o-(chloroacetylcarbamoyl)fumagillol and Obesity

The angiogenic inhibitor TNP-470 attenuates high-fat diet-induced obesity; however, it is not clear how the compound alters energy balance to prevent weight gain. Five-week-old C57BL/6J mice were fed high-fat diet (45% energy from fat) for 6.5 weeks and treated with TNP-470 (20 mg/kg body weight; n = 7) or vehicle (saline; n = 7). Control mice (n = 8) received standard chow and sham injection. TNP-470 mice initially gained weight, but by day 5 body weight was significantly less than high-fat fed (HFF) mice and not different from that of chow-fed mice, an effect maintained to the end of the study (28.6 ± 0.6 vs. 22.4 ± 0.6 and 22.2 ± 0.5 g). Percent body fat was reduced in TNP-470 compared to HFF mice, but was greater than that of chow mice (34.0 ± 1.5, 23.9 ± 1.5, and 17.0 ± 1.4%, P < 0.05). Food intake in TNP-470-treated mice was less (P < 0.05) than that in HFF mice by day 5 of treatment (2.5 ± 0.1 vs. 2.8 ± 0.1 g/mouse/day) and remained so to the end of the study. Twenty-four hours energy expenditure was greater (P < 0.05) in TNP-470 than HFF or chow mice (7.05 ± 0.07 vs. 6.69 ± 0.08 vs. 6.79 ± 0.09 kcal/kg/h), an effect not explained by a difference in energy expended in locomotion. Despite normalization of body weight, TNP-470 mice exhibited impaired glucose tolerance (area under the curve 30,556 ± 1,918 and 29,290 ± 1,584 vs. 24,421 ± 903 for TNP, HFF, and chow fed, P < 0.05). In summary, the angiogenic inhibitor TNP-470 attenuates weight gain in HFF mice via a reduction in caloric intake and an increase in energy expenditure.

Topics: Absorptiometry, Photon; Adiposity; Angiogenesis Inhibitors; Animals; Area Under Curve; Blood Glucose; Cyclohexanes; Diet, High-Fat; Energy Intake; Energy Metabolism; Glucose Tolerance Test; Mice; Mice, Inbred C57BL; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Sesquiterpenes; Weight Gain

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.

Topics: Adipocytes; Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Weight; Cell Size; Cinnamates; Cyclohexanes; Eating; Epoxy Compounds; Hypothalamus; Lithium Chloride; Male; Mice; Mice, Obese; Neuropeptides; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Rats; Rats, Inbred OLETF; Sesquiterpenes; Taste

Adipose tissue growth has been proposed to involve recruitment of new blood vessels. Here, we test the hypothesis that delivery of an angiogenesis inhibitor in mice may prevent diet-induced obesity, the most common type of obesity in humans. We show that systemic administration of a selective angiogenesis inhibitor, TNP-470 (AGM-1470), prevents obesity in high caloric diet-fed wt mice as well as in genetically leptin-deficient ob/ob mice. Inhibition of obesity in mice by TNP-470 involves a reduction of vascularity in the adipose tissue. This therapeutic strategy appears to selectively affect the growth of adipose tissue as measured by the ratio between total fat and lean body mass. Interestingly, the treatment with TNP-470 results in decreased serum levels of low-density lipoprotein cholesterol. Furthermore, insulin levels are reduced, which indicates increased insulin sensitivity, suggesting that angiogenesis inhibitors may prevent the development of type II diabetes. Our findings suggest that similarly to growth and organogenesis in other tissues, adipose tissue growth is dependent on angiogenesis. Our observations may have conceptual implications for the prevention of obesity and related disorders.

Topics: 3T3-L1 Cells; Adipose Tissue; Angiogenesis Inhibitors; Animals; Anti-Obesity Agents; Body Composition; Carbohydrate Metabolism; Cattle; Cornea; Cyclohexanes; Dietary Fats; Drug Evaluation, Preclinical; Endothelial Cells; Endothelium, Vascular; Insulin Resistance; Lipid Metabolism; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neovascularization, Physiologic; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Oxygen Consumption; Sesquiterpenes

Tumor growth is angiogenesis dependent. We hypothesized that nonneoplastic tissue growth also depends on neovascularization. We chose adipose tissue as an experimental system because of its remodeling capacity. Mice from different obesity models received anti-angiogenic agents. Treatment resulted in dose-dependent, reversible weight reduction and adipose tissue loss. Marked vascular remodeling was evident in adipose tissue sections, which revealed decreased endothelial proliferation and increased apoptosis in treated mice compared with controls. Continuous treatment maintained mice near normal body weights for age without adverse effects. Metabolic adaptations in food intake, metabolic rate, and energy substrate utilization were associated with anti-angiogenic weight loss. We conclude that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature.

Topics: Adipose Tissue; Angiogenesis Inhibitors; Angiostatins; Animals; Antineoplastic Agents; Biphenyl Compounds; Body Composition; Body Weight; Collagen; Cyclohexanes; Disease Models, Animal; Endostatins; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Obesity; Organic Chemicals; Peptide Fragments; Phenylbutyrates; Plasminogen; Sesquiterpenes; Thalidomide; Time Factors