Compound C attenuates NLRP3 inflammasome despite AMPK knockdown in LPS plus palmitate-induced THP-1 cells.

NLRP3 inflammasome is a key contributor to obesity-related insulin resistance and type 2 diabetes (T2D). Adenosine monophosphate-activated protein kinase (AMPK) is a principle intracellular energy sensor exerting protective effect against T2D. Strikingly, compound C, an inhibitor of AMPK, considerably inhibited the secretion of IL-1β when THP-1 cells were stimulated with LPS plus palmitic acid (PA). The underlying mechanism was examined with respect to the effect of compound C on NLRP3 inflammasome, a multiprotein complex which controls the processing and production of IL-1β. Interestingly, compound C significantly attenuated the activation of NLRP3 inflammasome. This phenomenon was reproduced in AMPK siRNA-transfected THP-1 cells, indicating that compound C exerts this function despite AMPK knockdown. Also, it significantly suppresses the mitochondria-generated reactive oxygen species (ROS) required for NLRP3 inflammasome activation. In conclusion, compound C was shown to significantly attenuate the NLRP3 inflammasome despite AMPK knockdown, rendering it as the novel target of compound C. Potentially, compound C attenuates NLRP3 inflammasome through the suppression of mitochondrial ROS production. These findings offer initial evidence into compound C as a novel pharmacological agent with significant therapeutic potential in NLRP3 inflammasome-related disorders, including obesity, insulin resistance, and T2D. Thus, further studies are essential to identify the effect of compound C on these diseases in vitro.