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The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity

Martinez-Garcia, J. J.; Rodriguez, S.; Guijarro, A.; Quevedo-Romero, I.; Mateo, S. V.; Molina-Lopez, C.; Hurtado-Navarro, L.; Baroja-Mazo, A.; Pelegrin, P.

2025-01-21 immunology
10.1101/2025.01.16.633385 bioRxiv
Show abstract

The inflammasomes are a component of the innate immune system that induce inflammation after activation by danger and pathogen signals, this process is of extreme importance in the gut, where high-saturated fat diets modulate inflammasome activity resulting in dysbiosis and inflammation. In this work, we found that the common inflammasome adaptor protein, apoptosis speck-like protein with a caspase activation domain (ASC), is essential for the development of metabolic dysregulation during high fat diet. ASC-deficient mice (Pycard-/-) presented lower weight gain and improved glucose tolerance, enhancing metabolism, and reducing inflammation in both intestine and liver. The extracellular administration of ASC oligomers to Pycard-/- mice partially rescued dysbiosis, intestinal metabolism and inflammation. Therefore, ASC presents intracellular functions activating the inflammasome, as well as extracellular function as an oligomer during metabolic dysregulation, emerging ASC as a potential drug target beneficial to treat obesity and metabolism-associated liver diseases.

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