bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–12–08
twelve papers selected by
Xiong Weng, University of Edinburgh
  1. ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.
  2. Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
  3. Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice.
  4. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
  5. A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging.
  6. Mitochondrial metabolism and redox signaling.
  7. Interactions between the gut microbiome and DNA methylation patterns in blood and visceral adipose tissue in subjects with different metabolic characteristics.
  8. Genetic control of alternative splicing across blood cell types from diverse Asian donors.
  9. RAD51 plays critical roles in DNMT1-mediated maintenance methylation of genomic DNA by dually regulating the ubiquitin ligase UHRF1.
  10. The roles of lactate and the interplay with m6A modification in diseases.
  11. Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.
  12. GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders.
  1. Sci Signal. 2024 Dec 03. 17(865): eadk7971
    ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.
    Xu Xu, Arturo Mendoza, Christopher S Krumm, Shi Su, Mariana Acuña, Curtis J Bare, Corey D Holman, Marissa Cortopassi, Hayley T Nicholls, Vincent Dartigue, Anthony N Hollenberg, Ann-Hwee Lee, Susan J Hagen, David E Cohen.
      Activation of thermogenic brown adipose tissue (BAT) and inducible beige adipose tissue (BeAT) is triggered by environmental or metabolic stimuli, including cold ambient temperatures and nutrient stress. Thioesterase superfamily member 1 (Them1), a long-chain fatty acyl-CoA thioesterase that is enriched in BAT, suppresses acute cold-induced thermogenesis. Here, we demonstrate that Them1 expression was induced in BAT and BeAT by the carbohydrate response element binding protein (ChREBP) in response to chronic cold exposure or to the activation of the integrated stress response (ISR) by nutrient excess. Under either condition, Them1 suppressed energy expenditure. Consequently, mice lacking Them1 in BAT and BeAT exhibited resistance to obesity and glucose intolerance induced by feeding with a high-fat diet. During chronic cold exposure or ISR activation, Them1 accumulated in the nucleus, where it interacted with ChREBP and reduced the expression of its target genes, including those encoding enzymes that mediate glycolysis and de novo lipogenesis. These findings demonstrate that in response to chronic cold- or nutrient-induced stress, the induction of Them1 by ChREBP limits thermogenesis while coordinately reducing glucose utilization and lipid biosynthesis through its distinct cytoplasmic and nuclear activities. Targeted inhibition of Them1 could be a potential therapeutic approach to increase the activity of BAT and BeAT to enhance energy expenditure in the management of obesity-associated metabolic disorders.
    DOI:  https://doi.org/10.1126/scisignal.adk7971
  2. Cell Metab. 2024 Dec 03. pii: S1550-4131(24)00418-2. [Epub ahead of print]36(12): 2491-2492
    Mitochondrial respiratory supercomplexes gear up for heat generation in brown adipose tissue.
    Andreas Carlström, Martin Ott.
      Mitochondrial energy conversion supplies cellular energy but can also provide heat in brown adipose tissue (BAT). In a recent study, Shin and Latorre-Muro et al.1 show that respiratory supercomplexes in BAT are remodeled during cold to provide a tighter coupling, revealing a novel, physiologically important role for these supramolecular assemblies.
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.022
  3. iScience. 2024 Dec 20. 27(12): 111292
    Adipocyte Angptl8 deletion improves glucose and energy metabolism and obesity associated inflammation in mice.
    Anindya Ghosh, Isabelle Chénier, Yat Hei Leung, Abel K Oppong, Marie-Line Peyot, S R Murthy Madiraju, Irina Al-Khairi, Jehad Abubaker, Fahd Al-Mulla, Marc Prentki, Mohamed Abu-Farha.
      Angiopoietin-like protein 8 (Angptl8), expressed in the liver and adipocytes, forms a complex with Angptl3 or Angptl4, which regulates lipoprotein lipase and triglyceride metabolism. However, the precise functions of adipocyte Angptl8 remain elusive. Here we report that adipocyte-specific inducible Angptl8-knockout (AT-A8-KO) male mice on normal diet showed minor phenotypic changes, but after a high-fat high fructose (HFHF) diet, exhibited decreased body weight gain and glycemia, elevated rectal temperature and early dark phase energy expenditure compared to the Cre controls. AT-A8-KO mice also displayed improved glucose tolerance, a trend for better insulin sensitivity, improved insulin-stimulated glucose uptake in adipose tissues, and reduced visceral adipose tissue crown-like structures, plasma MCP-1 and leptin levels. The results indicate the importance of adipose Angptl8 in the context of nutri-stress and obesity, as its deletion in mice promotes a metabolically healthy obese phenotype by slightly ameliorating obesity, improving glucose and energy homeostasis, and mitigating inflammation.
    Keywords:  Biochemical mechanism
    DOI:  https://doi.org/10.1016/j.isci.2024.111292
  4. Nature. 2024 Dec 04.
    Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
    Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.
      Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
    DOI:  https://doi.org/10.1038/s41586-024-08285-0
  5. Nat Aging. 2024 Dec 02.
    A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging.
    Xinliang Ming, Ze Yang, Yuqiao Huang, Zhiguo Wang, Qingyan Zhang, Changchang Lu, Yandi Sun, Yuanhao Chen, Liang Zhang, Jicheng Wu, Hao Shou, Zhimin Lu, Ben Wang.
      The accumulation of senescent cells can lead to tissue degeneration, chronic inflammatory disease and age-related tumorigenesis. Interventions such as senolytics are currently limited by off-target toxicity, which could be circumvented by instead enhancing immune-mediated senescent cell clearance; however, immune surveillance of senescent cells is often impeded by immunosuppressive factors in the inflammatory microenvironment. Here, we employ a chimeric peptide as a 'matchmaker' to bind to the urokinase-type plasminogen activator receptor, a cell surface marker of senescent cells. This peptide modifies the cell surface with polyglutamic acid, promoting immune cell-mediated responses through glutamate recognition. By enhancing the recruitment of immune cells and directly coupling senescent cells and immune cells, we show that this chimeric peptide induces immune clearance of senescent cells and restores tissue homeostasis in conditions such as liver fibrosis, lung injury, cancer and natural aging in mice. This chimeric peptide introduces an immunological conversion strategy that rebalances the senescent immune microenvironment, offering a promising direction for aging immunotherapy.
    DOI:  https://doi.org/10.1038/s43587-024-00750-9
  6. Redox Biol. 2024 Nov 29. pii: S2213-2317(24)00426-9. [Epub ahead of print] 103448
    Mitochondrial metabolism and redox signaling.
    Annika Müller-Eigner, Andrew P Wojtovich.
      
    DOI:  https://doi.org/10.1016/j.redox.2024.103448
  7. J Transl Med. 2024 Dec 01. 22(1): 1089
    Interactions between the gut microbiome and DNA methylation patterns in blood and visceral adipose tissue in subjects with different metabolic characteristics.
    José Ignacio Martínez-Montoro, Gracia M Martín-Núñez, Andrés González-Jiménez, Lourdes Garrido-Sánchez, Isabel Moreno-Indias, Francisco J Tinahones.
       BACKGROUND: The gut microbiome has been reported to induce epigenetic modifications in the host, which may be involved in the pathophysiology of metabolic diseases.
    OBJECTIVE: To evaluate the potential interactions between the gut microbiome and DNA methylome in subjects with different metabolic characteristics.
    METHODS: Sixty-four participants with different metabolic characteristics (i.e., participants without obesity -healthy controls-, and participants with obesity and normal insulin sensitivity/insulin resistance/ type 2 diabetes-T2DM-) were included in this study. A machine learning approach was performed in order to identify distinctive patterns in three omics (gut microbiome, blood DNA methylome, and visceral adipose tissue-VAT- DNA methylome) according to the different study groups.
    RESULTS: Robust distinctive distribution patterns of the three different omics were found between healthy controls and patients with obesity; participants with and without T2DM, and patients with obesity with and without insulin resistance. Importantly, strong correlations between the gut microbiome (including Odoribacteriaceae and Christensenllaceae families) and both blood and VAT DNA methylome were found. Moreover, in the entire study population, three main bacterial genera (Sutterella, Collinsella and Eubacterium) were related to the epigenetic regulation of different genes involved in distinct processes related to cellular metabolism and metabolic diseases, including small ubiquitin-related modifier (SUMO) transferase activity or lipid binding.
    CONCLUSION: We show that distinctive interactions between the gut microbiome and DNA methylome may occur in subjects with different metabolic characteristics. Further research is needed to elucidate the potential role of these interactions in the pathophysiology of obesity and related comorbidities.
    Keywords:  DNA methylation; Epigenetics; Gut microbiota; Insulin resistance; Obesity; Type 2 diabetes; Visceral adipose tissue
    DOI:  https://doi.org/10.1186/s12967-024-05746-y
  8. Nat Genet. 2024 Dec 04.
    Genetic control of alternative splicing across blood cell types from diverse Asian donors.
      
    DOI:  https://doi.org/10.1038/s41588-024-02020-1
  9. Proc Natl Acad Sci U S A. 2024 Dec 10. 121(50): e2410119121
    RAD51 plays critical roles in DNMT1-mediated maintenance methylation of genomic DNA by dually regulating the ubiquitin ligase UHRF1.
    Guangxue Liu, Kaiyan Huang, Shiyao Liu, Yali Xie, Jinyan Huang, Tingbo Liang, Pumin Zhang.
      RAD51 is related to the bacterial RecA protein and is best known for its role in homologous recombination-mediated repair of DNA damage. Here, we report an unexpected function of RAD51 in the maintenance methylation of genomic DNA, a function that is separable from its role in homologous recombination. First, it acts as an inhibitor of the E3 ubiquitin ligase UHRF1. Deficiency in RAD51 causes excessive ubiquitination and degradation of the DNA methyltransferase DNMT1, leading to the loss of global DNA methylation. Second, RAD51 helps UHRF1 to monoubiquitinate histone H3 to generate DNMT1 recruiting signal. It binds H3 directly, enabling UHRF1 to bind and ubiquitinate H3 more readily. Disrupting the interaction between RAD51 and H3 diminishes DNMT1 recruitment and the failure of maintenance methylation of genomic DNA. Thus, RAD51 dually regulates UHRF1. These results establish RAD51 as a guardian of the integrity of both the genome and the epigenome.
    Keywords:  DNA methylation; DNMT1; RAD51; UHRF1; epigenetics
    DOI:  https://doi.org/10.1073/pnas.2410119121
  10. Cell Biol Toxicol. 2024 Dec 02. 40(1): 107
    The roles of lactate and the interplay with m6A modification in diseases.
    Fajuan Tang, Dongqiong Xiao, Xihong Li, Lina Qiao.
      Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m6A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m6A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m6A modifications by enhancing the transcriptional expression levels of m6A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m6A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m6A alterations to impact lactate levels and subsequently affect lactylation processes.
    Keywords:  Glycolysis; Lactate; Lactylation; M6A modification
    DOI:  https://doi.org/10.1007/s10565-024-09951-9
  11. BMC Med. 2024 12 02. 22(1): 572
    Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism.
    Charlotte Ling, Magdalena Vavakova, Bilal Ahmad Mir, Johanna Säll, Alexander Perfilyev, Melina Martin, Per-Anders Jansson, Cajsa Davegårdh, Olof Asplund, Ola Hansson, Allan Vaag, Emma Nilsson.
       BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.
    METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.
    RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.
    CONCLUSIONS: Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.
    Keywords:  DNA methylation; Discordant monozygotic twins; Epigenetics; Gene expression; MicroRNA (miRNA); Skeletal muscle; Type 2 diabetes (T2D)
    DOI:  https://doi.org/10.1186/s12916-024-03789-y
  12. Circ Res. 2024 Dec 04.
    GSK3β Deficiency Expands Obese Adipose Vasculature to Mitigate Metabolic Disorders.
    Li Wang, Jiajia Li, Ping Tang, Dongliang Zhu, Lixin Tai, Yuan Wang, Tsukiko Miyata, James R Woodgett, Lijun Di.
       BACKGROUND: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported.
    METHODS: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3βADKO and GSK3αADKO). A comprehensive whole-body metabolism analysis was performed on obese GSK3βADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3βADKO and GSK3αADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3βADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition.
    RESULTS: Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER stress in obese AT and improve metabolic disorders associated with obesity.
    CONCLUSIONS: Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity.
    Keywords:  AMP-activated protein kinases; basic helix-loop-helix transcription factors; glycogen synthase kinase 3; metabolic diseases; obesity; vascular endothelial growth factor A
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325187
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