Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1
Jonathan Mowers,
Maeran Uhm,
Shannon M Reilly,
Joshua Simon,
Dara Leto,
Shian-Huey Chiang,
Louise Chang,
Alan R Saltiel
Affiliations
Jonathan Mowers
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Maeran Uhm
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Shannon M Reilly
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Joshua Simon
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Dara Leto
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Shian-Huey Chiang
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Louise Chang
Life Sciences Institute, University of Michigan, Ann Arbor, United States
Alan R Saltiel
Life Sciences Institute, University of Michigan, Ann Arbor, United States; Department of Internal Medicine, University of Michigan, Ann Arbor, United States; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
Obesity produces a chronic inflammatory state involving the NFκB pathway, resulting in persistent elevation of the noncanonical IκB kinases IKKε and TBK1. In this study, we report that these kinases attenuate β-adrenergic signaling in white adipose tissue. Treatment of 3T3-L1 adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and lipolysis attenuated by TNFα 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 β-3 adrenergic agonist. These studies suggest that by reducing production of cAMP in adipocytes, IKKε and TBK1 may contribute to the repression of energy expenditure during obesity.
