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.
abstract: 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.
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Kievit
authors.forename: Heather
authors.initials: H
authors.lastname: Halem
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
authors.forename: Jesse Z
authors.initials: JZ
authors.lastname: Dong
authors.forename: Maria M
authors.initials: MM
authors.lastname: Glavas
authors.forename: Puspha
authors.initials: P
authors.lastname: Sinnayah
authors.forename: Lindsay
authors.initials: L
authors.lastname: Pranger
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D019440:Anti-Obesity Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002908:Chronic Disease; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D018149:Glucose Intolerance / Q000188:drug therapy; D006339:Heart Rate / Q000187:drug effects; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology; D010455:Peptides / Q000627:therapeutic use*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D015431:Weight Loss / Q000187:drug effects*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D019440:Anti-Obesity Agents; C579664:LY2112688; D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; C579663:setmelanotide; D000521:alpha-MSH