Adipose tissue-specific suppression of c-JUN terminal kinase attenuates obesity-related metabolic disorders in a genetic mouse model of obesity and type 2 diabetes

Abstract

RESULTS: Mice with genetic or diet-induced obesity have markedly increased activity of c-Jun NH2-terminal kinase (JNK), a key regulator of inflammatory responses, in their liver, muscle and adipose tissue (AT). To determine the role of JNK in adipose tissue inflammation and insulin sensitivity, we have previously generated a transgenic mouse model that expresses a dominant negative form of JNK (dn-JNK) under the transcriptional control of the ap2 gene promoter, leading to the selective inactivation of JNK1 and JNK2 in AT. In this study, we investigated whether selective AT JNK inactivation could ameliorate the development of metabolic dysfunctions in db/db mice, a mouse model of genetic obesity and type 2 diabetes. We cross-bred the ap2-(dn)-JNK(+/-) mice with C57 BKS db/db(+/-) mice to obtain db/db(-/-)/ap2-dn-JNK(-/-) mice as controls, and db/db mice with AT overexpression of dn-JNK: db/db(-/-)/ap2-dn-JNK(+/-). The db/db(-/-)/ap2-dn-JNK(+/-) transgenic mice had reduced body weight gain from week 5 of age (p<0.05 versus controls, despite similar intake), which may be attributed in part to an increased locomotor activity (p<0.05 versus controls during dark cycle) and greater energy expenditure and lipid utilization, as reflected by a higher oxygen consumption rate (VO2) and lower respiratory exchange ratio (RER, VCO2/VO2), compared to controls. The transgenic mice were less insulin resistant and had lower glucose levels during intraperitoneal GTT (p<0.05 versus controls). Furthermore, JNK inactivation in the db/db mice led to reduced adipocyte size in both white and brown AT, a lesser degree of AT macrophage infiltration and hepatic steatosis, and reduced circulating levels of A-FABP (p<0.01 versus controls), in keeping with the JNK-mediated regulation of A-FABP expression. In conclusion, the selective suppression of JNK activation in AT alone was sufficient to attenuate the development of obesity-induced metabolic disturbances, even in the context of a genetic predisposition to obesity due to leptin resistance.