title: Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity.
abstract: Adipocyte fatty acid binding protein 4, aP2, contributes to the pathogenesis of several common diseases including type 2 diabetes, atherosclerosis, fatty liver disease, asthma, and cancer. Although the biological functions of aP2 have classically been attributed to its intracellular action, recent studies demonstrated that aP2 acts as an adipokine to regulate systemic metabolism. However, the mechanism and regulation of aP2 secretion remain unknown. Here, we demonstrate a specific role for lipase activity in aP2 secretion from adipocytes in vitro and ex vivo. Our results show that chemical inhibition of lipase activity, genetic deficiency of adipose triglyceride lipase and, to a lesser extent, hormone-sensitive lipase blocked aP2 secretion from adipocytes. Increased lipolysis and lipid availability also contributed to aP2 release as determined in perilipin1-deficient adipose tissue explants ex vivo and upon treatment with lipids in vivo and in vitro. In addition, we identify a nonclassical route for aP2 secretion in exosome-like vesicles and show that aP2 is recruited to this pathway upon stimulation of lipolysis. Given the effect of circulating aP2 on glucose metabolism, these data support that targeting aP2 or the lipolysis-dependent secretory pathway may present novel mechanistic and translational opportunities in metabolic disease.
authors.affiliation: Department of Genetics and Complex Diseases Harvard School of Public Health, Boston, MA Sabri Ülker Center, Harvard School of Public Health, Boston, MA.
authors.forename: Meric Erikci
authors.initials: ME
authors.lastname: Ertunc
authors.affiliation: Department of Biosciences, National Institutes of Health, Bethesda, MD.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Sikkeland
authors.affiliation: Department of Biosciences, National Institutes of Health, Bethesda, MD.
authors.forename: Federico
authors.initials: F
authors.lastname: Fenaroli
authors.affiliation: Department of Biosciences, National Institutes of Health, Bethesda, MD.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
authors.affiliation: University of Oslo, Oslo, Norway; and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Mathew P
authors.initials: MP
authors.lastname: Daniels
authors.affiliation: University of Oslo, Oslo, Norway; and National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Haiming
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Biosciences, National Institutes of Health, Bethesda, MD.
authors.forename: Fahri
authors.initials: F
authors.lastname: Saatcioglu
authors.affiliation: Department of Genetics and Complex Diseases Harvard School of Public Health, Boston, MA Sabri Ülker Center, Harvard School of Public Health, Boston, MA.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D008049:Lipase; D000070778:Perilipin-1; D010750:Phosphoproteins; C493411:Fabp4 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: adipokine; adipose triglyceride lipase; hormone; hormone-sensitive lipase; lipolysis; obesity