bims-obesme Biomed News
on Obesity metabolism
Issue of 2024‒09‒22
six papers selected by
Xiong Weng, University of Edinburgh
  1. IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
  2. Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.
  3. Fundamental equations linking methylation dynamics to maximum lifespan in mammals.
  4. Challenges and recommendations for the translation of biomarkers of aging.
  5. Metabolomics Dysfunction in Replicative Senescence of Periodontal Ligament Stem Cells Regulated by AMPK Signaling Pathway.
  6. METTL3-mediated TIM1 promotes macrophage M1 polarization and inflammation through IGF2BP2-dependent manner.
  1. EMBO J. 2024 Sep 16.
    IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.
    Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt.
      While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
    Keywords:  Adipocytes; Metabolism; Mitochondria; Thermogenesis; UCP1
    DOI:  https://doi.org/10.1038/s44318-024-00215-0
  2. Nat Commun. 2024 Sep 14. 15(1): 8068
    Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy.
    Natalie DeForest, Yuqi Wang, Zhiyi Zhu, Jacqueline S Dron, Ryan Koesterer, Pradeep Natarajan, Jason Flannick, Tiffany Amariuta, Gina M Peloso, Amit R Majithia.
      Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.
    DOI:  https://doi.org/10.1038/s41467-024-52105-y
  3. Nat Commun. 2024 Sep 16. 15(1): 8093
    Fundamental equations linking methylation dynamics to maximum lifespan in mammals.
    Steve Horvath, Joshua Zhang, Amin Haghani, Ake T Lu, Zhe Fei.
      We describe a framework that addresses concern that the rate of change in any aging biomarker displays a trivial inverse relation with maximum lifespan. We apply this framework to methylation data from the Mammalian Methylation Consortium. We study the relationship of lifespan with the average rate of change in methylation (AROCM) from two datasets: one with 90 dog breeds and the other with 125 mammalian species. After examining 54 chromatin states, we conclude three key findings: First, a reciprocal relationship exists between the AROCM in bivalent promoter regions and maximum mammalian lifespan: AROCM ∝ 1/MaxLifespan. Second, the correlation between average methylation and age bears no relation to maximum lifespan, Cor(Methyl,Age) ⊥ MaxLifespan. Third, the rate of methylation change in young animals is related to that in old animals: Young animals' AROCM ∝ Old AROCM. These findings critically hinge on the chromatin context, as different results emerge in other chromatin contexts.
    DOI:  https://doi.org/10.1038/s41467-024-51855-z
  4. Nat Aging. 2024 Sep 16.
    Challenges and recommendations for the translation of biomarkers of aging.
    Biomarkers of Aging Consortium
      Biomarkers of aging (BOA) are quantitative parameters that predict biological age and ideally its changes in response to interventions. In recent years, many promising molecular and omic BOA have emerged with an enormous potential for translational geroscience and improving healthspan. However, clinical translation remains limited, in part due to the gap between preclinical research and the application of BOA in clinical research and other translational settings. We surveyed experts in these areas to better understand current challenges for the translation of aging biomarkers. We identified six key barriers to clinical translation and developed guidance for the field to overcome them. Core recommendations include linking BOA to clinically actionable insights, improving affordability and availability to broad populations and validation of biomarkers that are robust and responsive at the level of individuals. Our work provides key insights and practical recommendations to overcome barriers impeding clinical translation of BOA.
    DOI:  https://doi.org/10.1038/s43587-024-00683-3
  5. Stem Cells Dev. 2024 Sep 20.
    Metabolomics Dysfunction in Replicative Senescence of Periodontal Ligament Stem Cells Regulated by AMPK Signaling Pathway.
    Meilin Hu, Ruiqi Liu, Xiaoyu Chen, Shen Yan, Jian Gao, Yao Zhang, Di Wu, Lu Sun, Zhi Jia, Yunhao Sunguang, Dayong Liu.
      Periodontal ligament mesenchymal stem cells (PDLSCs) are a promising cell resource for stem cell-based regenerative medicine in dentistry, but they inevitably acquire a senescent phenotype after prolonged in vitro expansion. The key regulators of PDLSCs during replicative senescence are remain unclear. Here, we sought to elucidate the role of metabolomic changes in determining cellular senescence of PDLSCs. PDLSCs were cultured to passages 4, 10 and 20. The senescent phenotypes of PDLSCs were detected, and metabolomics analysis was performed. We found that PDLSCs manifested senescence phenotype during passaging. Metabolomics analysis showed that the metabolism of replicative senescence in PDLSCs varied significantly. The AMPK signaling pathway was closely related to AMP levels. The AMP:ATP ratio increased in senescent PDLSCs; however, the levels of p-AMPK, FOXO1 and FOXO3a decreased with senescence. We treated PDLSCs with an activator of the AMPK pathway (AICAR), and observed that the phosphorylated AMPK level at P20 PDLSCs was partially restored. These data delineate that the metabolic process of PDLSCs is active in the early stage of senescence, and attenuated in the later stages of senescence; however, the sensitivity of AMPK phosphorylation sites is impaired, causing senescent PDLSCs to fail to respond to changes in energy metabolism.
    DOI:  https://doi.org/10.1089/scd.2024.0112
  6. J Biochem Mol Toxicol. 2024 Oct;38(10): e23845
    METTL3-mediated TIM1 promotes macrophage M1 polarization and inflammation through IGF2BP2-dependent manner.
    Xianrong Du, Yinguang Guo, Xiaoqin Zhao, Lijuan Zhang, Ru Fan, Yafeng Li.
      Macrophage polarization and inflammation may play an important role in the development of sepsis. T-cell immunoglobulin mucin 1 (TIM1) has been demonstrated to promote macrophage inflammatory responses. However, whether TIM1 regulates macrophage polarization and inflammation to affect sepsis development remains unclear. Human monocytic leukemia cell line was induced into macrophages, followed by stimulated with LPS and IL-4 to induce M1 polarization and M2 polarization. The expression levels of TIM1, methyltransferase 3 (METTL3), and insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) were examined by qRT-PCR and western blot. IL-6, IL-1β, and TNF-α levels were tested by ELISA. CD86+cell rate was analyzed by flow cytometry. The m6A methylation level of TIM1 was assessed by MeRIP assay. The interaction of between TIM1 and METTL3 or IGF2BP2 was assessed by dual-luciferase reporter assay and RIP assay. TIM1 knockdown repressed LPS-induced macrophage M1 polarization and inflammation. In terms of mechanism, METTL3 promoted TIM1 expression through m6A modification, and this modification could be recognized by IGF2BP2. Besides, knockdown of METTL3/IGF2BP2 suppressed LPS-induced macrophage M1 polarization and inflammation, while this effect could be eliminated by TIM1 overexpression. METTL3/IGF2BP2/TIM1 axis promoted macrophage M1 polarization and inflammation, which might provide potential target for sepsis treatment.
    Keywords:  IGF2BP2; M1 polarization; METTL3; Sepsis; TIM1; m6A modification
    DOI:  https://doi.org/10.1002/jbt.23845
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