Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1

Obesity produces a chronic inflammatory state involving the NF kappa B pathway, resulting in persistent elevation of the noncanonical I kappa B kinases IKK epsilon and TBK1. In this study, we report that these kinases attenuate beta-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored beta-adrenergic signaling and lipolysis attenuated by TNF alpha and Poly (I:C). Conversely, overexpression of the kinases reduced induction of Ucp1, lipolysis, cAMP levels, and phosphorylation of hormone sensitive lipase in response to isoproterenol or forskolin. Noncanonical IKKs reduce catecholamine sensitivity by phosphorylating and activating the major adipocyte phosphodiesterase PDE3B. In vivo inhibition of these kinases by treatment of obese mice with the drug amlexanox reversed obesity-induced catecholamine resistance, and restored PKA signaling in response to injection of a beta-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKe and TBK1 may contribute to the repression of energy expenditure during obesity.