Disturbed secretion of mutant adiponectin associated with the metabolic syndrome.
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.
Kishida
Ken
K
Department of Internal Medicine and Molecular Science, Graduate School of Medicine, B5, Osaka University, 2-2, Yamadaoka, Suita, 565-0871, Osaka, Japan.
Nagaretani
Hiroyuki
H
Kondo
Hidehiko
H
Kobayashi
Hideki
H
Tanaka
Sachiyo
S
Maeda
Norikazu
N
Nagasawa
Azumi
A
Hibuse
Toshiyuki
T
Ohashi
Koji
K
Kumada
Masahiro
M
Nishizawa
Hitoshi
H
Okamoto
Yoshihisa
Y
Ouchi
Noriyuki
N
Maeda
Kazuhisa
K
Kihara
Shinji
S
Funahashi
Tohru
T
Matsuzawa
Yuji
Y
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
D052242:Adiponectin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins