title: σ1B adaptin regulates adipogenesis by mediating the sorting of sortilin in adipose tissue.
abstract: Here, we describe altered sorting of sortilin in adipocytes deficient for the σ1B-containing AP-1 complex, leading to the inhibition of adipogenesis. The AP-1 complex mediates protein sorting between the trans-Golgi network and endosomes. Vertebrates express three AP1 σ1 subunit isoforms - σ1A, σ1B and σ1C (also known as AP1S1, AP1S2 and AP1S3, respectively). σ1B-deficient mice display impaired recycling of synaptic vesicles and lipodystrophy. Here, we show that sortilin is overexpressed in adipose tissue from σ1B(-/-) mice, and that its overexpression in wild-type cells is sufficient to suppress adipogenesis. σ1B-specific binding of sortilin requires the sortilin DxxD-x12-DSxxxL motif. σ1B deficiency does not lead to a block of sortilin transport out of a specific organelle, but the fraction that reaches lysosomes is reduced. Sortilin binds to the receptor DLK1, an inhibitor of adipocyte differentiation, and the overexpression of sortilin prevents DLK1 downregulation, leading to enhanced inhibition of adipogenesis. DLK1 and sortilin expression are not increased in the brain tissue of σ1B(-/-) mice, although this is the tissue with the highest expression of σ1B and sortilin. Thus, adipose-tissue-specific and σ1B-dependent routes for the transport of sortilin exist and are involved in the regulation of adipogenesis and adipose-tissue mass.
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baltes
authors.affiliation: MIND Center Department of Biomedicine, Ole Worms Allé 3, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Jakob Vejby
authors.initials: JV
authors.lastname: Larsen
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Radhakrishnan
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Geumann
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Kratzke
authors.affiliation: MIND Center Department of Biomedicine, Ole Worms Allé 3, Aarhus University, 8000 Aarhus, Denmark.
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
authors.affiliation: Georg-August University Göttingen, Department for Cellular Biochemistry, Humboldtallee 23, D-37073 Göttingen, Germany pschu@gwdg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Schu
mesh_terms: D033961:Adaptor Protein Complex 1 / Q000235:genetics / Q000378:metabolism*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D000099183:Sortilin
chemical_list: D033961:Adaptor Protein Complex 1; D034002:Adaptor Protein Complex sigma Subunits; D033942:Adaptor Proteins, Vesicular Transport; D020033:Protein Isoforms; D000099183:Sortilin; C499071:adaptor protein complex 1, sigma 1 subunit
keywords: AP-1; Adipogenesis; Clathrin; DLK1; Sortilin