Angiogenesis inhibitor, TNP-470, prevents diet-induced and genetic obesity in mice.
Adipose tissue growth has been proposed to involve recruitment of new blood vessels. Here, we test the hypothesis that delivery of an angiogenesis inhibitor in mice may prevent diet-induced obesity, the most common type of obesity in humans. We show that systemic administration of a selective angiogenesis inhibitor, TNP-470 (AGM-1470), prevents obesity in high caloric diet-fed wt mice as well as in genetically leptin-deficient ob/ob mice. Inhibition of obesity in mice by TNP-470 involves a reduction of vascularity in the adipose tissue. This therapeutic strategy appears to selectively affect the growth of adipose tissue as measured by the ratio between total fat and lean body mass. Interestingly, the treatment with TNP-470 results in decreased serum levels of low-density lipoprotein cholesterol. Furthermore, insulin levels are reduced, which indicates increased insulin sensitivity, suggesting that angiogenesis inhibitors may prevent the development of type II diabetes. Our findings suggest that similarly to growth and organogenesis in other tissues, adipose tissue growth is dependent on angiogenesis. Our observations may have conceptual implications for the prevention of obesity and related disorders.
Bråkenhielm
Ebba
E
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
Cao
Renhai
R
Gao
Bihu
B
Angelin
Bo
B
Cannon
Barbara
B
Parini
Paolo
P
Cao
Yihai
Y
D041721:3T3-L1 Cells / Q000187:drug effects; D000273:Adipose Tissue / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001823:Body Composition / Q000187:drug effects; D050260:Carbohydrate Metabolism; D002417:Cattle; D003315:Cornea / Q000098:blood supply; D003510:Cyclohexanes; D004041:Dietary Fats / Q000008:administration & dosage; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018919:Neovascularization, Physiologic / Q000187:drug effects; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D019440:Anti-Obesity Agents; D003510:Cyclohexanes; D004041:Dietary Fats; D008055:Lipids; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol