Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Abstract

The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2 ؊/؊ mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1 ؊/؊ and Jnk2 ؊/؊ mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1 ؊/؊ and Jnk1 ؉/؊ Jnk2 ؊/؊ mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.diabetes ͉ fatty liver ͉ metabolic syndrome ͉ inflammation ͉ stress

Ameliorative effect of Ruellia tuberosa L. on hyperglycemia in type 2 diabetes mellitus and glucose uptake in mouse C2C12 myoblasts

“…Del Aguila, Claffey, and Kirwan (1999) utilized C2C12 cells induced by TNF‐α at a concentration of 10 ng/ml for 1 hr and found that under these conditions, the activity of IRS‐1/2 is inhibited, resulting in a decrease in PI3‐kinase activity and The present study demonstrates inhibition of P42 MARK and P44 MARK phosphorylation, thereby enabling insulin to stimulate the decrease in glucose uptake of C2C12 cells. When TNF‐α binds to its receptor, it activates the JNK pathway and directly inhibits the activity of IRS‐1/2, resulting in the failure of the insulin signaling pathway, leading to cellular IR emergence (Boden et al., 2005; Samuel & Shulman, 2012; Tuncman et al., 2006). Thus, in the present study, a concentration of 10 ng/ml of TNF‐α was also used as a cellular model for the induction of IR in C2C12 cells.…”

“…Type 2 diabetes mellitus (T2DM) occurs mainly due to insufficient or a lack of insulin secretion from the pancreatic β cells and insulin insensitivity for a tissue, resulting in insulin cannot effectively be exerted, causing insulin resistance (IR; Boden et al., 2005; Tuncman et al., 2006). To maintain homeostasis of blood glucose in the body, pancreatic β cells compensatorily secrete more insulin to elevate the blood insulin level, subsequently contributing to hyperinsulinemia (ADA, 2015; Jiang, Chang, Tai, Chen, & Chuang, 2012; Samuel & Shulman, 2012).…”

“…It may eventually generate some specific lipid metabolites that converge to the liver and skeletal muscle, resulting in the destruction of the insulin signaling pathway and the occurrence of IR (Chang & Shen, 2013; Chang et al., 2013, 2015). Previous studies reported that tumor necrosis factor‐α (TNF‐α) may activate the inhibitor of nuclear factor κ‐B kinase and c‐Jun N‐terminal protein kinase (JNK) pathways, resulting in IR in skeletal muscle cells (Boden et al., 2005; Samuel & Shulman, 2012; Tuncman et al., 2006). …”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Based on these studies, one could suppose that JNK2 is not involved in metabolic alterations. Therefore, in order to address the question of the role of JNK2 in metabolism, Tuncman and coworkers generated jnk2 null mice with one jnk1 allele and found that these mice were protected from high-fat diet-induced obesity (Tuncman et al, 2006). These studies indicate that JNK1 and JNK2 are both involved in metabolic disorders such as obesity, and that JNK1 is able to compensate a loss of function of JNK2.…”

Preventive Effects of (−)-Epigallocatechin Gallate on Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BL/KsJ-db/db Mice

“…3B, P < 0.01). Furthermore, irrespective of DEN treatment, EGCG drinking decreased the expression levels of the p-Stat3 and p-JNK proteins, which play a role in obesity/TNFa-mediated hepatic inflammation (34,35) and are increased by DEN, in the livers of experimental mice (Fig. 3C).…”