Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732

Abstract

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 . 8G13 . 4 g vs 170 . 7G20 . 6 g, 7 . 9G0 . 5% decrease vs 0 . 3G2 . 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.

Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration

“…47 When the vascular supply feeding adipose tissue was made profoundly insufficient through inhibition of angiogenesis, the ability to develop obesity was significantly impaired. 48 This suggests that the vascularity of adipose tissue plays a large role in its ability to expand. Given the fact that our high-fat fed and ob/ob mice do indeed become quite obese, it is unlikely that their adipose vasculature is profoundly deficient, but it is reasonable to hypothesize that the vasculature support of rapidly enlarging white adipose tissue may prove marginal, rendering it susceptible to intermittent local hypoxia in times of rapid lipid accumulation.…”

Intermedin

“…The effect of IMD on body weight may result from a nonspecific effect resulting from the antiangiogenic therapies, because systemic treatment with angiogenesis inhibitor has been shown to result in reduced food intake and bodyweight reduction, as well as adipose tissue loss in various models of obesity. 34,35 We used 2 additional human tumor models and anti-IMD antibodies to further evaluate this tumor inhibitory effect. SW620 and A549 xenograft tumor models were established in nude mice and treated with IMD 17-47 or anti-IMD.…”

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial

“…In preclinical models of obesity and diabetes, MetAP2 inhibitors produce weight loss characterised by markedly reduced adiposity and increased glycaemic control, as well as transiently reduced food intake [1,2]. The MetAP2 inhibitor beloranib has demonstrated consistent and substantial weight loss and glucose-lowering effects in clinical studies of general obesity, hypothalamicinjury-associated obesity and Prader-Willi syndrome (PWS) [3][4][5][6].…”