The angiogenic inhibitor TNP-470 decreases caloric intake and weight gain in high fat fed mice

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±0.5g). 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. 24 h 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 (AUC 30556±1918 and 29290±1584 vs. 24421±903 for TNP, HFF, and chow fed, P<0.05). In summary, the angiogenic inhibitor TNP-470 attenuates weight gain in high fat fed mice via a reduction in caloric intake and an increase in energy expenditure.