Inhibition of adipogenesis by RGD-dependent disintegrin.
Adipogenesis plays a central role in obesity development. The processes of adipogenesis include migration, adhesion, proliferation and survival of preadipocytes and differentiation to mature adipocytes. Many of these biological functions are related to integrins. Here, we found that snake venom-derived arginine-glycine-aspartic acid (RGD)-containing disintegrin inhibited adipogenesis. Rhodostomin but not rhodostomin RGD mutants (RGE-Rn and AKGDWN-Rn) caused the detachment of primary cultured preadipocyte. Furthermore, rhodostomin also inhibited focal adhesion of preadipocyte, including the inhibition of the expression of focal adhesion kinase (FAK) and FAK phosphorylation, assembly of vinculin and reorganization of actin cytoskeleton. Cell viability of preadipocytes was decreased after rhodostomin treatment in a concentration-dependent manner. The results of flow cytometric analysis showed that rhodostomin induced cell apoptosis. In addition, chromatin condensation was observed in DAPI staining. The increase of Bax expression and activation of capsase-3 was detected following rhodostomin treatment. Addition of dexamethasone, IBMX and insulin induced differentiation of preadipocytes into mature adipocytes and treatment of cells with rhodostomin during the initial 3 days showed less mature adipocytes following 9-10 days of differentiating period. The triglyceride content and gene expression of peroxisome proliferators-activated receptor gamma (PPARgamma) and leptin also decreased in response to the treatment of rhodostomin. These results suggest that disintegrin inhibits processes of adipogenesis and may be developed to treat obesity.
Lin
Yu-Ting
YT
Department of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan.
Tang
Chih-Hsin
CH
Chuang
Woei-Jer
WJ
Wang
Seu-Mei
SM
Huang
Tur-Fu
TF
Fu
Wen-Mei
WM
D000199:Actins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D050156:Adipogenesis / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003435:Crotalid Venoms / Q000737:chemistry; D003599:Cytoskeleton / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D019483:Disintegrins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020738:Leptin / Q000737:chemistry / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D047495:PPAR gamma / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D016596:Vinculin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
D000199:Actins; D003435:Crotalid Venoms; D019483:Disintegrins; D039302:Integrin alphaVbeta3; D020738:Leptin; D009842:Oligopeptides; D047495:PPAR gamma; D010455:Peptides; D012333:RNA, Messenger; D016596:Vinculin; C072026:rhodostomin; C047981:arginyl-glycyl-aspartic acid; D051416:Focal Adhesion Protein-Tyrosine Kinases