Agouti-Related Peptide

Chemical Identity

Property	Value
Name	Agouti-Related Peptide
Gene	AGRP (chromosome 16q12)
Length	113 amino acids (human)
C-terminal	Agouti-signaling sequence (81-113)
Key domain	C-terminal 13-aa cysteine-rich domain (MC3R/MC4R binding)
PDB Structures	1HYU (NMR)

Distribution

Central Nervous System

• Arcuate nucleus: Primary site (co-localized with NPY)
• Lateral hypothalamus: Projection target
• Paraventricular nucleus: Terminal field

Receptor Antagonism

Melanocortin System

POMC neuron → α-MSH → MC4R → ↓ Appetite (satiety)
     ↑                    ↑
Leptin          AgRP (antagonist) → ↑ Appetite (hunger)

Receptor Selectivity

Receptor	AgRP Affinity	α-MSH Affinity	Effect
MC3R	Antagonist	Agonist	Energy balance
MC4R	Antagonist	Agonist	Appetite suppression
MC1R	No effect	Agonist	Pigmentation

Physiological Functions

Appetite Stimulation

• AgRP is the most potent known appetite stimulant (more potent than NPY)
• Blocks MC4R → prevents α-MSH-mediated satiety
• Mechanism: Inverse agonist at MC4R (not just antagonist)

Energy Expenditure

• MC4R antagonism → ↓ Energy expenditure
• Contributes to positive energy balance
• AgRP knockout mice are lean and hypophagic

Fasting Response

• Fasting → ↑ AgRP expression (rapid, within hours)
• AgRP neurons are activated by ghrelin, inhibited by leptin
• Part of the starvation response circuit

Clinical Significance

Obesity

• AgRP is overexpressed in obesity
• MC4R mutations (most common monogenic obesity) → AgRP overactivity
• Therapeutic target: MC4R agonists (setmelanotide) counteract AgRP

Setmelanotide (Imcivree®)

• Mechanism: MC4R agonist → overcomes AgRP blockade
• Indications: POMC deficiency, PCSK1 deficiency, BBS
• Weight loss: 10-15% in responders

Manufacturing

• SPPS (Fmoc): C-terminal domain (81-113) synthesized
• Recombinant: Full-length in E. coli
• Purification: RP-HPLC, affinity chromatography

References

1. Ollmann MM, et al. “Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.” Science 278:135-138, 1997. doi:10.1038/35027588
2. Fan W, et al. “Melanocortin-3 receptors: a therapeutic target for appetite and weight regulation.” Journal of Clinical Investigation 107:211-218, 2001.
3. Cone RD. “Anatomy and regulation of the central melanocortin system.” Nature Neuroscience 8:571-578, 2005.
4. Kuo LE, et al. “AgRP and NPY: orexigenic neurons.” Trends in Endocrinology & Metabolism 16:27-32, 2005.
5. Butler AA, et al. “Melanocortin-4 receptors: therapeutic potential for obesity.” Pharmacology & Therapeutics 92:57-74, 2001.