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Chronic Treatment With a Melanocortin-4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques

KIEVIT, Paul ; HALEM, Heather ; MARKS, Daniel L ; DONG, Jesse Z ; GLAVAS, Maria M ; SINNAYAH, Puspha ; PRANGER, Lindsay ; COWLEY, Michael A ; GROVE, Kevin L ; CULLER, Michael D

Diabetes (New York, N.Y.), 2013, Vol.62 (2), p.490-497 [Peer Reviewed Journal]

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Title:
Chronic Treatment With a Melanocortin-4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques
Author: KIEVIT, Paul ; HALEM, Heather ; MARKS, Daniel L ; DONG, Jesse Z ; GLAVAS, Maria M ; SINNAYAH, Puspha ; PRANGER, Lindsay ; COWLEY, Michael A ; GROVE, Kevin L ; CULLER, Michael D
Subjects: Obesity ; Diabetes. Impaired glucose tolerance ; Biological and medical sciences ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Metabolic diseases ; Medical sciences ; Endocrine pancreas. Apud cells (diseases) ; Adiposity - drug effects ; Obesity - drug therapy ; Insulin Resistance ; Diet, High-Fat - adverse effects ; Male ; Cardiovascular System - drug effects ; Macaca mulatta ; Receptor, Melanocortin, Type 4 - agonists ; Weight Loss - drug effects ; alpha-MSH - therapeutic use ; Anti-Obesity Agents - therapeutic use ; Eating - drug effects ; Glucose Intolerance - drug therapy ; Heart Rate - drug effects ; Animals ; Obesity - etiology ; Blood Pressure - drug effects ; alpha-MSH - analogs & derivatives ; Chronic Disease ; Peptides - therapeutic use ; Weight loss ; Physiological aspects ; Insulin resistance ; Genetic aspects ; Research ; Intermedin ; Risk factors ; Index Medicus ; Abridged Index Medicus ; Obesity Studies
Is Part Of: Diabetes (New York, N.Y.), 2013, Vol.62 (2), p.490-497
Description: The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.
Publisher: Alexandria, VA: American Diabetes Association
Language: English
Identifier: ISSN: 0012-1797
EISSN: 1939-327X
DOI: 10.2337/db12-0598
PMID: 23048186
CODEN: DIAEAZ

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Chronic Treatment With a Melanocortin-4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques

KIEVIT, Paul ; HALEM, Heather ; MARKS, Daniel L ; DONG, Jesse Z ; GLAVAS, Maria M ; SINNAYAH, Puspha ; PRANGER, Lindsay ; COWLEY, Michael A ; GROVE, Kevin L ; CULLER, Michael D

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