Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732.
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.
Kim
Yoo Mee
YM
Division of Endocrinology, Department of Internal Medicine, NHIC Ilsan Hospital, Goyang, Republic of Korea.
An
Juan Ji
JJ
Jin
Yong-Jun
YJ
Rhee
Yumie
Y
Cha
Bong Soo
BS
Lee
Hyun Chul
HC
Lim
Sung-Kil
SK
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001111:Arcuate Nucleus of Hypothalamus / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003510:Cyclohexanes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007031:Hypothalamus / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009479:Neuropeptides / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D020334:Rats, Inbred OLETF; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013649:Taste / Q000187:drug effects
D019440:Anti-Obesity Agents; D002934:Cinnamates; D003510:Cyclohexanes; D004852:Epoxy Compounds; D009479:Neuropeptides; D012717:Sesquiterpenes; C487952:CKD732; D018021:Lithium Chloride; D000077609:O-(Chloroacetylcarbamoyl)fumagillol