Endostatin Prevents Dietary-Induced Obesity by Inhibiting Adipogenesis and Angiogenesis

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 7; pp. 2442 - 2456
• Main Authors: Wang, Hui, Chen, Yang, Lu, Xin-an, Liu, Guanghua, Fu, Yan, Luo, Yongzhang
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2015
• Subjects: 3T3-L1 Cells; Adaptor Proteins, Signal Transducing - physiology; Adipogenesis - drug effects; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Diet; Diet, High-Fat; Endostatins - pharmacology; Glucose; Insulin resistance; Introns; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Metabolic syndrome; Mice; Mice, Inbred C57BL; Multiprotein Complexes - antagonists & inhibitors; Obesity; Obesity - prevention & control; RNA-Binding Proteins - physiology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db14-0528

Endostatin is a well-known angiogenesis inhibitor. Although angiogenesis has been considered as a potential therapeutic target of obesity, the inhibitory effect of endostatin on adipogenesis and dietary-induced obesity has never been demonstrated. Adipogenesis plays a critical role in controlling adipocyte cell number, body weight, and metabolic profile in a homeostatic state. Here we reveal that endostatin inhibits adipogenesis and dietary-induced obesity. The antiadipogenic mechanism of endostatin lies in its interaction with Sam68 RNA-binding protein in the nuclei of preadipocytes. This interaction competitively impairs the binding of Sam68 to intron 5 of mammalian target of rapamycin (mTOR), causing an error in mTOR transcript. This consequently decreases the expression of mTOR, results in decreased activities of the mTOR complex 1 pathway, and leads to defects in adipogenesis. Moreover, our findings demonstrate that the antiangiogenic function of endostatin also contributes to its obesity-inhibitory activity. Through the combined functions on adipogenesis and angiogenesis, endostatin prevents dietary-induced obesity and its related metabolic disorders, including insulin resistance, glucose intolerance, and hepatic steatosis. Thus, our findings reveal that endostatin has a potential application for antiobesity therapy and the prevention of obesity-related metabolic syndromes.