bims-mimead Biomed News
on Mitochondrial metabolism in ageing and metabolic disease
Issue of 2024–12–01
six papers selected by
Rachel M. Handy, University of Guelph
  1. Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity.
  2. The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.
  3. Endurance Exercise Training Alters Lipidomic Profiles of Plasma and Eight Tissues in Rats: a MoTrPAC study.
  4. The role of macrophage and adipocyte mitochondrial dysfunction in the pathogenesis of obesity.
  5. Effects of Resveratrol on Adipocytes: Evidence from In Vitro and In Vivo Studies.
  6. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
  1. Elife. 2024 Nov 26. pii: e99162. [Epub ahead of print]13
    Adipocyte microRNA-802 promotes adipose tissue inflammation and insulin resistance by modulating macrophages in obesity.
    Yue Yang, Bin Huang, Yimeng Qin, Danwei Wang, Yinuo Jin, Linmin Su, Qingxin Wang, Yi Pan, Yanfeng Zhang, Yumeng Shen, Wenjun Hu, Zhengyu Cao, Liang Jin, Fangfang Zhang.
      Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.99162
  2. medRxiv. 2024 Nov 18. pii: 2024.11.18.24317277. [Epub ahead of print]
    The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.
    Emeli Chatterjee, Michael J Betti, Quanhu Sheng, Phillip Lin, Margo P Emont, Guoping Li, Kaushik Amancherla, Worawan B Limpitikul, Olivia Rosina Whittaker, Kathy Luong, Christopher Azzam, Denise Gee, Matthew Hutter, Karen Flanders, Parul Sahu, Marta Garcia-Contreras, Priyanka Gokulnath, Charles R Flynn, Jonathan Brown, Danxia Yu, Evan D Rosen, Kendall Van-Keuren Jensen, Eric R Gamazon, Ravi Shah, Saumya Das.
      We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity. Since circulating EVs may have broad origin, we compared this obesity EV transcriptome to expression from human visceral adipose tissue derived EVs from freshly collected and cultured biopsies from the same obese individuals. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by BMI-associated SNPs from a large-scale GWAS. Using a phenome-wide association study of the regulatory SNPs for the EV-derived transcripts, we identified a substantial enrichment for inflammatory phenotypes, including type 2 diabetes. Collectively, these findings represent the convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, enabling powerful future genomic studies of complex diseases.
    DOI:  https://doi.org/10.1101/2024.11.18.24317277
  3. Res Sq. 2024 Nov 21. pii: rs.3.rs-5263273. [Epub ahead of print]
    Endurance Exercise Training Alters Lipidomic Profiles of Plasma and Eight Tissues in Rats: a MoTrPAC study.
    Eric Ortlund, Zhenxin Hou, Chih-Yu Chen, David Gaul, Tiantian Zhang, Samuel Moore, Xueyun Liu, Anna Ivanova, Kristal Maner-Smith, Christopher Newgard, Sue Bodine, Evan Savage, Alexis Bennett, Facundo Fernandez.
      Endurance exercise training (ExT) induces metabolic, structural, and functional adaptations via lipidomic modifications, yet the systematic elucidation of lipidome alterations in response to ExT remains incomplete. As a part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we leveraged non-targeted and targeted lipidomics for the systematic discovery of lipid alterations in the brown adipose tissue, heart, hippocampus, kidney, liver, lung, skeletal muscle gastrocnemius, subcutaneous white adipose tissue, and plasma in response to 1, 2, 4 or 8 weeks of ExT in 6-month-old male and female Fischer-344 rats. This study demonstrates that these tissues, each with distinct lipidomic features, underwent dynamic, sexually dimorphic lipid remodeling. Exercise trained animals showed reduced whole-body adiposity and improved cardiorespiratory fitness, along with enhanced utilization of lipid stores and dynamic triacylglycerol remodeling compared to sedentary controls in all tissues except hippocampus. They also showed modifications in phospholipids, lysophospholipids, oxylipins, and ceramides in several tissues. Coordinated changes across tissues reflect systemic tissue communication, with liver-plasma-heart connection potentially playing a key role in systemic lipid metabolism during ExT. These data will improve our understanding of lipid-associated biological processes underlying the health-promoting benefits of ExT.
    DOI:  https://doi.org/10.21203/rs.3.rs-5263273/v1
  4. Front Immunol. 2024 ;15 1481312
    The role of macrophage and adipocyte mitochondrial dysfunction in the pathogenesis of obesity.
    Min Wang, Min Min, Haojie Duan, Jia Mai, Xiaojuan Liu.
      Obesity has emerged as a prominent global public health concern, leading to the development of numerous metabolic disorders such as cardiovascular diseases, type-2 diabetes mellitus (T2DM), sleep apnea and several system diseases. It is widely recognized that obesity is characterized by a state of inflammation, with immune cells-particularly macrophages-playing a significant role in its pathogenesis through the production of inflammatory cytokines and activation of corresponding pathways. In addition to their immune functions, macrophages have also been implicated in lipogenesis. Additionally, the mitochondrial disorders existed in macrophages commonly, leading to decreased heat production. Meantime, adipocytes have mitochondrial dysfunction and damage which affect thermogenesis and insulin resistance. Therefore, enhancing our comprehension of the role of macrophages and mitochondrial dysfunction in both macrophages and adipose tissue will facilitate the identification of potential therapeutic targets for addressing this condition.
    Keywords:  adipose tissue; macrophages; mitochondrial disorder; obesity; pathogenesis
    DOI:  https://doi.org/10.3389/fimmu.2024.1481312
  5. Molecules. 2024 Nov 14. pii: 5359. [Epub ahead of print]29(22):
    Effects of Resveratrol on Adipocytes: Evidence from In Vitro and In Vivo Studies.
    Matthew Terzo, Michael Iantomasi, Evangelia Tsiani.
      Obesity, a prevalent global health issue, arises from an imbalance between caloric intake and energy expenditure, leading to the expansion of adipose tissue and metabolic dysfunction. White adipose tissue (WAT) stores energy as lipids, while brown adipose tissue (BAT) plays a pivotal role in energy dissipation through adaptive thermogenesis. Recent research initiatives have focused on finding strategies to decrease adipogenesis and fat mass accumulation and increase thermogenesis. Finding chemicals with anti-obesity properties would be beneficial. Resveratrol, a polyphenolic compound abundantly found in the skin of grapes and red wine, possesses anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity properties. This literature review examines the effects of resveratrol on adipocytes in culture and adipose tissue in animal models of obesity. The existing evidence indicates that resveratrol may exert its anti-obesity effects by inhibiting adipogenesis, promoting the apoptosis of mature adipocytes, reducing lipid accumulation, and increasing thermogenesis. Further research utilizing animal and clinical studies is required to understand in detail the anti-obesity potential of resveratrol.
    Keywords:  adipocytes; adipose tissue; obesity; resveratrol
    DOI:  https://doi.org/10.3390/molecules29225359
  6. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121
    ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
    Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.
      The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
    Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2410486121
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