KS-356, a novel inhibitor of TGF-beta superfamily signaling, improves obesity and obesity-related hepatic steatosis by inhibition of TGF-beta/Smad3 signaling pathway in high-fat diet-induced mice

초록

Background and aims: Obesity-induced inflamed visceral adiposetissue (VAT) secretes pro-inflammatory cytokines thereby promoting systemic inflammation and insulin resistance which further exacerbate obesity-associated non-alcoholic fatty liver disease (NAFLD).TGF-β/Smad3 signaling has a crucial role in the inflammatory events within the VAT. Here, we investigate whether KS-356, a novel anti-inflammatory synthetic small molecule compound, can inhibit TGF-β/Smad3 signaling thereby exhibiting therapeutic effect against inflamed VAT and subsequent NAFLD in high-fat diet-induced mice. Method: NAFLD was induced by a high-fat diet (60% fat) for 20 weeks using the male C57BL/6 mice. KS-356 (50 mg/kg) was orally given daily for 20 weeks. In vivo VAT- and systemic inflammation were measured by using 18F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Both insulin tolerance- and glucose tolerance test were performed to assess the status of insulin resistance and glucose intolerance. Histological and molecular analyses were performed on harvested liver and VAT. Results: KS-356 inhibited TGF-β/Smad3 signaling pathway and remarkably suppressed high-fat diet-induced VAT inflammation and its related systemic inflammation. Furthermore, KS-356 significantly improved insulin sensitivity with glucose homeostasis and reduced hepatic steatosis. Conclusion: KS-356 mitigates the development of NAFLD through attenuation of VAT inflammation. Our novel findings support the potential use of KS-356 as a therapeutic drug for NAFLD.