Setmelanotide is a selective MC4R agonist designed to treat genetic obesity syndromes (e.g., POMC, PCSK1, LEPR, Bardet-Biedl). It activates the melanocortin-4 receptor to suppress appetite and enhance energy expenditure.
Setmelanotide
Also known as: RM-493; BIM-22493; Imcivree
Overview
Benefits
- Appetite suppression
- Weight loss
- Improved metabolism
- Energy balance
- Genetic obesity management
Consider This Peptide If You Want To
- Reduce appetite and improve energy balance
- Manage genetic or metabolic obesity
Dosage & Administration
Dosage Guidelines
Recommended Dosage
• Amount:1 mg
• Frequency:daily
• Duration:2 weeks
• Rest Period:2 weeks
• Time of Day:morning
• Ingestion:subcutaneous
Administration Routes:Subcutaneous
Research Findings on Dosage:
• Subcutaneous Administration:
◦ Commonly Reported Dosage: 1-3 mg once daily.
◦ Duration: 2 weeks
Mechanism of Action
Mechanism of Action
How this peptide works in the body
MC4R Activation:
Setmelanotide binds selectively to melanocortin-4 receptors (MC4R) in the hypothalamus, mimicking α-melanocyte-stimulating hormone (α-MSH). This receptor activation initiates neuronal signaling that suppresses appetite and enhances energy expenditure, directly addressing genetic obesity disorders caused by POMC, PCSK1, and LEPR deficiencies.
cAMP Pathway Modulation:
MC4R activation stimulates adenylyl cyclase, increasing cyclic adenosine monophosphate (cAMP) levels and activating protein kinase A (PKA). This cascade enhances neuronal excitability in appetite-suppressing pathways, reducing food intake while increasing metabolic activity.
Neurotransmitter Regulation:
Setmelanotide enhances pro-opiomelanocortin (POMC)-derived α-MSH release, which binds MC4R to reduce hunger and promote satiety. Simultaneously, it inhibits agouti-related peptide (AgRP) neurons, which normally antagonize MC4R, preventing excessive appetite stimulation and reinforcing satiety signals.
Energy Balance:
Setmelanotide enhances lipolysis and thermogenesis by activating sympathetic nervous system pathways. This increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), driving energy expenditure through non-shivering thermogenesis. Concurrently, it reduces caloric intake by sustaining hypothalamic appetite suppression.
Specificity for MC4R:
Setmelanotide exhibits high affinity and selectivity for MC4R, avoiding off-target interactions with MC3R and MC5R, which minimizes cardiovascular risks associated with earlier MC4R agonists. This specificity ensures effective weight regulation without impacting blood pressure or heart rate.
Consider Stacking With
- Semaglutide/Tirzepatide
- Mazdutide
- AOD-9604
- PT-141
- Epitalon
- Livagen
- Tesofensine
Side Effects & Cautions
Common Side Effects
- Nausea, vomiting, injection site reactions, skin pigmentation, headache
Cautions
- Mood changes, depression, or suicidal ideation
- Monitor mood; avoid in uncontrolled psychiatric conditions
Rare Side Effects
- Rare sexual side effects
Research & References
Research Highlights
MC4R Selectivity: Demonstrated high potency and specificity, reducing hyperphagia and facilitating sustained weight loss in clinical trials.
Weight Loss Efficacy: Showed consistent reductions in body weight and improvements in metabolic markers in patients with genetic obesity syndromes.
Safety Profile: Maintains a favorable safety profile compared to previous MC4R-targeting therapies, with fewer cardiovascular side effects.
References
Collet TH, Dubern B, Mokrosinski J, et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency. Mol Metab. 2017;6(10):1321-1329
FDA Approval Letter for Imcivree (Setmelanotide). U.S. Food and Drug Administration. 2020
Kim GW, Lin JE, Blomain ES, Waldman SA. Antiobesity pharmacotherapy: new drugs and emerging targets. Clin Pharmacol Ther. 2014;95(1):53-66
Chen KY, Muniyappa R, Abel BS, et al. RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals. J Clin Endocrinol Metab. 2015;100(4):1639-1645
Muniyappa R, Chen K, Brychta R, et al. A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Effect of a Melanocortin Receptor 4 (MC4R) Agonist on Resting Energy Expenditure. Endocr Rev. 2014;35(3):S-70