The TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages facilitates exercise-induced attenuation of hepatic inflammation and insulin resistance in db/db mice.

Abstract

Exercise has been proved to be effective in ameliorating diabetes but the underlying mechanisms remain obscure. It has been recently demonstrated that overactivation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome led to hepatic insulin resistance. Therefore, we aimed to explore the role and underlying mechanism of NLRP3 inflammasome in exercise-mediated hepatic insulin resistance. Wild type and db/db mice were sedentary or subjected to 8-week moderate intensity exercise, liver tissues and primary hepatic macrophages were isolated. Exercise mitigated hepatic steatosis and enhanced the hepatic insulin sensitivity of db/db mice. More importantly, exercise reduced the protein expression of two-pore domain weak inwardly rectifying K⁺ channel 2 (TWIK2) to suppress cellular K⁺ efflux, blunted the generation of mitochondrial ROS (mROS) and the release of oxidized mitochondrial DNA (ox-mtDNA) into cytosol, leading to the inhibition of NLRP3 inflammasome in hepatic macrophages of db/db mice. Accordingly, the hepatic macrophages switched from pro-inflammatory phenotype to anti-inflammatory phenotype and the infiltration of macrophages into liver was decreased in response to exercise. Moreover, inhibition of TWIK2 expression with TWIK2 inhibitor or shRNA interference in hepatic macrophages blunted the TWIK2-mtDNA-NLRP3 inflammasome signaling. The macrophages switched to anti-inflammatory phenotype upon TWIK2 deficiency. Additionally, the insulin sensitivity was elevated in primary hepatocytes which were exposed to culture medium from hepatic macrophages with TWIK2 deficiency, suggesting that inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages could attenuate hepatic insulin resistance Taken together, we first observed the inhibition of TWIK2-mtDNA-NLRP3 inflammasome signaling in hepatic macrophages of diabetic mice in response to exercise intervention, implying a probable role for TWIK2-mtDNA-NLRP3 inflammasome signaling in exercise-mediated alleviation of hepatic inflammation and insulin resistance, hoping to provide theoretical basis and new target for the prevention and treatment of metabolic diseases.