bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–10–27
seven papers selected by
Xiong Weng, University of Edinburgh
  1. Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.
  2. Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
  3. Mitochondrial fatty acid oxidation drives senescence.
  4. The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
  5. Mitochondrial quality control in alcohol-associated liver disease.
  6. Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
  7. The double-edged sword of eliminating senescent cells.
  1. Cell Metab. 2024 Oct 15. pii: S1550-4131(24)00376-0. [Epub ahead of print]
    Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity.
    Kenichi Sakamoto, Mary A Butera, Chunxue Zhou, Giulia Maurizi, Bandy Chen, Li Ling, Adham Shawkat, Likhitha Patlolla, Kavira Thakker, Victor Calle, Donald A Morgan, Kamal Rahmouni, Gary J Schwartz, Azeddine Tahiri, Christoph Buettner.
      The mechanisms underlying obesity-induced insulin resistance remain incompletely understood, as impaired cellular insulin signaling, traditionally considered the primary driver of insulin resistance, does not always accompany impaired insulin action. Overnutrition rapidly increases plasma norepinephrine (NE), suggesting overactivation of the sympathetic nervous system (SNS). However, the role of the SNS in obesity is controversial, as both increased and decreased SNS activity (SNA) have been reported. Here, we show that reducing catecholamine (CA) release from the SNS protects against overnutrition-induced insulin resistance as well as hyperglucagonemia, adipose tissue dysfunction, and fatty liver disease, as we demonstrate utilizing a mouse model of inducible and peripherally restricted deletion of tyrosine hydroxylase (th; THΔper). A key mechanism through which heightened SNA induces insulin resistance is by triggering adipose tissue lipolysis. Increased SNA emerges as a critical driver in the pathogenesis of overnutrition-induced insulin resistance and metabolic disease independent of cellular insulin signaling.
    Keywords:  adipose tissue dysfunction; adipose tissue lipolysis; diabetes; insulin resistance; liver steatosis; metabolic disease; metabolic inflammation; norepinephrine; obesity; sympathetic nervous system
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.012
  2. Nat Commun. 2024 Oct 24. 15(1): 9181
    Uncoupling of mTORC1 from E2F activity maintains DNA damage and senescence.
    Leighton H Daigh, Debarya Saha, David L Rosenthal, Katherine R Ferrick, Tobias Meyer.
      DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16INK4 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
    DOI:  https://doi.org/10.1038/s41467-024-52820-6
  3. Sci Adv. 2024 Oct 25. 10(43): eado5887
    Mitochondrial fatty acid oxidation drives senescence.
    Shota Yamauchi, Yuki Sugiura, Junji Yamaguchi, Xiangyu Zhou, Satoshi Takenaka, Takeru Odawara, Shunsuke Fukaya, Takao Fujisawa, Isao Naguro, Yasuo Uchiyama, Akiko Takahashi, Hidenori Ichijo.
      Cellular senescence is a stress-induced irreversible cell cycle arrest involved in tumor suppression and aging. Many stresses, such as telomere shortening and oncogene activation, induce senescence by damaging nuclear DNA. However, the mechanisms linking DNA damage to senescence remain unclear. Here, we show that DNA damage response (DDR) signaling to mitochondria triggers senescence. A genome-wide small interfering RNA screen implicated the outer mitochondrial transmembrane protein BNIP3 in senescence induction. We found that BNIP3 is phosphorylated by the DDR kinase ataxia telangiectasia mutated (ATM) and contributes to an increase in the number of mitochondrial cristae. Stable isotope labeling metabolomics indicated that the increase in cristae enhances fatty acid oxidation (FAO) to acetyl-coenzyme A (acetyl-CoA). This promotes histone acetylation and expression of the cyclin-dependent kinase inhibitor p16INK4a. Notably, pharmacological activation of FAO alone induced senescence both in vitro and in vivo. Thus, mitochondrial energy metabolism plays a critical role in senescence induction and is a potential intervention target to control senescence.
    DOI:  https://doi.org/10.1126/sciadv.ado5887
  4. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2401218121
    The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
    Yumei Yang, Baomin Wang, Haoru Dong, Huige Lin, Melody Yuen-Man Ho, Ke Hu, Na Zhang, Jing Ma, Rong Xie, Kenneth King-Yip Cheng, Xiaomu Li.
      Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.
    Keywords:  MDM2; cellular senescence; diabetes; p53; pyruvate carboxylase
    DOI:  https://doi.org/10.1073/pnas.2401218121
  5. Hepatol Commun. 2024 Nov 01. pii: e0534. [Epub ahead of print]8(11):
    Mitochondrial quality control in alcohol-associated liver disease.
    Themis Thoudam, Hui Gao, Yanchao Jiang, Nazmul Huda, Zhihong Yang, Jing Ma, Suthat Liangpunsakul.
      Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.
    DOI:  https://doi.org/10.1097/HC9.0000000000000534
  6. Nat Genet. 2024 Oct 23.
    Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification.
    Simone M Haag, Shiqi Xie, Celine Eidenschenk, Jean-Philippe Fortin, Marinella Callow, Mike Costa, Aaron Lun, Chris Cox, Sunny Z Wu, Rachana N Pradhan, Jaclyn Lock, Julia A Kuhn, Loryn Holokai, Minh Thai, Emily Freund, Ariane Nissenbaum, Mary Keir, Christopher J Bohlen, Scott Martin, Kathryn Geiger-Schuller, Hussein A Hejase, Brian L Yaspan, Sandra Melo Carlos, Shannon J Turley, Aditya Murthy.
      Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.
    DOI:  https://doi.org/10.1038/s41588-024-01962-w
  7. Nat Rev Mol Cell Biol. 2024 Oct 24.
    The double-edged sword of eliminating senescent cells.
    Eric Gilson.
      
    DOI:  https://doi.org/10.1038/s41580-024-00798-w
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