Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

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  • Alejandro Sola-García
  • María Ángeles Cáliz-Molina
  • Isabel Espadas
  • Concepción Panadero-Morón
  • Daniel González-Morán
  • María Eugenia Martín-Vázquez
  • Álvaro Jesús Narbona-Pérez
  • Livia López-Noriega
  • Guillermo Martínez-Corrales
  • Raúl López-Fernández-Sobrino
  • Enrique Martínez-Force
  • Oscar Yanes
  • Maria Vinaixa
  • Daniel López-López
  • José Carlos Reyes
  • Joaquín Dopazo
  • Franz Martín
  • Benoit R. Gauthier
  • Vivian Capilla-González
  • Alejandro Martín-Montalvo

ATP-citrate lyase is a central integrator of cellular metabolism in the interface of protein, carbohydrate, and lipid metabolism. The physiological consequences as well as the molecular mechanisms orchestrating the response to long-term pharmacologically induced Acly inhibition are unknown. We report here that the Acly inhibitor SB-204990 improves metabolic health and physical strength in wild-type mice when fed with a high-fat diet, while in mice fed with healthy diet results in metabolic imbalance and moderated insulin resistance. By applying a multiomic approach using untargeted metabolomics, transcriptomics, and proteomics, we determined that, in vivo, SB-204990 plays a role in the regulation of molecular mechanisms associated with aging, such as energy metabolism, mitochondrial function, mTOR signaling, and folate cycle, while global alterations on histone acetylation are absent. Our findings indicate a mechanism for regulating molecular pathways of aging that prevents the development of metabolic abnormalities associated with unhealthy dieting. This strategy might be explored for devising therapeutic approaches to prevent metabolic diseases.

Original languageEnglish
Article number250
JournalCommunications Biology
Volume6
ISSN2399-3642
DOIs
Publication statusPublished - 2023

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© 2023, The Author(s).

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