A novel role of the c-Jun NH(2)-Terminal Kinase (JNK) in obesity-associated insulin resistance

Abstract

[eng] Obesity is the most common metabolic disorder that have alarmingly increased all over the world in the last few decades. The hormone insulin is one of the major endocrine axis deregulated in obesity and will be the focus of this study. Regarding insulin, obesity is associated with a decreased response to this hormone, a condition known as insulin resistance, and an increased level in blood, namely hyperinsulinemia. The molecular mechanisms of how insulin resistance and hyperinsulinemia develop are still unclear, thus it is currently difficult to disentangle cause and effect.

The c-Jun N-terminal kinase (JNK) pathway has emerged as a central regulator of insulin sensitivity, locally and systematically. Almost all metabolic stressors that cause insulin resistance or pancreatic islet dysfunction, such as inflammatory cytokines and free fatty acids (FFAs), activate the JNK signal transduction pathway, so this protein kinase seems to be a potential link between obesity, metabolic inflammation, glucose homeostasis disorders, insulin resistance and T2D.

This study aimed to investigate the effect of impaired insulin paracrine action on obesity- disrupted glucose homeostasis. For this purpose, we took advantage of a transgenic mouse model (MKK7D mice), which do not secrete insulin in response to hyperglycemia due to the JNK-mediated inhibition of insulin receptor signalling in pancreatic  -cells.

Our results showed that insulin signaling pathway blockade in pancreatic -cells by JNK activation does not impair the development of diet-induced obesity although prevents the development of obesity-associated insulin resistance and hyperinsulinemia.

We observed that hyperinsulinemia has a casual role in the development of obesity- associated insulin resistance in insulin-target tissues and systemic level. In adipose tissue, a chronic low-grade inflammation may be required but is not sufficient to induce insulin resistance, also JNK activation and increased expression of some cytokines, such as IL-10, could be needed to induce hyperinsulinemia and insulin resistance in adipose tissue of obese mice. Therefore, more investigations are required to identify the signaling molecules released by the overexpanded adipose tissue to induce systemic insulin resistance.