Identification of amino-terminal region of adiponectin as a physiologically functional domain.
Adiponectin is an abundant adipose-specific protein, which acts as an anti-diabetic, anti-atherogenic, and anti-inflammatory adipokine. Although recent advances in the field of adiponectin have been made by the identification of adiponectin receptors and by the understanding about relationship between its multimerization and functions, detailed molecular background remains unclear. Our established anti-human adiponectin antibodies, ANOC 9103 and ANOC 9104, blocked some adiponectin functions such as the growth inhibition of B-lymphocytes on stromal cells and the inhibition of acetylated LDL uptake in macrophages, suggesting that they may recognize important functional regions of adiponectin. As a result of epitope mapping based on the ability to bind to the deleted adiponectin mutants, we identified that these antibodies recognize amino-terminal region of adiponectin before the beginning of the collagen-like domain. Notably, a peptide fragment (DQETTTQGPGVLLPLPKGACTGWMA) corresponding to amino acid residues 17-41 of human adiponectin could bind to restricted types of cells and block adiponectin-induced cyclooxygenase-2 gene expression and prostaglandin E2 production in MS-5 stromal cells. Moreover, the deletion of its amino-terminal region reduced the abilities to inhibit not only collagen-induced platelet aggregation but also diet-induced hepatic steatosis. These data indicate that amino-terminal region of adiponectin is a physiologically functional domain and that a novel receptor, which recognizes amino-terminal region of adiponectin, may exist on some types of cells. Further investigations will contribute to the understanding of molecular mechanisms about adiponectin functions as well as to the designing of novel strategies for the treatment of patients with insulin-resistance, vascular dysfunction, and chronic inflammation.
Ujiie
Hidetoshi
H
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Oritani
Kenji
K
Kato
Hisashi
H
Yokota
Takafumi
T
Takahashi
Isao
I
Maeda
Tetsuo
T
Masaie
Hiroaki
H
Ichii
Michiko
M
Kamada
Yoshihiro
Y
Tamura
Shinji
S
Kihara
Shinji
S
Funahashi
Tohru
T
Tomiyama
Yoshiaki
Y
Kanakura
Yuzuru
Y
D052242:Adiponectin / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology
D052242:Adiponectin; D000939:Epitopes; D010446:Peptide Fragments