bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–11–24
nine papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
  2. Textbook oxidative phosphorylation needs to be rewritten.
  3. Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks.
  4. Adipose tissue retains an epigenetic memory of obesity after weight loss.
  5. Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
  6. Electrogenic and non-electrogenic ion antiporters participate in controling membrane potential.
  7. Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
  8. DFCP1 is a Regulator of Starvation-driven ATGL-mediated Lipid Droplet Lipolysis.
  9. Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer.
  1. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00414-5. [Epub ahead of print]
    Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
    Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P Blondin, Pierre-Damien Denechaud, André C Carpentier, Dominique Langin.
      Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [11C]-acetate and [11C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.
    Keywords:  PET/CT; adipose triglyceride lipase; body temperature; brown adipose tissue; hormone-sensitive lipase; lipid droplet; lipolysis; mouse models; obesity; oxidative metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.018
  2. Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]
    Textbook oxidative phosphorylation needs to be rewritten.
    Alicia J Kowaltowski, Fernando Abdulkader.
      Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
    Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange
    DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
  3. bioRxiv. 2024 Oct 28. pii: 2024.10.28.620609. [Epub ahead of print]
    Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks.
    Georgios K Paschos, Ronan Lordan, Taylor Hollingsworth, Damien Lekkas, Sean Kelch, Emanuele Loro, Ioannis Verginadis, Tejvir Khurana, Arjun Sengupta, Aalim Weljie, Garret A FitzGerald.
      Circadian misalignment has been associated with obesity both in rodents and humans. Brown adipose tissue (BAT) thermogenesis contributes to energy expenditure and can be activated in adults to reduce body weight. Although previous studies suggest control of BAT thermogenesis by the circadian clock, the site and mechanisms of regulation remain unclear. We used mice with genetic disruption of the circadian clock in the suprachiasmatic nucleus (SCN) and peripheral tissues to delineate their role in BAT thermogenesis. Global post-natal deletion of Bmal1 in adult mice ( Bmal1 -/- ) abolishes the rhythms of interscapular BAT temperature, a measure of thermogenesis, while normal locomotor activity rhythms are maintained under a regular 12h light-12h dark schedule. Activation of thermogenesis either by exposure to cold or adrenergic stimulation of BAT displays a diurnal rhythm with higher activation during the active period. Both the rhythm and the magnitude of the thermogenic response is preserved in Bmal1 -/- mice. In contrast to mice with global deletion of Bmal1 , mice with brown adipocyte (Ucp1- Bmal1 -/- ) or brown and white adipocyte (Ad- Bmal1 -/- ) deletion of Bmal1 show intact rhythms of BAT thermogenic activity. The capacity of Ucp1- Bmal1 -/- mice to activate thermogenesis in response to exposure to cold is identical to WT mice, independent of time of stimulation. Circadian rhythmicity of interscapular BAT temperature is lost in mice with SCN deletion of Bmal1 (SCN- Bmal1 -/- ), indicating control of BAT thermogenesis rhythms by the SCN. Control mice exhibit rhythmic BAT glucose and fatty acid uptake - a rhythm that is not recapitulated in Bmal1 -/- and SCN- Bmal1 -/- mice but is present in Ucp1- Bmal1 -/- and Ad- Bmal1 -/- mice. BAT cAMP and phosphorylated hormone-sensitive lipase (pHSL) is reduced during the active period in Bmal1 -/- and SCN- Bmal1 -/- mice consistent with reduced sympathetic tone. Furthermore, sympathetic denervation of BAT ablates BAT temperature rhythms in WT mice. Taken together, our findings suggest that the SCN drives rhythms of BAT thermogenesis through adipocyte clock-independent, sympathetic signaling to the BAT.
    DOI:  https://doi.org/10.1101/2024.10.28.620609
  4. Nature. 2024 Nov 18.
    Adipose tissue retains an epigenetic memory of obesity after weight loss.
    Laura C Hinte, Daniel Castellano-Castillo, Adhideb Ghosh, Kate Melrose, Emanuel Gasser, Falko Noé, Lucas Massier, Hua Dong, Wenfei Sun, Anne Hoffmann, Christian Wolfrum, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Ferdinand von Meyenn.
      Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic 'yo-yo' effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.
    DOI:  https://doi.org/10.1038/s41586-024-08165-7
  5. J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004
    Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
    Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.
      Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.
    Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux
    DOI:  https://doi.org/10.1016/j.jbc.2024.108004
  6. Cell Calcium. 2024 Nov 16. pii: S0143-4160(24)00129-5. [Epub ahead of print]124 102971
    Electrogenic and non-electrogenic ion antiporters participate in controling membrane potential.
    Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.
      In a comment to our recent publication, Nicholls question our results and interpretation based on theoretical arguments that reveal a profound misunderstanding of our publication.
    Keywords:  Antiporters; Membrane potential; Mitochondria; Sodium proton exchange
    DOI:  https://doi.org/10.1016/j.ceca.2024.102971
  7. bioRxiv. 2024 Oct 29. pii: 2024.10.25.620374. [Epub ahead of print]
    Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
    Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Calvin Pan, Aldons J Lusis, Kevin J Williams, Baolong Su, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.
      Complex genetic and dietary cues contribute to the development of obesity, but how these are integrated on a molecular level is incompletely understood. Here, we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, a membrane-bound O-acyltransferase that enriches diet-derived omega-6 ( n -6) polyunsaturated fatty acids (PUFAs) in the phospholipidome. In high-fat diet-fed mice, lowering membrane n -6 PUFA levels by adipocyte-specific Lpcat3 knockout ( Lpcat3 AKO ) or by dietary lipid manipulation leads to dysfunctional triglyceride (TG) storage, ectopic fat deposition and insulin resistance. Aberrant lipolysis of stored TGs in Lpcat3 AKO adipose tissues instigates a non-canonical adaptive response that engages a futile lipid cycle to increase energy expenditure and limit further body weight gain. Mechanistically, we find that adipocyte LPCAT3 activity promotes TG storage by selectively enriching n -6 arachidonoyl-phosphatidylethanolamine at the ER-lipid droplet interface, which in turn favours the budding of large droplets that exhibit greater resistance to ATGL-dependent hydrolysis. Thus, our study highlights the PPARγ-LPCAT3 pathway as a molecular link between dietary n -6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1101/2024.10.25.620374
  8. J Lipid Res. 2024 Nov 18. pii: S0022-2275(24)00205-0. [Epub ahead of print] 100700
    DFCP1 is a Regulator of Starvation-driven ATGL-mediated Lipid Droplet Lipolysis.
    V A Ismail, M N Harvey, Zak Baker, J Castillo-Badillo, T Naismith, D J Pagliarini, D J Kast.
      Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks, and therefore play a central role in cellular metabolism. Double FYVE Domain Containing Protein 1 (DFCP1/ZFYV1) has emerged as a key regulator of LD metabolism, where the nucleotide-dependent accumulation of DFCP1 on LDs influences their size, number, and dynamics. Here we show that DFCP1 regulates lipid metabolism by directly modulating the activity of Adipose Triglyceride Lipase (ATGL/PNPLA2), the rate-limiting lipase driving the catabolism of LDs. We show through pharmacological inhibition of key enzymes associated with LD metabolism that DFCP1 specifically regulates lipolysis and, to a lesser extent, lipophagy. Consistent with this observation, DFCP1 interacts with and recruits ATGL to LDs in starved cells, irrespective of other known regulatory factors of ATGL. We further establish that this interaction prevents dynamic disassociation of ATGL from LDs and thereby impedes the rate of LD lipolysis. Collectively, our findings indicate that DFCP1 is a nutrient-sensitive regulator of LD catabolism.
    Keywords:  ABHD5; ATGL; CGI-58; DFCP1; FRAP; PLPL2; ZFYVE1; diglycerides; fatty acids; lipid droplets; triglycerides
    DOI:  https://doi.org/10.1016/j.jlr.2024.100700
  9. Redox Biol. 2024 Nov 10. pii: S2213-2317(24)00404-X. [Epub ahead of print]78 103426
    Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer.
    Lucynda Pham, Tasnim Arroum, Junmei Wan, Lauren Pavelich, Jamie Bell, Paul T Morse, Icksoo Lee, Lawrence I Grossman, Thomas H Sanderson, Moh H Malek, Maik Hüttemann.
      Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.
    DOI:  https://doi.org/10.1016/j.redox.2024.103426
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