title: RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals.
abstract: BACKGROUND
  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
  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.
  
  
  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.
authors: Diabetes, Endocrinology, and Obesity Branch (K.Y.C., R.M., B.S.A., K.P.M., P.S., R.J.B., X.Z., M.R., T.L.P., M.L.R., M.C.S.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; Department of Molecular Physiology and Biophysics (R.D.C., B.L.P.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Rhythm Pharmaceuticals (K.M.G., L.H.T.V.d.P.), Boston, Massachusetts 02116.
authors: Kong Y
authors: KY
authors: Chen
authors: Ranganath
authors: R
authors: Muniyappa
authors: Brent S
authors: BS
authors: Abel
authors: Katherine P
authors: KP
authors: Mullins
authors: Pamela
authors: P
authors: Staker
authors: Robert J
authors: RJ
authors: Brychta
authors: Xiongce
authors: X
authors: Zhao
authors: Michael
authors: M
authors: Ring
authors: Tricia L
authors: TL
authors: Psota
authors: Roger D
authors: RD
authors: Cone
authors: Brandon L
authors: BL
authors: Panaro
authors: Keith M
authors: KM
authors: Gottesdiener
authors: Lex H T
authors: LH
authors: Van der Ploeg
authors: Marc L
authors: ML
authors: Reitman
authors: Monica C
authors: MC
authors: Skarulis
mesh_terms: D000328:Adult; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism* / Q000628:therapy; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D012146:Rest; D061217:Weight Reduction Programs; D055815:Young Adult; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D019440:Anti-Obesity Agents; D044105:Receptor, Melanocortin, Type 4; C579663:setmelanotide; D000521:alpha-MSH