Adipose tissue mass can be regulated through the vasculature. This study shows that adipose tissue growth is angiogenesis-dependent and can be inhibited by anti-angiogenesis agents. Ob/ob mice, which develop obesity due to a lack of functional leptin, were treated with various angiogenesis inhibitors, including TNP-470, angiostatin, endostatin, Bay 12-9566, and thalidomide. These treatments resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Treated mice showed decreased endothelial cell proliferation and increased apoptosis in adipose tissue compared to controls. Continuous treatment maintained mice near normal body weights without adverse effects. Metabolic adaptations, including changes in food intake, metabolic rate, and energy substrate utilization, were associated with anti-angiogenic weight loss. The study concludes that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature. Adipose tissue is uniquely suited to study the role of angiogenesis in nonneoplastic adult tissue growth due to its high vascularization and angiogenic properties. The findings suggest that adipose tissue vessels may be maintained in a relatively immature state, making them susceptible to anti-angiogenic agents even when not actively growing. The study also highlights the potential for anti-angiogenic agents to selectively reduce adipose tissue, resulting in weight loss. The mechanisms governing metabolic adaptations during anti-angiogenic-induced weight loss are not fully understood, but may involve adipocyte-secreted factors. The study was supported by grants from the National Institutes of Health.Adipose tissue mass can be regulated through the vasculature. This study shows that adipose tissue growth is angiogenesis-dependent and can be inhibited by anti-angiogenesis agents. Ob/ob mice, which develop obesity due to a lack of functional leptin, were treated with various angiogenesis inhibitors, including TNP-470, angiostatin, endostatin, Bay 12-9566, and thalidomide. These treatments resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Treated mice showed decreased endothelial cell proliferation and increased apoptosis in adipose tissue compared to controls. Continuous treatment maintained mice near normal body weights without adverse effects. Metabolic adaptations, including changes in food intake, metabolic rate, and energy substrate utilization, were associated with anti-angiogenic weight loss. The study concludes that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature. Adipose tissue is uniquely suited to study the role of angiogenesis in nonneoplastic adult tissue growth due to its high vascularization and angiogenic properties. The findings suggest that adipose tissue vessels may be maintained in a relatively immature state, making them susceptible to anti-angiogenic agents even when not actively growing. The study also highlights the potential for anti-angiogenic agents to selectively reduce adipose tissue, resulting in weight loss. The mechanisms governing metabolic adaptations during anti-angiogenic-induced weight loss are not fully understood, but may involve adipocyte-secreted factors. The study was supported by grants from the National Institutes of Health.