bims-mimbat Biomed News
on Mitochondrial metabolism in brown adipose tissue
Issue of 2024‒09‒08
fourteen papers selected by
José Carlos de Lima-Júnior, Washington University
  1. Cold-induced phosphatidylethanolamine synthesis in liver and brown adipose tissue of mice.
  2. Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
  3. Transcriptional regulation of adipocyte lipolysis by IRF2BP2.
  4. In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
  5. Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
  6. Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
  7. Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex.
  8. PPARγ activation by lipolysis-generated ligands is required for cAMP dependent UCP1 induction in human thermogenic adipocytes.
  9. Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.
  10. Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.
  11. Mitochondrial transplants to treat mitochondrial dysfunction.
  12. Lipid- and protein-directed photosensitizer proximity labeling captures the cholesterol interactome.
  13. Is it time to rethink the relationship between adipose inflammation and insulin resistance?
  14. Chronic cold exposure causes left ventricular hypertrophy that appears to be physiological.
  1. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Aug 28. pii: S1388-1981(24)00112-4. [Epub ahead of print]1870(1): 159562
    Cold-induced phosphatidylethanolamine synthesis in liver and brown adipose tissue of mice.
    Maria Soledad Hidrobo, Marcus Höring, Sarah Brunner, Gerhard Liebisch, Sabine Schweizer, Martin Klingenspor, Renate Schreiber, Rudolf Zechner, Ralph Burkhardt, Josef Ecker.
      Increasing energy expenditure in brown adipose (BAT) tissue by cold-induced lipolysis is discussed as a potential strategy to counteract imbalanced lipid homeostasis caused through unhealthy lifestyle and cardiometabolic disease. Yet, it is largely unclear how liberated fatty acids (FA) are metabolized. We investigated the liver and BAT lipidome of mice housed for 1 week at thermoneutrality, 23 °C and 4 °C using quantitative mass spectrometry-based lipidomics. Housing at temperatures below thermoneutrality triggered the generation of phosphatidylethanolamine (PE) in both tissues. Particularly, the concentrations of PE containing polyunsaturated fatty acids (PUFA) in their acyl chains like PE 18:0_20:4 were increased at cold. Investigation of the plasma's FA profile using gas chromatography coupled to mass spectrometry revealed a negative correlation of PUFA with unsaturated PE in liver and BAT indicating a flux of FA from the circulation into these tissues. Beta-adrenergic stimulation elevated intracellular levels of PE 38:4 and PE 40:6 in beige wildtype adipocytes, but not in adipose triglyceride lipase (ATGL)-deficient cells. These results imply an induction of PE synthesis in liver, BAT and thermogenic adipocytes after activation of the beta-adrenergic signaling cascade.
    Keywords:  Cold exposure; Lipidomics; Lipolysis; Liver lipidome; PUFA; Phosphatidylethanolamine
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159562
  2. Nat Commun. 2024 Aug 29. 15(1): 7483
    Adipocyte deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality.
    Rongling Wang, Mario Gomez Salazar, Iris Pruñonosa Cervera, Amanda Coutts, Karen French, Marlene Magalhaes Pinto, Sabrina Gohlke, Ruben García-Martín, Matthias Blüher, Christopher J Schofield, Ioannis Kourtzelis, Roland H Stimson, Cécile Bénézech, Mark Christian, Tim J Schulz, Elias F Gudmundsson, Lori L Jennings, Vilmundur G Gudnason, Triantafyllos Chavakis, Nicholas M Morton, Valur Emilsson, Zoi Michailidou.
      Enhancing thermogenic brown adipose tissue (BAT) function is a promising therapeutic strategy for metabolic disease. However, predominantly thermoneutral modern human living conditions deactivate BAT. We demonstrate that selective adipocyte deficiency of the oxygen-sensor HIF-prolyl hydroxylase (PHD2) gene overcomes BAT dormancy at thermoneutrality. Adipocyte-PHD2-deficient mice maintain higher energy expenditure having greater BAT thermogenic capacity. In human and murine adipocytes, a PHD inhibitor increases Ucp1 levels. In murine brown adipocytes, antagonising the major PHD2 target, hypoxia-inducible factor-(HIF)-2a abolishes Ucp1 that cannot be rescued by PHD inhibition. Mechanistically, PHD2 deficiency leads to HIF2 stabilisation and binding of HIF2 to the Ucp1 promoter, thus enhancing its expression in brown adipocytes. Serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study reveal that serum PHD2 associates with increased risk of metabolic disease. Here we show that adipose-PHD2-inhibition is a therapeutic strategy for metabolic disease and identify serum PHD2 as a disease biomarker.
    DOI:  https://doi.org/10.1038/s41467-024-51718-7
  3. bioRxiv. 2024 Jul 31. pii: 2024.07.31.605689. [Epub ahead of print]
    Transcriptional regulation of adipocyte lipolysis by IRF2BP2.
    Yang Chen, Lin Liu, Ryan Calhoun, Lan Cheng, David Merrick, David J Steger, Patrick Seale.
      Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by post-translational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify the transcriptional factor interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a repressor of adipocyte lipolysis. Deletion of IRF2BP2 in primary human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA-seq and ChIP-seq analyses reveal that IRF2BP2 directly represses several lipolysis-related genes, including LIPE ( HSL , hormone sensitive lipase), which encodes the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of Irf2bp2 in mice increases Lipe expression and free fatty acid levels, resulting in elevated adipose tissue inflammation and glucose intolerance. Altogether, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens new avenues to target lipolysis for the treatment of metabolic disease.
    DOI:  https://doi.org/10.1101/2024.07.31.605689
  4. Science. 2024 Sep 06. 385(6713): 1086-1090
    In situ structure and rotary states of mitochondrial ATP synthase in whole Polytomella cells.
    Lea Dietrich, Ahmed-Noor A Agip, Christina Kunz, Andre Schwarz, Werner Kühlbrandt.
      Cells depend on a continuous supply of adenosine triphosphate (ATP), the universal energy currency. In mitochondria, ATP is produced by a series of redox reactions, whereby an electrochemical gradient is established across the inner mitochondrial membrane. The ATP synthase harnesses the energy of the gradient to generate ATP from adenosine diphosphate (ADP) and inorganic phosphate. We determined the structure of ATP synthase within mitochondria of the unicellular flagellate Polytomella by electron cryo-tomography and subtomogram averaging at up to 4.2-angstrom resolution, revealing six rotary positions of the central stalk, subclassified into 21 substates of the F1 head. The Polytomella ATP synthase forms helical arrays with multiple adjacent rows defining the cristae ridges. The structure of ATP synthase under native operating conditions in the presence of a membrane potential represents a pivotal step toward the analysis of membrane protein complexes in situ.
    DOI:  https://doi.org/10.1126/science.adp4640
  5. J Biol Chem. 2024 Aug 31. pii: S0021-9258(24)02241-5. [Epub ahead of print] 107740
    Identification of SLC25A46 interaction interfaces with mitochondrial membrane fusogens Opa1 and Mfn2.
    Sivakumar Boopathy, Bridget E Luce, Camila Makhlouta Lugo, Pusparanee Hakim, Julie McDonald, Ha Lin Kim, Jackeline Ponce, Beatrix M Ueberheide, Luke H Chao.
      Mitochondrial fusion requires the sequential merger of four bilayers to two. The outer-membrane solute carrier protein SLC25A46 interacts with both the outer and inner-membrane dynamin family GTPases Mfn1/2 and Opa1. While SLC25A46 levels are known to affect mitochondrial morphology, how SLC25A46 interacts with Mfn1/2 and Opa1 to regulate membrane fusion is not understood. In this study, we use crosslinking mass-spectrometry and AlphaFold 2 modeling to identify interfaces mediating a SLC25A46 interactions with Opa1 and Mfn2. We reveal that the bundle signaling element of Opa1 interacts with SLC25A46, and present evidence of a Mfn2 interaction involving the SLC25A46 cytosolic face. We validate these newly identified interaction interfaces and show that they play a role in mitochondrial network maintenance.
    Keywords:  GTPase; Mass spectrometry; Membrane fusion; Mitochondria; Mitochondrial solute carrier; Protein cross-linking; Protein-protein interaction; Structural model
    DOI:  https://doi.org/10.1016/j.jbc.2024.107740
  6. J Biol Chem. 2024 Sep 03. pii: S0021-9258(24)02247-6. [Epub ahead of print] 107746
    Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.
    Antonio J Rua, Wayne Mitchell, Steven M Claypool, Nathan N Alder, Andrei T Alexandrescu.
      Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin. Mutations in tafazzin are the primary cause of Barth syndrome. Here, we investigated how defects in cardiolipin biosynthesis and remodeling impacts metabolic flux through the TCA cycle and associated yeast pathways. Nuclear magnetic resonance was used to monitor in real-time the metabolic fate of 13C3-pyruvate in isolated mitochondria from three isogenic yeast strains. We compared mitochondria from a wild-type strain to mitochondria from a Δtaz1 strain that lacks tafazzin and contains lower amounts of unremodeled cardiolipin, and mitochondria from a Δcrd1 strain that lacks cardiolipin synthase and cannot synthesize cardiolipin. We found that the 13C-label from the pyruvate substrate was distributed through twelve metabolites. Several of the metabolites were specific to yeast pathways including branched chain amino acids and fusel alcohol synthesis. While most metabolites showed similar kinetics amongst the different strains, mevalonate concentrations were significantly increased in Δtaz1 mitochondria. Additionally, the kinetic profiles of α-ketoglutarate, as well as NAD+ and NADH measured in separate experiments, displayed significantly lower concentrations for Δtaz1 and Δcrd1 mitochondria at most time points. Taken together, the results show how cardiolipin remodeling influences pyruvate metabolism, tricarboxylic acid cycle flux, and the levels of mitochondrial nucleotides.
    Keywords:  3-methylglutaconic acid (3MGA); Barth syndrome (BTHS); Krebs cycle; adenosine triphosphate (ATP); metabolic disease; mitochondrial respiration; nuclear magnetic resonance (NMR); tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1016/j.jbc.2024.107746
  7. bioRxiv. 2024 Jul 26. pii: 2024.07.25.605195. [Epub ahead of print]
    Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex.
    Chao Li, Xue-Nan Sun, Jan-Bernd Funcke, Lauri Vanharanta, Nolwenn Joffin, Yan Li, Xavier Prasanna, Megan Paredes, Chanmin Joung, Ruth Gordillo, Csaba Vörös, Waldemar Kulig, Leon Straub, Shuiwei Chen, Joselin Velasco, Ayanna Cobb, Davide La Padula, May-Yun Wang, Toshiharu Onodera, Oleg Varlamov, Yang Li, Chen Liu, Andrea R Nawrocki, Shangang Zhao, Da Young Oh, Zhao V Wang, Joel M Goodman, R Max Wynn, Ilpo Vattulainen, Yan Han, Elina Ikonen, Philipp E Scherer.
      Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98Å overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.
    DOI:  https://doi.org/10.1101/2024.07.25.605195
  8. bioRxiv. 2024 Aug 11. pii: 2024.08.10.607465. [Epub ahead of print]
    PPARγ activation by lipolysis-generated ligands is required for cAMP dependent UCP1 induction in human thermogenic adipocytes.
    Anand Desai, Zinger Yang Loureiro, Tiffany DeSouza, Qin Yang, Javier Solivan-Rivera, Silvia Corvera.
      Objective: The uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes. To explore this, we employed human adipocytes differentiated from progenitor cells and examined their acute response to Rsg, to the adenylate-cyclase activator forskolin (Fsk), or to both simultaneously.Methods: Adipocytes generated from primary human progenitor cells were differentiated without exposure to PPARγ agonists, and treated for 3, 6 or 78 hours to Fsk, to Rsg, or to both simultaneously. Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 mediated knockout, oxygen consumption and western blotting were used to assess cellular responses.
    Results: UCP1 mRNA expression was induced within 3 hours of exposure to either Rsg or Fsk, indicating that Rsg's effect is independent on additional adipocyte differentiation. Although Rsg and Fsk induced distinct overall transcriptional responses, both induced genes associated with calcium metabolism, lipid droplet assembly, and mitochondrial remodeling, denoting core features of human adipocyte beiging. Unexpectedly, we found that Fsk-induced UCP1 expression was reduced by approximately 80% following CRISPR-Cas9-mediated knockout of PNPLA2 , the gene encoding the triglyceride lipase ATGL. As anticipated, ATGL knockout suppressed lipolysis; however, the associated suppression of UCP1 induction indicates that maximal cAMP-mediated UCP1 induction requires products of ATGL-catalyzed lipolysis. Supporting this, we observed that the reduction in Fsk-stimulated UCP1 induction caused by ATGL knockout was reversed by Rsg, implying that the role of lipolysis in this process is to generate natural PPARγ agonists.
    Conclusion: UCP1 transcription is known to be stimulated by transcription factors activated downstream of cAMP-dependent protein kinases. Here we demonstrate that UCP1 transcription can also be acutely induced through PPARγ-activation. Moreover, both pathways are activated in human adipocytes in response to cAMP, synergistically inducing UCP1 expression. The stimulation of PPARγ in response to cAMP occurs as a result of the production of natural PPARγ activating ligands through ATGL-mediated lipolysis.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.1101/2024.08.10.607465
  9. Nat Commun. 2024 Sep 05. 15(1): 7746
    Sortilin-mediated translocation of mitochondrial ACSL1 impairs adipocyte thermogenesis and energy expenditure in male mice.
    Min Yang, Jing Ge, Yu-Lian Liu, Huan-Yu Wang, Zhi-Han Wang, Dan-Pei Li, Rui He, Yu-Yu Xie, Hong-Yan Deng, Xue-Min Peng, Wen-She Wang, Jia-Dai Liu, Zeng-Zhe Zhu, Xue-Feng Yu, Pema Maretich, Shingo Kajimura, Ru-Ping Pan, Yong Chen.
      Beige fat activation involves a fuel switch to fatty acid oxidation following chronic cold adaptation. Mitochondrial acyl-CoA synthetase long-chain family member 1 (ACSL1) localizes in the mitochondria and plays a key role in fatty acid oxidation; however, the regulatory mechanism of the subcellular localization remains poorly understood. Here, we identify an endosomal trafficking component sortilin (encoded by Sort1) in adipose tissues that shows dynamic expression during beige fat activation and facilitates the translocation of ACSL1 from the mitochondria to the endolysosomal pathway for degradation. Depletion of sortilin in adipocytes results in an increase of mitochondrial ACSL1 and the activation of AMPK/PGC1α signaling, thereby activating beige fat and preventing high-fat diet (HFD)-induced obesity and insulin resistance. Collectively, our findings indicate that sortilin controls adipose tissue fatty acid oxidation by substrate fuel selection during beige fat activation and provides a potential targeted approach for the treatment of metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52218-4
  10. J Lipid Res. 2024 Aug 30. pii: S0022-2275(24)00143-3. [Epub ahead of print] 100638
    Modification in mitochondrial function is associated with the FADS1 variant and its interaction with alpha-linolenic acid-enriched diet - an exploratory study.
    Maija Vaittinen, Mariana Ilha, Ratika Sehgal, Maria A Lankinen, Jyrki Ågren, Pirjo Käkelä, Kirsi A Virtanen, Markku Laakso, Ursula Schwab, Jussi Pihlajamäki.
      Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 has been shown to be related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases.
    Keywords:  Adipocytes; Alpha-linolenic acid; Dietary fat; FADS1; Fatty acid oxidation; Human adipose-derived stromal cell; Lipids/oxidation; Mitochondria; Omega-3 fatty acids; Polyunsaturated fatty acid
    DOI:  https://doi.org/10.1016/j.jlr.2024.100638
  11. Nat Metab. 2024 Sep 02.
    Mitochondrial transplants to treat mitochondrial dysfunction.
    Alessandro Bitto.
      
    DOI:  https://doi.org/10.1038/s42255-024-01124-6
  12. bioRxiv. 2024 Aug 24. pii: 2024.08.20.608660. [Epub ahead of print]
    Lipid- and protein-directed photosensitizer proximity labeling captures the cholesterol interactome.
    Andrew P Becker, Elijah Biletch, John Paul Kennelly, Ashley R Julio, Miranda Villaneuva, Rohith T Nagari, Daniel W Turner, Nikolas R Burton, Tomoyuki Fukuta, Liujuan Cui, Xu Xiao, Soon-Gook Hong, Julia J Mack, Peter Tontonoz, Keriann M Backus.
      The physical properties of cellular membranes, including fluidity and function, are influenced by protein and lipid interactions. In situ labeling chemistries, most notably proximity-labeling interactomics are well suited to characterize these dynamic and often fleeting interactions. Established methods require distinct chemistries for proteins and lipids, which limits the scope of such studies. Here we establish a singlet-oxygen-based photocatalytic proximity labeling platform (POCA) that reports intracellular interactomes for both proteins and lipids with tight spatiotemporal resolution using cell-penetrant photosensitizer reagents. Using both physiologically relevant lipoprotein-complexed probe delivery and genetic manipulation of cellular cholesterol handling machinery, cholesterol-directed POCA captured established and unprecedented cholesterol binding proteins, including protein complexes sensitive to intracellular cholesterol levels and proteins uniquely captured by lipoprotein uptake. Protein-directed POCA accurately mapped known intracellular membrane complexes, defined sterol-dependent changes to the non-vesicular cholesterol transport protein interactome, and captured state-dependent changes in the interactome of the cholesterol transport protein Aster-B. More broadly, we find that POCA is a versatile interactomics platform that is straightforward to implement, using the readily available HaloTag system, and fulfills unmet needs in intracellular singlet oxygen-based proximity labeling proteomics. Thus, we expect widespread utility for POCA across a range of interactome applications, spanning imaging to proteomics.
    DOI:  https://doi.org/10.1101/2024.08.20.608660
  13. J Clin Invest. 2024 Sep 03. pii: e184663. [Epub ahead of print]134(17):
    Is it time to rethink the relationship between adipose inflammation and insulin resistance?
    Evan D Rosen, Shingo Kajimura.
      
    DOI:  https://doi.org/10.1172/JCI184663
  14. J Exp Biol. 2024 Aug 29. pii: jeb.247476. [Epub ahead of print]
    Chronic cold exposure causes left ventricular hypertrophy that appears to be physiological.
    McKenna P A Burns, Caroline R Reges, Spencer W Barnhill, Kenna N Koehler, Brandon C Lewis, Alyssa T Colombo, Nick J Felter, Paul J Schaeffer.
      Exposure to winter cold causes an increase in energy demands to meet the challenge of thermoregulation. In small rodents, this increase in cardiac output leads to a profound cardiac hypertrophy, 2-3x that typically seen with exercise training. The nature of this hypertrophy and its relevance to winter mortality remains unclear. Our goal was to characterize cold-induced cardiac hypertrophy and to assess its similarity to either exercise-induced (physiological) hypertrophy or the pathological hypertrophy of hypertension. We hypothesized that cold-induced hypertrophy will most closely resemble exercise-induced hypertrophy, but be another unique pathway for physiological cardiac growth. We found that cold-induced hypertrophy was largely reversed after return to warm temperatures. Further, metabolic rates were elevated while gene expression and mitochondrial enzyme activities indicative of pathology were absent. A gene expression panel comparing hearts of exercised and cold exposed mice further suggests that these activities are similar, although not identical. In conclusion, we found that chronic cold led to a phenotype that most closely resembled physiological hypertrophy, with enhanced metabolic rate, without induction of fetal genes , but with decreased expression of genes associated with fatty acid oxidation, suggesting that heart failure is not a cause of winter mortality in small rodents and identifying a novel approach for the study of cardiac growth.
    Keywords:  Cold acclimation; Microtus pennsylvanicus; Mus musculus; Pathological hypertrophy; Peromyscus leucopis; Rodent; Seasonality; Volume overload; Winter
    DOI:  https://doi.org/10.1242/jeb.247476
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