A multitarget angiogenesis inhibitor, CTT peptide-endostatin mimic-kringle 5, prevents diet-induced obesity.

Abstract

Adipose tissue vasculature has been considered an attractive target for prevention and treatment of obesity. AARP (CTT peptide-endostatin mimic-kringle 5) is a novel multitarget fusion protein against tumor angiogenesis. This study aimed to examine the effects of AARP on diet-induced obesity and its possible molecular mechanism. Treatment with AARP markedly prevented weight gains, improved metabolic disturbances, and decreased adipose tissue angiogenesis in diet-induced obese mice without noticeable toxicities. In addition to its potent antiangiogenic and MMP-2/9 inhibitory activities, AARP administration also significantly increased energy expenditure, influenced the metabolic and angiogenic gene expression profiles, and attenuated obesity-induced inflammation, demonstrating its systemic beneficial effects. Importantly, AARP exhibited no effect on mice fed with standard normal mouse diet. Furthermore, the AARP-treated HFD-fed mice experienced a significant increase in lifespan during the posttreatment observation period, compared with untreated HFD-fed mice. Our results suggest that AARP might be pharmacologically useful for treatment of obesity or obesity-related metabolic disorders in humans. KEY MESSAGES: What is already known • More effective and safe therapies for obesity are in urgent need. • AARP is a novel multitarget fusion protein against tumor angiogenesis. What this study adds • AARP prevents obesity, improves metabolic disorders in mice fed high-fat diet. • AARP increases energy expenditure, decreases adipose tissue angiogenesis, and increases lifespan. • AARP is well tolerated and exhibits no observable toxicity. Clinical significance • AARP may be a promising therapeutic agent against obesity or obesity-related metabolic disturbances.