Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques

Paul Kievit, Heather Halem, Daniel Marks, Jesse Z. Dong, Maria M. Glavas, Puspha Sinnayah, Lindsay Pranger, Michael A. Cowley, Kevin Grove, Michael D. Culler

Research output: Contribution to journalArticle

90 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)490-497
Number of pages8
JournalDiabetes
Volume62
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Receptor, Melanocortin, Type 4
Macaca mulatta
Insulin Resistance
Weight Loss
Diet
Heart Rate
Blood Pressure
Rodentia
Obesity
Eating
Melanocortins
Adiposity
Primates
Homeostasis
Body Weight
Pharmacology
Glucose
Peptides
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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; Dong, Jesse Z.; Glavas, Maria M.; Sinnayah, Puspha; Pranger, Lindsay; Cowley, Michael A.; Grove, Kevin; Culler, Michael D.

In: Diabetes, Vol. 62, No. 2, 02.2013, p. 490-497.

Research output: Contribution to journalArticle

Kievit, Paul ; Halem, Heather ; Marks, Daniel ; Dong, Jesse Z. ; Glavas, Maria M. ; Sinnayah, Puspha ; Pranger, Lindsay ; Cowley, Michael A. ; Grove, Kevin ; Culler, Michael D. / Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. In: Diabetes. 2013 ; Vol. 62, No. 2. pp. 490-497.
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