Uncoupling of Inflammation and Insulin Resistance by NF-κB in Transgenic Mice through Elevated Energy Expenditure

To study the metabolic activity of NF-kappa B, we investigated phenotypes of two different mouse models with elevated NF-kappa B activities. The transcriptional activity of NF-kappa B is enhanced either by overexpression of NF-kappa B p65 (RelA) in aP2-p65 mice or inactivation of NF-kappa Bp50 (NF-kappa B1) through gene knock-out. In these models, energy expenditure was elevated in day and night time without a change in locomotion. The mice were resistant to adulthood obesity and diet-induced obesity without reduction in food intake. The adipose tissue growth and adipogenesis were inhibited by the elevated NF-kappa B activity. Peroxisome proliferator-activator receptor gamma expression was reduced by NF-kappa B at the transcriptional level. The two models exhibited elevated inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) in adipose tissue and serum. However, insulin sensitivity was not reduced by the inflammation in the mice on a chow diet. On a high fat diet, the mice were protected from insulin resistance. The glucose infusion rate was increased more than 30% in the hyperinsulinemic-euglycemic clamp test. Our data suggest that the transcription factor NF-kappa B promotes energy expenditure and inhibits adipose tissue growth. The two effects lead to prevention of adulthood obesity and dietary obesity. The energy expenditure may lead to disassociation of inflammation with insulin resistance. The study indicates that inflammation may prevent insulin resistance by eliminating lipid accumulation.