipose tissue; gut microbiota; postnatal development; thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2023.113021
  10. Nature. 2023 Aug 30.
    Identification of an alternative triglyceride biosynthesis pathway.
    Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.
      Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
    DOI:  https://doi.org/10.1038/s41586-023-06497-4
  11. Biochem Biophys Res Commun. 2023 Aug 24. pii: S0006-291X(23)01000-8. [Epub ahead of print]678 200-206
    Malonate induces the browning of white adipose tissue in high-fat diet induced obesity model.
    Shoma Oki, Sou Kageyama, Yuki Morioka, Takushi Namba.
      Obesity increases the risk of various diseases, and many studies have examined prevention and treatment strategies. Browning of white adipocytes promotes triglyceride (TG) metabolism and is the new focus for treating obesity. This study investigated the role of malonate-a modulator of mitochondrial function-in adipocyte browning, and its potential as a therapeutic agent in obesity. Our findings revealed that malonate increased oxygen consumption without inhibiting ATP synthesis. Malonate induced expression of PRDM16-an important transcription factor for browning-and uncoupling protein 1 (beige adipocyte marker), suggesting that malonate induces browning in white adipocytes. In an obesity mouse model induced by a high-fat diet, malonate significantly reduced body weight and white adipose tissue weight, as well as improved insulin resistance. Importantly, malonate stimulated browning in white adipose tissue and maintained the mass of brown adipose tissue in the high-fat diet-induced obesity mouse model. We propose that manipulation of mitochondrial function by malonate is a promising therapeutic approach for obesity.
    Keywords:  Beige adipocytes; Browning; Mitochondria; Obesity
    DOI:  https://doi.org/10.1016/j.bbrc.2023.08.054
  12. Science. 2023 Sep;381(6661): eadh5207
    Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.
    Wen Dai, Heng Zhang, Hayley Lund, Ziyu Zhang, Mark Castleberry, Maya Rodriguez, George Kuriakose, Sweta Gupta, Magdalena Lewandowska, Hayley R Powers, Swati Valmiki, Jieqing Zhu, Amy D Shapiro, M Mahmood Hussain, José A López, Mary G Sorci-Thomas, Roy L Silverstein, Henry N Ginsberg, Daisy Sahoo, Ira Tabas, Ze Zheng.
      Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels. Plasminogen activator inhibitor 1 (PAI-1) sequesters tPA away from apoB and increases VLDL assembly. Humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of apoB-lipoprotein cholesterol. These results suggest a mechanism that fine-tunes VLDL assembly by intracellular interactions among tPA, PAI-1, and apoB in hepatocytes.
    DOI:  https://doi.org/10.1126/science.adh5207
  13. J Clin Endocrinol Metab. 2023 Aug 29. pii: dgad509. [Epub ahead of print]
    Prolonged endurance exercise increases macrophage content and mitochondrial respiration in adipose tissue in trained men.
    Ronni Eg Sahl, Ioanna Patsi, Mikkel Thunestvedt Hansen, Tue Rømer, Jacob Frandsen, Hanne Kruuse Rasmusen, Arthur Ingersen, Steen Seier Poulsen, Flemming Dela, Steen Larsen, Jørn Wulff Helge.
      BACKGROUND: The aim was to investigate the effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in young and old men.METHODS: Young (aged 30 years, n = 7) and old (aged 65 years, n = 7) trained men were exposed to an exercise intervention of 15 consecutive days biking 7-9 hours/day at 63% and 65% of maximal heart rate (young and old, respectively), going from Copenhagen, Denmark to Palermo, Italy. Adipose tissue was sampled from both the gluteal and abdominal depot before and after the intervention. Mitochondrial respiration was measured by high-resolution respirometry and adipose inflammation was assessed by immunohistochemical staining of paraffin embedded sections.
    RESULTS: An increased number of CD163 + macrophages was observed in both the gluteal and abdominal depot (P < 0.01). In addition, an increased mitochondrial respiration was observed in the abdominal adipose tissue from the young group with complex I (CIp) stimulated respiration, complex I + II (CI + IIp) stimulated respiration and the capacity of the electron transport system (ETS)(P < 0.05), and in the old group an increase in CIp and CI + IIp stimulated respiration (P < 0.05) was found.
    CONCLUSION: Overall, we found a positive effect of prolonged endurance exercise on adipose tissue inflammation markers and mitochondrial respiration in both young and old trained men, and no sign of attenuated function in AT with age.
    Keywords:  Aging; adipose tissue; exercise; human; inflammation; mitochondrial respiration
    DOI:  https://doi.org/10.1210/clinem/dgad509
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