title: White Adipocyte Adiponectin Exocytosis Is Stimulated via β3-Adrenergic Signaling and Activation of Epac1: Catecholamine Resistance in Obesity and Type 2 Diabetes.
abstract: We investigated the physiological regulation of adiponectin exocytosis in health and metabolic disease by a combination of membrane capacitance patch-clamp recordings and biochemical measurements of short-term (30-min incubations) adiponectin secretion. Epinephrine or the β3-adrenergic receptor (AR) agonist CL 316,243 (CL) stimulated adiponectin exocytosis/secretion in cultured 3T3-L1 and in primary subcutaneous mouse adipocytes, and the stimulation was inhibited by the Epac (Exchange Protein directly Activated by cAMP) antagonist ESI-09. The β3AR was highly expressed in cultured and primary adipocytes, whereas other ARs were detected at lower levels. 3T3-L1 and primary adipocytes expressed Epac1, whereas Epac2 was undetectable. Adiponectin secretion could not be stimulated by epinephrine or CL in adipocytes isolated from obese/type 2 diabetic mice, whereas the basal (unstimulated) adiponectin release level was elevated twofold. Gene expression of β3AR and Epac1 was reduced in adipocytes from obese animals, and corresponded to a respective ∼35% and ∼30% reduction at the protein level. Small interfering RNA-mediated knockdown of β3AR (∼60%) and Epac1 (∼50%) was associated with abrogated catecholamine-stimulated adiponectin secretion. We propose that adiponectin exocytosis is stimulated via adrenergic signaling pathways mainly involving β3ARs. We further suggest that adrenergically stimulated adiponectin secretion is disturbed in obesity/type 2 diabetes as a result of the reduced expression of β3ARs and Epac1 in a state we define as "catecholamine resistance."
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Ali M
authors.initials: AM
authors.lastname: Komai
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Saliha
authors.initials: S
authors.lastname: Musovic
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Eduard
authors.initials: E
authors.lastname: Peris
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Alrifaiy
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Mickaël F
authors.initials: MF
authors.lastname: El Hachmane
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wernstedt Asterholm
authors.affiliation: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden charlotta.olofsson@gu.se.
authors.forename: Charlotta S
authors.identifier: http://orcid.org/0000-0001-8824-3151
authors.initials: CS
authors.lastname: Olofsson
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004594:Electrophysiology; D005089:Exocytosis / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000378:metabolism; D006835:Hydrazones / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; D052242:Adiponectin; D002395:Catecholamines; D004149:Dioxoles; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007555:Isoxazoles; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate