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: Clinton T Elfers, Christian L Roth
• Journal: Endocrinology (Endocrinology) Vol. 158 Issue 1 Pg. 41-55 (01 01 2017) ISSN: 1945-7170 [Electronic] United States
• PMID: 27849360 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by the Endocrine Society.

Chemical References

• Cinnamates
• Cyclohexanes
• Epoxy Compounds
• Leptin
• Receptor, Melanocortin, Type 4
• Sesquiterpenes
• melanocortin receptor type 4, rat
• Aminopeptidases
• methionine aminopeptidase 2
• Metalloendopeptidases
• CKD732

Topics

• Aminopeptidases (antagonists & inhibitors)
• Animals
• Body Temperature
• Body Weight
• Cinnamates (pharmacology, therapeutic use)
• Cyclohexanes (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Eating
• Epoxy Compounds (pharmacology, therapeutic use)
• Gene Expression
• Glucose Tolerance Test
• Hyperphagia (complications)
• Hypothalamus, Middle (injuries)
• Insulin Resistance
• Leptin (blood)
• Lipid Metabolism
• Liver (enzymology)
• Male
• Metalloendopeptidases (antagonists & inhibitors)
• Obesity (blood, drug therapy, etiology)
• Rats, Sprague-Dawley
• Rats, Transgenic
• Receptor, Melanocortin, Type 4 (genetics)
• Sesquiterpenes (pharmacology, therapeutic use)