title: Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production.
abstract: Proper control of hepatic glucose production is central to whole-body glucose homeostasis, and its disruption plays a major role in diabetes. Here, we demonstrate that although established as an intracellular lipid chaperone, aP2 is in fact actively secreted from adipocytes to control liver glucose metabolism. Secretion of aP2 from adipocytes is regulated by fasting- and lipolysis-related signals, and circulating aP2 levels are markedly elevated in mouse and human obesity. Recombinant aP2 stimulates glucose production and gluconeogenic activity in primary hepatocytes in vitro and in lean mice in vivo. In contrast, neutralization of secreted aP2 reduces glucose production and corrects the diabetic phenotype of obese mice. Hyperinsulinemic-euglycemic and pancreatic clamp studies upon aP2 administration or neutralization demonstrated actions of aP2 in liver. We conclude that aP2 is an adipokine linking adipocytes to hepatic glucose production and that neutralizing secreted aP2 may represent an effective therapeutic strategy against diabetes.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Haiming
authors.initials: H
authors.lastname: Cao
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.forename: Meric Erikci
authors.initials: ME
authors.lastname: Ertunc
authors.forename: M Furkan
authors.initials: MF
authors.lastname: Burak
authors.forename: Jared R
authors.initials: JR
authors.lastname: Mayers
authors.forename: Ariel
authors.initials: A
authors.lastname: White
authors.forename: Karen
authors.initials: K
authors.lastname: Inouye
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rickey
authors.forename: Baris C
authors.initials: BC
authors.lastname: Ercal
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Gürol
authors.initials: G
authors.lastname: Tuncman
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D054392:Adipokines / Q000378:metabolism*; D000818:Animals; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008055:Lipids; D008066:Lipolysis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018832:Molecular Chaperones / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism
chemical_list: D054392:Adipokines; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008055:Lipids; D018832:Molecular Chaperones; D005947:Glucose