bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024–05–19
eight papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.
  2. The role of compartmentalized β-AR/cAMP signaling in the regulation of lipolysis in white and brown adipocytes.
  3. Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
  4. The septin modifier, forchlorfenuron, activates NLRP3 via a potassium-independent mitochondrial axis.
  5. Physiological temperature drives TRPM4 ligand recognition and gating.
  6. Ancestral sequence reconstruction of Mic60 reveals a residue signature supporting respiration in yeast.
  7. Remodeling of skeletal muscle myosin metabolic states in hibernating mammals.
  8. Energy Expenditure in Humans: Principles, Methods, and Changes Throughout the Life Course.
  1. Physiol Res. 2024 May 15.
    Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.
    K Bardova, P Janovska, A Vavrova, J Kopecky, P Zouhar.
      Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.
  2. FEBS J. 2024 May 15.
    The role of compartmentalized β-AR/cAMP signaling in the regulation of lipolysis in white and brown adipocytes.
    Kirstie A De Jong, Sana Siddig, Alexander Pfeifer, Viacheslav O Nikolaev.
      White and brown adipocytes are central mediators of lipid metabolism and thermogenesis, respectively. Their function is tightly regulated by all three β-adrenergic receptor (β-AR) subtypes which are coupled to the production of the second messenger 3',5'-cyclic adenosine monophosphate (cAMP). While known for decades in other cell types, compartmentation of adipocyte β-AR/cAMP signaling by spatial organization of the pathway and by cAMP degrading phosphodiesterases (PDEs) as well as its role in the regulation of lipolysis is only beginning to emerge. Here, we provide a short overview of recent findings which shed light on compartmentalized signaling using live cell imaging of cAMP in adipocytes and discuss possible future directions of research which could open up new avenues for the treatment of metabolic disorders.
    Keywords:  3′,5′‐cyclic adenosine monophosphate; adipocytes; compartmentation; diabetes; fluorescence resonance energy transfer; phosphodiesterases; β‐adrenergic receptor
    DOI:  https://doi.org/10.1111/febs.17157
  3. Nat Commun. 2024 May 17. 15(1): 4214
    Liver ACOX1 regulates levels of circulating lipids that promote metabolic health through adipose remodeling.
    Dongliang Lu, Anyuan He, Min Tan, Marguerite Mrad, Amal El Daibani, Donghua Hu, Xuejing Liu, Brian Kleiboeker, Tao Che, Fong-Fu Hsu, Monika Bambouskova, Clay F Semenkovich, Irfan J Lodhi.
      The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-024-48471-2
  4. Cell Chem Biol. 2024 May 16. pii: S2451-9456(24)00174-0. [Epub ahead of print]31(5): 962-972.e4
    The septin modifier, forchlorfenuron, activates NLRP3 via a potassium-independent mitochondrial axis.
    Caroline L Holley, Stefan Emming, Mercedes M Monteleone, Manasa Mellacheruvu, Kirsten M Kenney, Grace M E P Lawrence, Jared R Coombs, Sabrina S Burgener, Kate Schroder.
      The Nod-like receptor protein 3 (NLRP3) inflammasome is activated by stimuli that induce perturbations in cell homeostasis, which commonly converge on cellular potassium efflux. NLRP3 has thus emerged as a sensor for ionic flux. Here, we identify forchlorfenuron (FCF) as an inflammasome activator that triggers NLRP3 signaling independently of potassium efflux. FCF triggers the rearrangement of septins, key cytoskeletal proteins that regulate mitochondrial function. We report that FCF triggered the rearrangement of SEPT2 into tubular aggregates and stimulated SEPT2-independent NLRP3 inflammasome signaling. Similar to imiquimod, FCF induced the collapse of the mitochondrial membrane potential and mitochondrial respiration. FCF thereby joins the imidazoquinolines as a structurally distinct class of molecules that triggers NLRP3 inflammasome signaling independent of potassium efflux, likely by inducing mitochondrial damage.
    Keywords:  NLRP3; forchlorfenuron; inflammasome; inflammation; macrophage; septin
    DOI:  https://doi.org/10.1016/j.chembiol.2024.04.012
  5. Nature. 2024 May 15.
    Physiological temperature drives TRPM4 ligand recognition and gating.
    Jinhong Hu, Sung Jin Park, Tyler Walter, Ian J Orozco, Garrett O'Dea, Xinyu Ye, Juan Du, Wei Lü.
      Temperature profoundly affects macromolecular function, particularly in proteins with temperature sensitivity1,2. However, its impact is often overlooked in biophysical studies that are typically performed at non-physiological temperatures, potentially leading to inaccurate mechanistic and pharmacological insights. Here we demonstrate temperature-dependent changes in the structure and function of TRPM4, a temperature-sensitive Ca2+-activated ion channel3-7. By studying TRPM4 prepared at physiological temperature using single-particle cryo-electron microscopy, we identified a 'warm' conformation that is distinct from those observed at lower temperatures. This conformation is driven by a temperature-dependent Ca2+-binding site in the intracellular domain, and is essential for TRPM4 function in physiological contexts. We demonstrated that ligands, exemplified by decavanadate (a positive modulator)8 and ATP (an inhibitor)9, bind to different locations of TRPM4 at physiological temperatures than at lower temperatures10,11, and that these sites have bona fide functional relevance. We elucidated the TRPM4 gating mechanism by capturing structural snapshots of its different functional states at physiological temperatures, revealing the channel opening that is not observed at lower temperatures. Our study provides an example of temperature-dependent ligand recognition and modulation of an ion channel, underscoring the importance of studying macromolecules at physiological temperatures. It also provides a potential molecular framework for deciphering how thermosensitive TRPM channels perceive temperature changes.
    DOI:  https://doi.org/10.1038/s41586-024-07436-7
  6. bioRxiv. 2024 Apr 29. pii: 2024.04.26.591372. [Epub ahead of print]
    Ancestral sequence reconstruction of Mic60 reveals a residue signature supporting respiration in yeast.
    Friederike M C Benning, Tristan A Bell, Tran H Nguyen, Della Syau, Louise B Connell, Corrie J B daCosta, Luke H Chao.
      In eukaryotes, the essential process of cellular respiration takes place in the cristae of mitochondria. The protein Mic60 is known to stabilize crista junctions; however, how the C-terminal Mitofilin domain of Mic60 mediates cristae-supported respiration remains elusive. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast-lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors with different respiratory phenotypes, we identify four residues that explain the difference between respiration functional yeast- and non-functional animal-derived common Mitofilin ancestors. Our results imply that Mitofilin-supported respiration in yeast stems from a conserved mechanism, and provide a foundation for investigating the divergence of candidate crista junction interactions present during the emergence of eukaryotes.
    DOI:  https://doi.org/10.1101/2024.04.26.591372
  7. Elife. 2024 May 16. pii: RP94616. [Epub ahead of print]13
    Remodeling of skeletal muscle myosin metabolic states in hibernating mammals.
    Christopher T A Lewis, Elise G Melhedegaard, Marija M Ognjanovic, Mathilde S Olsen, Jenni Laitila, Robert A E Seaborne, Magnus Gronset, Changxin Zhang, Hiroyuki Iwamoto, Anthony L Hessel, Michel N Kuehn, Carla Merino, Nuria Amigo, Ole Frobert, Sylvain Giroud, James F Staples, Anna V Goropashnaya, Vadim B Fedorov, Brian Barnes, Oivind Toien, Kelly Drew, Ryan J Sprenger, Julien Ochala.
      Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20 °C). Upon repeating loaded Mant-ATP chase experiments at 8 °C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77-107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.
    Keywords:  biochemistry; cell biology; chemical biology; eliomys quercinus; ictidomys tridecemlineatus; ursus americanus; ursus arctos
    DOI:  https://doi.org/10.7554/eLife.94616
  8. Annu Rev Nutr. 2024 May 17.
    Energy Expenditure in Humans: Principles, Methods, and Changes Throughout the Life Course.
    Rodrigo Fernández-Verdejo, Guillermo Sanchez-Delgado, Eric Ravussin.
      Humans require energy to sustain their daily activities throughout their lives. This narrative review aims to (a) summarize principles and methods for studying human energy expenditure, (b) discuss the main determinants of energy expenditure, and (c) discuss the changes in energy expenditure throughout the human life course. Total daily energy expenditure is mainly composed of resting energy expenditure, physical activity energy expenditure, and the thermic effect of food. Total daily energy expenditure and its components are estimated using variations of the indirect calorimetry method. The relative contributions of organs and tissues determine the energy expenditure under different physiological conditions. Evidence shows that energy expenditure varies along the human life course, at least in part due to changes in body composition, the mass and specific metabolic rate of organs and tissues, and levels of physical activity. This information is crucial to estimate human energy requirements for maintaining health throughout the life course.
    DOI:  https://doi.org/10.1146/annurev-nutr-062122-031443
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