RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals

Abstract

Context: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date.

Objective, design, and setting: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting.

Study participants and methods: Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods.

Results: RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed.

Conclusions: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.

Trial registration: ClinicalTrials.gov NCT01867437.

Figure 1.

Study design. Subjects received 72-hour infusions of RM-493 or placebo and then immediately were crossed over to the other treatment. In each period, after 48 hours of treatment, subjects entered the metabolic chamber at 8:00 am. REE_C was measured at 9:30 to 10:00 and 10:30 to 11:00 am, meals were at noon (40% of kcal), 6:30 pm (50% of kcal), and 9:00 pm (10% of kcal), exercise was at 5:00 to 5:30 pm, and REE_H was measured after subjects left the chamber.

Figure 2.

Effect of RM-493 vs placebo on REE_C at the end of the treatment period. REE_C was measured on the third treatment day of each treatment arm in the metabolic chamber at thermoneutrality with subjects in the resting, postabsorptive state as the mean of 2 30-minute rest periods. Individual data points and aggregate data with error bars are the overall mean ± 95% CI. P values indicate significance of treatment differences using a paired t test.