WISP1 promotes non‐alcoholic fatty liver disease and skeletal muscle insulin resistance via TLR4/JNK signaling

Abstract

Wnt1-inducible signaling pathway protein-1 (WISP1) is a Cyr61/CTGF/NOV (CCN) family matricellular protein involved in adipogenesis and low-grade inflammation in obesity. However, the roles of WISP1 in hepatic steatosis and insulin resistance in skeletal muscle remain elusive. Mouse primary hepatocytes and differentiated mouse skeletal muscle cells (C2C12) were treated with various concentrations of WISP1 and the functions and signaling pathways were analyzed by Western blot analysis. In vivo transfection for WISP1 knockdown was also performed to examine the effects of WISP1 on hepatic steatosis and skeletal muscle insulin resistance. Knockdown of WISP1 in high-fat diet-fed C57BL/6 mice significantly reduced (0.45-0.5%; p < 0.05) inflammation and JNK phosphorylation (45-50%; P < 0.01) and attenuated hepatic steatosis (approximately 55%; p < 0.001) and skeletal muscle insulin resistance (30-40%; p < 0.05). Treatment with WISP1 significantly induced inflammation (hepatocytes: approximately 500%; p < 0.01, C2C12 cells: approximately 500%; p < 0.01) and JNK phosphorylation (hepatocytes: approximately 200%; p < 0.01, C2C12 cells: approximately 280%; p < 0.01) in mouse primary hepatocytes and C2C12 mouse skeletal muscle cells. Moreover, it increased lipogenesis-associated gene expression (200-300%; p < 0.01) and accumulation of triglycerides (approximately 320%; p < 0.01) in hepatocytes, and suppressed insulin signaling (approximately 50%; p < 0.01) in C2C12 cells. These WISP1-induced effects were significantly abrogated in NFκB-, JNK-, and TLR4-knockdown hepatocytes (p < 0.05) and C2C12 cells (p < 0.05). These results indicate that WISP1 contributes to hepatic steatosis and skeletal muscle insulin resistance through a TLR4-activated inflammation/JNK signaling pathway and could be a useful therapeutic target for treatment of non-alcoholic fatty liver disease and type 2 diabetes.

C2C12 cell model: its role in understanding of insulin resistance at the molecular level and pharmaceutical development at the preclinical stage

“…Therefore, WISP1 adipokines are the activators of TLR4-induced inflammation and JNK signalling pathway, and therapeutic agents that can suppress WISP1 would be potential for the management of hepatic steatosis and insulin resistance. [249] Impaired growth Growth and metabolism of infants can be influenced by suboptimal physiological environments due to maternal inflammation, nutrients insufficiency, hormone imbalance, obesity and diabetes. It was stated that infants with reduced muscle mass and poor muscle development are risk factors for the development of obesity and diabetes.…”

“…[ 248 ] A study assessed three outcomes of WISP1 treatment, including insulin signalling, TLR4‐induced inflammation and JNK pathway, in differentiated C2C12 cells. [ 249 ] It was found that WISP1 impeded insulin signalling pathway via inflammation‐related JNK phosphorylation in both animal and C2C12 cell models. When TLR4 was knockdown in C2C12 cells, the examined outcomes including WISP1‐induced lipid accumulation, inflammation, insulin resistance and JNK phosphorylation were mitigated.…”

“…Therefore, WISP1 adipokines are the activators of TLR4‐induced inflammation and JNK signalling pathway, and therapeutic agents that can suppress WISP1 would be potential for the management of hepatic steatosis and insulin resistance. [ 249 ]…”

Wingless‐type inducible signaling pathway protein‐1 (WISP1) adipokine and glucose homeostasis

“…Increase in triglyceride accumulation increasing adipose synthesis (Al-Hamodi et al, 2014;Barchetta et al, 2017;Cernea et al, 2016;Jung et al, 2018;Murahovschi et al, 2015) Note. Akt: protein kinase B; IRS: insulin receptor substrate; WISP1: wingless-type inducible signaling pathway protein-1.…”

Association of WISP1/CCN4 with Risk of Overweight and Gestational Diabetes Mellitus in Chinese Pregnant Women

“…And previous research revealed that circulatory levels of WISP1 adipokine were higher in obese patients accompanied with increased insulin resistance [22]. Jung et al demonstrated that WISP1 may play an essential role in obesity-induced hepatic steatosis and insulin resistance [23]. In diabetes research, tissue biopsies showed greater WISP1 expression among diabetic subjects compared with nondiabetic subjects independent of glycemic control in adult males [24].…”