Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway

Abstract

The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined dietinduced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway.

The roles of c‐Jun NH2‐terminal kinases (JNKs) in obesity and insulin resistance

“…Importantly, compound deletion of both JNK1 and JNK2 in the pituitary using the glycoprotein hormone α‐subunit promoter to drive Cre ‐recombinase expression did not affect JNK1 or JNK2 expression in the hypothalamus or other regions of the brain (Vernia et al . ). Remarkably, anterior pituitary‐specific deletion of JNK1 and JNK2 largely prevented HFD‐induced obesity (Vernia et al .…”

The PPARα-FGF21 Hormone Axis Contributes to Metabolic Regulation by the Hepatic JNK Signaling Pathway

“…Studies of tissue-specific JNK-deficient mice demonstrate that these obesity and insulin resistance phenotypes can be separated. Thus, JNK regulation of the hypothalamic-pituitary hormone axis that regulates energy expenditure is critically required for the development of diet-induced obesity (Belgardt et al, 2010; Sabio et al, 2010a; Vernia et al, 2013). In contrast, JNK function in peripheral tissues, including fat, muscle, and inflammatory cells contributes to diet-induced insulin resistance (Sabio et al, 2008; Sabio et al, 2010b; Han et al, 2013).…”

“…Activated JNK contributes to obesity development by increasing Activating Protein 1 (AP1)-dependent Dio2 gene expression in the anterior pituitary gland (Vernia et al, 2013). In contrast, targets of JNK signaling that cause insulin resistance are unclear.…”

The mAb against adipocyte fatty acid-binding protein 2E4 attenuates the inflammation in the mouse model of high-fat diet-induced obesity via toll-like receptor 4 pathway

“…In addition, FFAs are potent Jun N-terminal kinases (JNK) activators (Hirosumi et al, 2002). The activity of obesity-induced-JNK is critical in the generation of inflammatory responses in adipose tissue (Vernia et al, 2013).…”