IKKβ Is Essential for Adipocyte Survival and Adaptive Adipose Remodeling in Obesity

I kappa B kinase beta (IKK beta), a central coordinator of inflammatory responses through activation of nuclear factor-kappa B (NF-kappa B), has been implicated as a critical molecular link between inflammation and metabolic disorders; however, the role of adipocyte IKK beta in obesity and related metabolic disorders remains elusive. Here we report an essential role of IKK beta in the regulation of adipose remodeling and adipocyte survival in diet-induced obesity. Targeted deletion of IKK beta in adipocytes does not affect body weight, food intake, and energy expenditure but results in an exaggerated diabetic phenotype when challenged with a high-fat diet (HFD). IKK beta-deficient mice have multiple histopathologies in visceral adipose tissue, including increased adipocyte death, amplified macrophage infiltration, and defective adaptive adipose remodeling. Deficiency of IKK beta also leads to increased adipose lipolysis, elevated plasma free fatty acid (FFA) levels, and impaired insulin signaling. Mechanistic studies demonstrated that IKK beta is a key adipocyte survival factor and that IKK beta protects murine and human adipocytes from HFD- or FFA-elicited cell death through NF-kappa B-dependent upregulation of antiapoptotic proteins and NF-kappa B-independent inactivation of proapoptotic BAD protein. Our findings establish IKK beta as critical for adipocyte survival and adaptive adipose remodeling in obesity.