Regulation of adipolin/CTRP12 cleavage by obesity.
Obesity is highly associated with the development of insulin resistance and type 2 diabetes. Recently we found that adipolin/CRTP12 is an adipocytokine that exerts beneficial actions on glucose metabolism. Here we investigated the regulation of circulating adipolin under conditions of obesity and assessed its potential mechanisms. Both full and cleaved forms of adipolin were observed in mouse plasma. Diet-induced obese (DIO) mice showed a significant reduction of plasma levels of full and total (full and cleaved) adipolin compared with control mice, resulting in an increase in the ratio of cleaved to full isoform. In vitro gene transfection studies using HEK293 cells revealed that a deletion mutant of adipolin gene (Δaa90-93) caused a reduction of cleaved production of adipolin in media. A bioinformatics analysis of adipolin amino acid sequence indicated the potential involvement of the family of proprotein convertases (PCs) in cleavage of adipolin. Treatment of 3T3-L1 adipocytes with an inhibitor for PCs abolished the expression of cleaved adipolin form in the media. The expression of furin, the member of PCs, was increased in adipose tissue of DIO mice. Furin expression was also increased in cultured adipocytes by treatment with an inducer of inflammation. These data suggest that obesity states facilitate the cleavage of adipolin presumably through upregulation of furin in adipose tissue.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takashi
T
Enomoto
Rei
R
Shibata
Koji
K
Ohashi
Takahiro
T
Kambara
Yoshiyuki
Y
Kataoka
Yusuke
Y
Uemura
Daisuke
D
Yuasa
Toyoaki
T
Murohara
Noriyuki
N
Ouchi
D041721:3T3-L1 Cells; D054392:Adipokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology; D020816:Amino Acid Motifs; D000818:Animals; D004032:Diet / Q000009:adverse effects; D045683:Furin / Q000096:biosynthesis*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017384:Sequence Deletion; D013851:Thinness / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation
D054392:Adipokines; C568466:C1qtnf12 protein, mouse; D043484:Proprotein Convertases; D045683:Furin