title: Essential roles of insulin, AMPK signaling and lysyl and prolyl hydroxylases in the biosynthesis and multimerization of adiponectin.
abstract: Post-translational modifications (PTMs) of the adiponectin molecule are essential for its full bioactivity, and defects in PTMs leading to its defective production and multimerization have been linked to the mechanisms of insulin resistance, obesity, and type-2 diabetes. Here we observed that, in differentiated 3T3-L1 adipocytes, decreased insulin signaling caused by blocking of insulin receptors (InsR) with an anti-InsR blocking antibody, increased rates of adiponectin secretion, whereas concomitant elevations in insulin levels counteracted this effect. Adenosine monophosphate-activated protein kinase (AMPK) signaling regulated adiponectin production by modulating the expression of adiponectin receptors, the secretion of adiponectin, and eventually the expression of adiponectin itself. We found that lysyl hydroxylases (LHs) and prolyl hydroxylases (PHs) were expressed in white-adipose tissue of ob/ob mice, wherein LH3 levels were increased compared with controls. In differentiated 3T3-L1 adipocytes, both non-specific inhibition of LHs and PHs by dipyridyl, and specific inhibition of LHs by minoxidil and of P4H with ethyl-3,4-dihydroxybenzoate, caused significant suppression of adiponectin production, more particularly of the higher-order isoforms. Transient gene knock-down of LH3 (Plod3) caused a suppressive effect, especially on the high molecular-weight (HMW) isoforms. These data indicate that PHs and LHs are both required for physiological adiponectin production and in particular are essential for the formation/secretion of the HMW isoforms.
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Li
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Marie
authors.initials: M
authors.lastname: Corcoran
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand.
authors.forename: Shaoping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Faculty of Science, University of Auckland, Auckland, New Zealand; Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; Department of Pharmacology, Medical Sciences Division, University of Oxford, Oxford OX1 3QT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom; Centre for Endocrinology & Diabetes, Institute of Human Development, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PT, United Kingdom. Electronic address: g.cooper@auckland.ac.nz.
authors.forename: Garth J S
authors.initials: GJ
authors.lastname: Cooper
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D008914:Minoxidil / Q000494:pharmacology; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D064828:Prolyl Hydroxylases / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D055503:Protein Multimerization / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D000959:Antihypertensive Agents; D062385:Hydroxybenzoates; D007004:Hypoglycemic Agents; D007328:Insulin; D020033:Protein Isoforms; C018063:ethyl protocatechuate; D008914:Minoxidil; D064828:Prolyl Hydroxylases; C510730:lysyl hydroxylase 3, mouse; D008240:Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase; D055372:AMP-Activated Protein Kinases
keywords: Adiponectin; Adipose tissue; Biosynthesis; Hormones; Molecular mechanisms; Post-translational modification