title: Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKKε and TBK1.
abstract: 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. DOI: http://dx.doi.org/10.7554/eLife.01119.001.
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mowers
authors.forename: Maeran
authors.initials: M
authors.lastname: Uhm
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Reilly
authors.forename: Joshua
authors.initials: J
authors.lastname: Simon
authors.forename: Dara
authors.initials: D
authors.lastname: Leto
authors.forename: Shian-Huey
authors.initials: SH
authors.lastname: Chiang
authors.forename: Louise
authors.initials: L
authors.lastname: Chang
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000201:enzymology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D002395:Catecholamines / Q000378:metabolism*; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004734:Energy Metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology* / Q000235:genetics; D007473:Ion Channels / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D011070:Poly I-C / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D002787:Sterol Esterase / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000071256:Uncoupling Protein 1
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000631:Aminopyridines; D002395:Catecholamines; D004149:Dioxoles; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C045742:amlexanox; D000242:Cyclic AMP; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; C496566:Ikbke protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D002787:Sterol Esterase; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human; C517293:Pde3b protein, mouse; D011070:Poly I-C
keywords: catecholamine resistance; energy expenditure; inflammation; obesity