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bioRxiv · 10.1101/2025.01.16.633385

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.
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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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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. The inflammasome adaptor protein ASC triggers immunometabolic dysregulation induced by dysbiosis during obesity. https://doi.org/10.1101/2025.01.16.633385

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