There are endocrine and immunological changes that occur during onset and progression of the overweight and obese states. The inhibitor of nuclear factor kappa B kinase subunit epsilon (IKKε) was originally described as an inducible protein kinase; whole-body gene deletion or systemic pharmaceutical targeting of this kinase improved insulin sensitivity and glucose tolerance in mice. To investigate the primary sites of action associated with IKKε during weight gain, we describe the first mouse

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... ne with conditional elimination of IKKε in the liver (IKKε alb-/-). IKKε alb-/- mice and littermate controls gain weight, show similar changes in body composition, and do not display any improvements in insulin sensitivity or whole-body glucose tolerance. These studies were conducted using both breeder chow diets and also matched low- versus high-fat diets. While glycogen accumulation in the liver is reduced in IKKεalb-/- mice, lipid storage in liver is similar IKKεalb-/- mice and littermate controls. Our results using IKKεalb-/- mice suggest that the primary action of this kinase to impact insulin sensitivity during weight gain lies predominantly within extrahepatic tissues.