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Division of Endocrinology, Department of Internal Medicine, NHIC Ilsan Hospital, Goyang, Republic of Korea
¹ Division of Endocrinology, Department of Internal Medicine, Yonsei University, College of Medicine, Seoul, South Korea
² BK21 Project for Medical Science, College of Medicine, Yonsei University, Seoul, South Korea
³ College of Medicine, Institute of Endocrine Research, Yonsei University, Seoul, South Korea
⁴ Division of Endocrinology, Department of Internal Medicine, YanBian University, Medical College, Affiliated Hospital, YanJi, People’s Republic of China

(Requests for offprints should be addressed to S-K Lim who is now at Division of Endocrinology, Department of Internal Medicine, College of Medicine, Yonsei University, 134 Shinchon-dong Seodaemun-ku, PO Box 120-749, Seoul, South Korea; Email: lsk{at}yumc.yonsei.ac.kr)

The systemic treatment with angiogenesis inhibitor has been shown to result in weight reduction and adipose tissue loss in various models of obesity. To verify the mechanism of CKD-732 (TNP-470 analog) against obesity, we evaluated CKD-732’s peripheral and central anti-obesity effects. CKD-732 was injected subcutaneously (s.c.) for 7 days in various animal models and intracerebroventricularly (i.c.v.) in arcuate nucleus (ARC) lesion mice, ob/ob mice, and normal littermates. Modulation of the hypothalamic neuropeptide mRNAs after i.c.v. injection was evaluated in ARC lesion mice and normal littermates. A conditioned taste aversion (CTA) was performed using lithium chloride (LiCl) as a positive control agent in Long–Evans Tokushima Otsuka and Otsuka Long–Evans Tokushima fatty (OLETF) rats. As a result, 7 days of CKD-732 s.c. injection reduced the cumulative food intake and the body weight significantly in both treated obese (e.g. 114.8 ± 13.4 g vs 170.7 ± 20.6 g, 7.9 ± 0.5% decrease vs 0.3 ± 2.2% decrease; in treated OLETF rat versus control OLETF rat, P < 0.01 respectively) and non-obese models. Epididymal and mesenteric fat pads, and the size of adipocytes were significantly decreased in treated rats. A single i.c.v. injection decreased food intake and body weight in ARC lesion mice and ob/ob mice but not in normal littermates. Unexpectedly, the hypothalamic neuropeptide mRNAs were not altered by single i.c.v. injection. CKD-732 also induced a dose-dependent CTA comparable with LiCl injection, which is a commonly used agent to produce a CTA. In conclusion, CKD-732 causes significant body weight and appetite reduction, possibly by decreasing adiposity directly and inducing central anorexia, which is partly explained by a CTA. These results should be carefully verified to assess the utility of CKD-732 as an anti-obesity drug.