This proposal focuses on a clinical proof of concept study to evaluate a novel hypothesis. We propose that overnutrition, leading to obesity, represents a state of excessive energy storage promoted by insulin. The stress of excessive energy storage initiates a set of homeostatic responses that includes the generation of adipose tissue and liver inflammation, which involves the secretion of proinflammatory cytokines that block energy storage in fat and liver by inducing insulin resistance, thus relieving stress on the adipocyte and hepatocyte. However, our recent data suggest that inflammation itself is countered by a secondary feedback loop, which we have termed "counter-inflammation". We propose that this process keeps inflammation in check, ensuring that it is maintained at low levels. At the same time counter-inflammation also promotes energy conservation via increased energy storage and decreased utilization in a manner that is insulin-independent. We hypothesize that the noncanonical IkB kinases Ikke and TBK1 are "counterinflammatory" kinases that feedback inhibit inflammatory pathways while helping to support a positive energy balance.