title: Robust Reductions of Excess Weight and Hyperphagia by Beloranib in Rat Models of Genetic and Hypothalamic Obesity.
abstract: Hypothalamic lesions or deficient melanocortin (MC) signaling via MC4 receptor (MC4r) mutations often lead to hyperphagia and severe treatment-resistant obesity. We tested the methionine aminopeptidase 2-inhibitor beloranib (ZGN-440) in 2 male rat models of obesity, one modeling hypothalamic obesity with a combined medial hypothalamic lesion (CMHL) and the other modeling a monogenic form of obesity with MC4r mutations (MC4r knockout [MC4rKO]). In CMHL rats (age 3 months), postsurgery excess weight gain was significantly inhibited (ZGN-440, 0.2 ± 0.7 g/d; vehicle, 3.8 ± 0.6 g/d; P < 0.001) during 12 days of ZGN-440 treatment (0.1 mg/kg daily subcutaneously) together with a 30% reduction of daily food intake vs vehicle injection. In addition, ZGN-440 treatment improved glucose tolerance and reduced plasma insulin, and circulating levels of α-melanocyte stimulating hormone were increased. Serum lipid levels did not differ significantly in ZGN-440-treated vs vehicle-treated rats. Similar results were found in MC4rKO rats: ZGN-440 treatment (14-21 d) was associated with significant reductions of body weight gain (MC4rKO, -1.7 ± 0.6 vs 2.8 ± 0.4 g/d; lean wild-type controls, -0.7 ± 0.2 vs 1.7 ± 0.7 g/d; ZGN-440 vs vehicle, respectively), reduction of food intake (MC4rKO, -28%; lean controls, -7.5%), and insulin resistance, whereas circulating levels of interleukin-1β did not change. In both obesity models, body temperature and locomotor activity were not affected by ZGN-440 treatment. In conclusion, the robust reduction of body weight in response to ZGN-440 observed in rats with severe obesity is related to a strong reduction of food intake that is likely related to changes in the central regulation of feeding.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101; and.
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Elfers
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98101; and.|Division of Endocrinology, Department of Pediatrics, University of Washington, Seattle, Washington 98105.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Roth
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D001831:Body Temperature; D001835:Body Weight; D002934:Cinnamates / Q000494:pharmacology / Q000627:therapeutic use*; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004435:Eating; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression; D005951:Glucose Tolerance Test; D006963:Hyperphagia / Q000150:complications; D007033:Hypothalamus, Middle / Q000293:injuries*; D007333:Insulin Resistance; D020738:Leptin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002934:Cinnamates; D003510:Cyclohexanes; D004852:Epoxy Compounds; D020738:Leptin; D044105:Receptor, Melanocortin, Type 4; D012717:Sesquiterpenes; C000613745:melanocortin receptor type 4, rat; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; C487952:CKD732