bims-mimead Biomed News
on Mitochondrial metabolism in ageing and metabolic disease
Issue of 2025–02–02
nine papers selected by
Rachel M. Handy, University of Guelph
  1. Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids.
  2. The secretory function of adipose tissues in metabolic regulation.
  3. Sex differences in the metabolism of glucose and fatty acids by adipose tissue and skeletal muscle in humans.
  4. Optimized Scaffold-Free Human 3D Adipose Tissue Organoid Culture for Obesity and Disease Modeling.
  5. Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns.
  6. Single-nucleus RNA sequencing reveals heterogeneity among multiple white adipose tissue depots.
  7. Clearing the path for whole-mount labeling and quantification of neuron- and vessel-density in adipose tissue.
  8. The roles of mitochondria in global and local intracellular calcium signalling.
  9. Characterization of Subcutaneous and Visceral De-differentiated Fat Cells.
  1. bioRxiv. 2025 Jan 16. pii: 2025.01.13.632607. [Epub ahead of print]
    Tissue-specific effects of dietary protein on cellular senescence are mediated by branched-chain amino acids.
    Mariah F Calubag, Ismail Ademi, Isaac Grunow, Lucia Breuer, Reji Babygirija, Penelope Lialios, Sandra Le, Dennis Minton, Michelle M Sonsalla, Julia Illiano, Bailey A Knopf, Fan Xiao, Adam R Konopka, David A Harris, Dudley W Lamming.
      Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cell senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male and female mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs - but not individual BCAAs - protecting from hepatic cellular senescence while potentiating cell senescence in white adipose tissue. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.
    DOI:  https://doi.org/10.1101/2025.01.13.632607
  2. Life Metab. 2024 Apr;3(2): loae003
    The secretory function of adipose tissues in metabolic regulation.
    Yang Liu, Shu-Wen Qian, Yan Tang, Qi-Qun Tang.
      In addition to their pivotal roles in energy storage and expenditure, adipose tissues play a crucial part in the secretion of bioactive molecules, including peptides, lipids, metabolites, and extracellular vesicles, in response to physiological stimulation and metabolic stress. These secretory factors, through autocrine and paracrine mechanisms, regulate various processes within adipose tissues. These processes include adipogenesis, glucose and lipid metabolism, inflammation, and adaptive thermogenesis, all of which are essential for the maintenance of the balance and functionality of the adipose tissue micro-environment. A subset of these adipose-derived secretory factors can enter the circulation and target the distant tissues to regulate appetite, cognitive function, energy expenditure, insulin secretion and sensitivity, gluconeogenesis, cardiovascular remodeling, and exercise capacity. In this review, we highlight the role of adipose-derived secretory factors and their signaling pathways in modulating metabolic homeostasis. Furthermore, we delve into the alterations in both the content and secretion processes of these factors under various physiological and pathological conditions, shedding light on potential pharmacological treatment strategies for related diseases.
    Keywords:  adipokines; autocrine; endocrine; metabolic regulation; paracrine
    DOI:  https://doi.org/10.1093/lifemeta/loae003
  3. Physiol Rev. 2025 Jan 27.
    Sex differences in the metabolism of glucose and fatty acids by adipose tissue and skeletal muscle in humans.
    Damla N Costa, Sylvia Santosa, Michael D Jensen.
      Adult males and females have markedly different body composition, energy expenditure, and have different degrees of risk for metabolic diseases. A major aspect of metabolic regulation involves the appropriate storage and disposal of glucose and fatty acids. The use of sophisticated calorimetry, tracer, and imaging techniques have provided insight into the complex metabolism of these substrates showing that the regulation of these processes varies tremendously throughout the day, from the overnight fasting condition to meal ingestion, to the effects of physical activity. The sexual dimorphism in substrate metabolism is most readily observed in how fatty acids are stored and mobilized. The objective of this review is to provide a comprehensive and critical summary of the reported sex-differences in the mobilization, oxidation and storage of fat and carbohydrate in adipose tissue and skeletal muscle. We will describe how adipose tissue lipolysis differs between sexes, and how this varies between fed, fasted and exercise conditions. We will also review what is known about endogenous and exogenous fatty acid storage in adipose tissue and muscle, as well as how oxidation compares between men and women in response to exercise. What has been learned about the cellular level regulation of these processes will be described. Although glucose metabolism exhibits fewer differences between men and women, we will also review the existing knowledge on this topic.
    Keywords:  exercise; fatty acids; glucose; metabolism; sex differences
    DOI:  https://doi.org/10.1152/physrev.00008.2024
  4. SLAS Discov. 2025 Jan 25. pii: S2472-5552(25)00011-5. [Epub ahead of print] 100218
    Optimized Scaffold-Free Human 3D Adipose Tissue Organoid Culture for Obesity and Disease Modeling.
    Rafael Dariolli, Raphael Nir, Tova Mushlam, Glauco R Souza, Stephen R Farmer, Miguel L Batista.
      Obesity and type 2 diabetes (T2D) are strongly linked to abnormal adipocyte metabolism and adipose tissue (AT) dysfunction. However, existing adipose tissue models have limitations, particularly in the stable culture of fat cells that maintain physiologically relevant phenotypes, hindering a deeper understanding of adipocyte biology and the molecular mechanisms behind differentiation. Current model systems fail to fully replicate in vivo metabolism, posing challenges in adipose research. Three-dimensional (3D) AT organoids, although promising, present significant handling challenges during long-term culture. As adipocytes mature and accumulate fat, they develop organotypic characteristics, increasing the buoyancy effect, which causes the organoids to oscillate, complicating culture manipulation and rendering multiple handling steps difficult. Due to these challenges, most adipose spheroid models are scaffold-based, despite many cell types' ability to secrete extracellular matrix (ECM) components and self-assemble into aggregates. Scaffold-free 3D organoids have been less explored. To address the shortage of affordable and reliable AT models, we utilized magnetic bioprinting technology to develop a human-derived 3D model of adipose tissue. This system incorporates a magnetic holder that restrains organoids, preventing them from floating and minimizing the risk of loss during manipulation. This study outlines a protocol for generating in vitro AT-derived organoid using 3D magnetic bioprinting, with a focus on manufacturing, culturing, and assessing the morpho-functional characteristics of late-stage AT organoids. Magnetic bioprinting allows for the replication of tissue structure and function in vitro without the risk of organoid loss, making it an ideal method for high-throughput AT organoid culture. Additionally, the combination of 3D scaffold-free manufacturing with in vitro disease modeling offers a valuable tool for discovering treatments for metabolic diseases such as obesity and T2D.
    Keywords:  Adipocyte Differentiation; Humanized, Adipose Tissue Organoids; Magnetic Bioprinting; Metabolic Disease Modeling; Scaffold-Free Models
    DOI:  https://doi.org/10.1016/j.slasd.2025.100218
  5. Nat Genet. 2025 Jan 24.
    Human subcutaneous and visceral adipocyte atlases uncover classical and nonclassical adipocytes and depot-specific patterns.
    Or Lazarescu, Maya Ziv-Agam, Yulia Haim, Idan Hekselman, Juman Jubran, Ariel Shneyour, Habib Muallem, Alon Zemer, Marina Rosengarten-Levin, Daniel Kitsberg, Liron Levin, Idit F Liberty, Uri Yoel, Oleg Dukhno, Miriam Adam, Julia Braune, Claudia Müller, Nora Raulien, Martin Gericke, Antje Körner, Rinki Murphy, Matthias Blüher, Naomi Habib, Assaf Rudich, Esti Yeger-Lotem.
      Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA sequencing (snRNA-seq) analyses largely uncovered overlapping or similar cell-type landscapes. We hypothesized that adipocyte subtypes, differentiation trajectories and/or intercellular communication patterns could illuminate this depot similarity-difference gap. For this, we performed snRNA-seq of human subcutaneous or visceral adipose tissues (five or ten samples, respectively). Of 27,665 adipocyte nuclei in both depots, most were 'classical', namely enriched in lipid metabolism pathways. However, we also observed 'nonclassical' adipocyte subtypes, enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization or angiogenesis or ribosomal and mitochondrial processes. Pseudo-temporal analysis showed a developmental trajectory from adipose progenitor cells to classical adipocytes via nonclassical adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Last, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation and intercellular communication patterns to human fat depot differences.
    DOI:  https://doi.org/10.1038/s41588-024-02048-3
  6. Life Metab. 2023 Dec;2(6): load045
    Single-nucleus RNA sequencing reveals heterogeneity among multiple white adipose tissue depots.
    Limin Xie, Wanyu Hu, Haowei Zhang, Yujin Ding, Qin Zeng, Xiyan Liao, Dandan Wang, Wanqin Xie, Hannah Xiaoyan Hui, Tuo Deng.
      Regardless of its anatomical site, adipose tissue shares a common energy-storage role but exhibits distinctive properties. Exploring the cellular and molecular heterogeneity of white adipose tissue (WAT) is crucial for comprehending its function and properties. However, existing single-nucleus RNA sequencing (snRNA-seq) studies of adipose tissue heterogeneity have examined only one or two depots. In this study, we employed snRNA-seq to test five representative depots including inguinal, epididymal, mesenteric, perirenal, and pericardial adipose tissues in mice under physiological conditions. By analyzing the contents of main cell categories and gene profiles of various depots, we identified their distinctive physiological properties. Immune cells and fibro-adipogenic progenitor cells (FAPs) showed dramatic differences among WAT depots, while adipocytes seemed to be conserved. The heightened presence of regulatory macrophages and B cells in pericardial adipose tissues implied their potential contribution to the preservation of coronary vascular function. Moreover, the selective aggregation of pericytes within mesenteric adipose tissue was likely associated with the maintenance of intestinal barrier homeostasis. Using a combination of RNA sequencing and snRNA-seq analysis, the major subpopulations of FAPs derived from these depots determined the site characteristics of FAPs to a certain extent. Our work establishes a systematic and reliable foundation for investigating the heterogeneity of WAT depots and elucidating the unique roles these depots play in coordinating the function of adjacent organs.
    Keywords:  adipocyte subpopulations; adipose tissue heterogeneity; snRNA-seq; white adipose tissue
    DOI:  https://doi.org/10.1093/lifemeta/load045
  7. J Cell Sci. 2025 Jan 29. pii: jcs.263438. [Epub ahead of print]
    Clearing the path for whole-mount labeling and quantification of neuron- and vessel-density in adipose tissue.
    Thomas Rauchenwald, Pia Benedikt-Kühnast, Sandra Eder, Gernot F Grabner, Sebastian Forstreiter, Michaela Lang, Roko Sango, Tobias Eisenberg, Thomas Rattei, Arvand Haschemi, Heimo Wolinski, Martina Schweiger.
      White adipose tissue (WAT) comprises a plethora of cell types beyond adipocytes forming a regulatory network that ensures systemic energy homeostasis. Intertissue communication is facilitated by metabolites and signaling molecules that are spread by vasculature and nerves. Previous works indicated that WAT responds to environmental cues by adapting the abundance of these "communication routes", however, high intra-tissue heterogeneity questions the informative value of bulk or single cell analyses and underscores the necessity of whole-mount imaging. The applicability of whole-mount WAT-imaging is currently limited by two factors: I) Methanol-based tissue clearing protocols restrict the usable antibody portfolio to methanol resistant antibodies and II) The vast amounts of data resulting from 3D imaging of whole-tissue samples require high computational expertise and advanced equipment. Here, we present a protocol for whole-mount WAT clearing, overcoming the constraints of antibody-methanol sensitivity. Additionally, we introduce TiNeQuant (Tissue Network Quantifier) a Fiji tool for automated 3D quantification of neuron- or vascular network density, freely available at https://github.com/SchweigerLab/TiNeQuant. Given TiNeQuants versatility beyond WAT, it simplifies future efforts studying neuronal or vascular alterations in numerous pathologies.
    Keywords:  Adipose tissue clearing; Image processing; Network density; Quantitative microscopy; Spatial analysis; Whole-mount imaging
    DOI:  https://doi.org/10.1242/jcs.263438
  8. Nat Rev Mol Cell Biol. 2025 Jan 27.
    The roles of mitochondria in global and local intracellular calcium signalling.
    Benjamín Cartes-Saavedra, Arijita Ghosh, György Hajnóczky.
      Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
    DOI:  https://doi.org/10.1038/s41580-024-00820-1
  9. Mol Metab. 2025 Jan 28. pii: S2212-8778(25)00012-2. [Epub ahead of print] 102105
    Characterization of Subcutaneous and Visceral De-differentiated Fat Cells.
    Yan Li, Houyu Zhang, Carlos F Ibáñez, Meng Xie.
      The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown. Here, we show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-κB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs. These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.
    Keywords:  DFAT cell re-differentiation; DNA methylation; NF-κB; adipocyte de-differentiation; diet intervention; scRNA-seq/snRNA-seq
    DOI:  https://doi.org/10.1016/j.molmet.2025.102105
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