Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice

Zhu, Yuyu, et al. “Celastrol Targets Adenylyl Cyclase-Associated Protein 1 to Reduce Macrophages-Mediated Inflammation and Ameliorates High Fat Diet-Induced Metabolic Syndrome in Mice.” Acta Pharmaceutica Sinica B, Elsevier BV, Dec. 2020. Crossref, doi:10.1016/j.apsb.2020.12.008.

Abstract

Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism. Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation. Here, we report celastrol, a traditional Chinese medicine, can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation. Mechanistically, celastrol binds to adenylyl cyclase associated protein 1 (CAP1) and inhibits the interaction between CAP1 and resistin, which restrains the cyclic adenylate monophosphate (cAMP)–protein kinase A (PKA)–nuclear factor kappa-B (NF-κB) signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome. Knockdown of CAP1 in macrophages abrogated the resistin-mediated inﬂammatory activity. In contrast, overexpression of CAP1 in macrophages aggravated inﬂammation. Taken together, our study identifies celastrol, which directly targets CAP1 in macrophages, might be a promising drug candidate for the treatment of inﬂammatory metabolic diseases, such as metabolic syndrome.