Selective inactivation of c-Jun NH2 terminal kinase (JNK) in the adipose tissue is sufficient to protect against diet-induced-obesity and its associated metabolic disorders in mice

Abstract

INTRODUCTION: Obesity caused by feeding a high fat diet is associated with increased activation of c-Jun NH2-terminal kinase (JNK), which has been implicated in the development of obesity-related insulin resistance and type 2 diabetes. However, the relative tissue-specific contribution and the underlying mechanisms remain to be defined. METHOD: In this study, we generated a transgenic mouse model with adipose tissue-specific over-expression of dominant negative (DN) JNK. Their phenotypic changes on a high fat diet were comprehensively characterized. Adipose tissues, liver, muscle and serum were collected for further biochemical and morphological analysis. RESULTS: On the standard chow diet, the transgenic mice showed no significant difference in body weight gain, insulin sensitivity, glucose or lipid profiles, from their wild-type littermates. However, on a high fat diet, the DN-JNK transgenic mice were protected against diet-induced obesity, with reduced weight gain, fat mass and size of adipocytes in the adipose tissues. Significantly, the DN-JNK transgenic mice were resistant to the deleterious impact of high-fat diet on systemic insulin sensitivity and glucose tolerance. They also demonstrated a lower level of hepatic gluconeogenesis in vivo, and greater insulin-induced glucose uptake in skeletal muscles ex vivo. These metabolic changes were accompanied by a markedly decreased macrophage infiltration in the adipose tissue, reduced production of pro-inflammatory adipokines, increased expression of adiponectin and reduced circulating levels of adipocyte fatty acid binding protein. As a secondary effect, the DN-JNK transgenic mice also exhibited a resistance to the hepatosteatosis induced by high fat diet. The DN-JNK mice, when on a high fat diet, had significant increases in 24-hour oxygen consumption and reductions in respiration exchange rates, compared with their wild-type littermates. CONCLUSION: Selective suppression of JNK activation in the adipose tissue alone was sufficient to counteract high fat diet-induced obesity and its associated metabolic dysregulations in mice, in part through an increase in energy expenditure and a decrease in systemic inflammation.