Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1
Copyright policy )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 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.
- University of California System United States
- University of Michigan–Flint United States
Male, obesity, Time Factors, Aminopyridines, White, Inbred C57BL, Ion Channels, Mice, Catecholamines, Receptors, energy expenditure, Chlorocebus aethiops, Adipocytes, Cyclic AMP, 2.1 Biological and endogenous factors, Aetiology, Phosphorylation, Biology (General), Uncoupling Protein 1, Q, R, Protein-Serine-Threonine Kinases, I-kappa B Kinase, Adipose Tissue, catecholamine resistance, Adrenergic, COS Cells, Medicine, Type 3, Signal Transduction, Cyclic Nucleotide Phosphodiesterases, QH301-705.5, Lipolysis, Science, Adipose Tissue, White, 610, Adrenergic beta-3 Receptor Agonists, Dioxoles, Protein Serine-Threonine Kinases, Transfection, Mitochondrial Proteins, 3T3-L1 Cells, Animals, Humans, Obesity, Protein Kinase Inhibitors, Metabolic and endocrine, Nutrition, Inflammation, Animal, Tumor Necrosis Factor-alpha, Cell Biology, Sterol Esterase, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 3, Enzyme Activation, Disease Models, Animal, Poly I-C, HEK293 Cells, inflammation, Disease Models, beta, Biochemistry and Cell Biology, Energy Metabolism
Male, obesity, Time Factors, Aminopyridines, White, Inbred C57BL, Ion Channels, Mice, Catecholamines, Receptors, energy expenditure, Chlorocebus aethiops, Adipocytes, Cyclic AMP, 2.1 Biological and endogenous factors, Aetiology, Phosphorylation, Biology (General), Uncoupling Protein 1, Q, R, Protein-Serine-Threonine Kinases, I-kappa B Kinase, Adipose Tissue, catecholamine resistance, Adrenergic, COS Cells, Medicine, Type 3, Signal Transduction, Cyclic Nucleotide Phosphodiesterases, QH301-705.5, Lipolysis, Science, Adipose Tissue, White, 610, Adrenergic beta-3 Receptor Agonists, Dioxoles, Protein Serine-Threonine Kinases, Transfection, Mitochondrial Proteins, 3T3-L1 Cells, Animals, Humans, Obesity, Protein Kinase Inhibitors, Metabolic and endocrine, Nutrition, Inflammation, Animal, Tumor Necrosis Factor-alpha, Cell Biology, Sterol Esterase, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 3, Enzyme Activation, Disease Models, Animal, Poly I-C, HEK293 Cells, inflammation, Disease Models, beta, Biochemistry and Cell Biology, Energy Metabolism
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