TY - JOUR

T1 - Metabolic reprogramming by Acly inhibition using SB-204990 alters glucoregulation and modulates molecular mechanisms associated with aging

AU - Sola-García, Alejandro

AU - Cáliz-Molina, María Ángeles

AU - Espadas, Isabel

AU - Petr, Michael

AU - Panadero-Morón, Concepción

AU - González-Morán, Daniel

AU - Martín-Vázquez, María Eugenia

AU - Narbona-Pérez, Álvaro Jesús

AU - López-Noriega, Livia

AU - Martínez-Corrales, Guillermo

AU - López-Fernández-Sobrino, Raúl

AU - Carmona-Marin, Lina M.

AU - Martínez-Force, Enrique

AU - Yanes, Oscar

AU - Vinaixa, Maria

AU - López-López, Daniel

AU - Reyes, José Carlos

AU - Dopazo, Joaquín

AU - Martín, Franz

AU - Gauthier, Benoit R.

AU - Scheibye-Knudsen, Morten

AU - Capilla-González, Vivian

AU - Martín-Montalvo, Alejandro

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-023-04625-4

DO - 10.1038/s42003-023-04625-4

M3 - Journal article

C2 - 36890357

AN - SCOPUS:85149657094

VL - 6

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

M1 - 250

ER -