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

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

SUBMITTER: Chen KY

PROVIDER: S-EPMC4399297 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Chen Kong Y KY Muniyappa Ranganath R Abel Brent S BS Mullins Katherine P KP Staker Pamela P Brychta Robert J RJ Zhao Xiongce X Ring Michael M Psota Tricia L TL Cone Roger D RD Panaro Brandon L BL Gottesdiener Keith M KM Van der Ploeg Lex H T LH Reitman Marc L ML Skarulis Monica C MC

The Journal of clinical endocrinology and metabolism 20150212 4

<h4>Context</h4>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.<h4>Objective, design, and setting</h4>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.<h4>Stu ...[more]

PMID: 25675384

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Project description:Background and Aims:The unique demographic and dietary characteristics of modern Arabic population require development of a new predictive equation for the estimation of resting energy expenditure (REE). This study presented new equations characteristic to Saudi population. Methods:A set of predictive equations for REE was derived for 427 healthy male and female subjects (aged 18-57?±?14 years). REE was measured (REEm) by indirect calorimetry (IC) and predicted (REEp) using nine equations. REEp was compared with REEm to determine the predictive accuracy of these equations. Using IC and anthropometrics for stepwise linear regression analysis, a new set of equations to predict REE of men and women was developed. Accuracy of the new main equations was further tested in an external sample of 48 subjects (men?=?50%). Results:Using a number of parameters (bias, underprediction, overprediction, and % accurate prediction), our results suggested that almost all (9/9 in men and 7/9 in women) equations either underpredicted or overpredicted (2/9) REE. None of the already existing equations showed an acceptable REEp/REEm difference as low as 5% and an accurate prediction (?55%) at the individual level. Based on these findings, a new prediction equation (hereafter referred to as the Almajwal-Abulmeaty (AA) equation) was developed using this study's data, after a rigorous stepwise regression analysis using the following formula: REE?=?3832.955?+?AdjWt (kg)?×?48.037?-?Ht (cm)?×?30.642?+?gender?×?141.268?-?age (years)?×?4.525 [AdjWt is Adjusted body weight?=?(Wt?-?IBW)/4?+?IBW. IBW is Ideal body weight; for men IBW?=?(Ht(cm)?-?152.4)?×?1.0714)?+?45.36 and for women IBW?=?(Ht(cm)-152.4)?×?0.8928)?+?45.36]. The regression model accounted for approximately 70% of the variance in REEm (R 2?=?0.702). Conclusion:Previous equations likely over- or underpredicted REE. Therefore, the new predictive AA equations developed in this study are recommended for the estimation of REE in young to middle-aged Saudi men and women with different body mass indexes. Future research is also required for further clinical and cross-validation of these new equations.

Project description:Background/objectivesThe aim of this study was to compare resting energy expenditure (REE) measured (MREE) by indirect calorimetry (IC) and REE predicted (PREE) from established predictive equations in a large sample of obese Caucasian adults.Subjects/methodsWe evaluated 1851 obese patients (body mass index (BMI)>30 kg m-2) aged between 18a and 65 years. Data were obtained by comparing MREE with PREE, derived from different equations, within and between normal weight and obese groups. The mean differences between PREE and MREE as well as the accuracy prediction within ±10% level were investigated in the whole sample and in three subgroups, classified by BMI (Group 1=30-39.9 kg m-2; Group 2=40-49.9 kg m-2; Group 3>50 kg m-2).ResultsWe observed that FAO, Henry and Muller3 (body composition (BC)) equations provided good mean PREE-MREE (bias -0.7, -0.3 and 0.9%; root mean standard error (RMSE) 273, 263 and 269 kcal per day, respectively); HB and Henry equations were more accurate individually (57 and 56.9%). Only the Muller1 (BC) equation gave the lowest PREE-MREE difference (bias -1.7%; RMSE 228 kcal per day) in females, while Johnstone and De Lorenzo equations were the most accurate (55.1 and 54.8%). When the sample was split into three subgroups according to BMI, no differences were found in males; however, the majority of the equations included in this study failed to estimate REE in severely obese females (BMI>40 kg m-2). Overall, prediction accuracy was low (~55%) for all predictive equations, regardless of BMI.ConclusionsDifferent established equations can be used for estimating REE at the population level in both sexes. However, the accuracy was very low for all predictive equations used, particularly among females and when BMI was high, limiting their use in clinical practice. Our findings suggest that the validation of new predictive equations would improve the accuracy of REE prediction, especially for severely obese subjects (BMI>40 kg m-2).

Dataset Information

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

Publications

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

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