title: Disturbed secretion of mutant adiponectin associated with the metabolic syndrome.
abstract: Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome.
authors.affiliation: Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2, Yamadaoka, Suita, 565-0871, Osaka, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kishida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nagaretani
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Kondo
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Tanaka
authors.forename: Norikazu
authors.initials: N
authors.lastname: Maeda
authors.forename: Azumi
authors.initials: A
authors.lastname: Nagasawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hibuse
authors.forename: Koji
authors.initials: K
authors.lastname: Ohashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kumada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishizawa
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Maeda
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Tohru
authors.initials: T
authors.lastname: Funahashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsuzawa
mesh_terms: D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism; D000595:Amino Acid Sequence; D002460:Cell Line; D017124:Conserved Sequence; D006801:Humans; D007120:Immunochemistry; D036341:Intercellular Signaling Peptides and Proteins; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D020125:Mutation, Missense; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014162:Transfection
chemical_list: D052242:Adiponectin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins