Chemical Identity

Property	Value
Name	Neuropeptide Y
Gene	NPY (chromosome 7p15.3)
Sequence	Tyr-Pro-Ser-Lys-Pro-Asp-Asn-Pro-Gly-Glu-Asp-Ala-Pro-Ala-Glu-Asp-Met-Ala-Arg-Tyr-Tyr-Ser-Ala-Leu-Arg-His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr-NH₂
Abbreviation	YPSKPDNPGEDAPAEDLARYYSALRHYINLITRQRY-NH₂
Length	36 amino acids
Chemical Formula	C₁₈₇H₂₈₃N₅₅O₅₇
Molecular Weight	4253.8 Da
C-terminal	Amidated
PDB Structures	1FME (NMR), 1QNJ (NMR)

Distribution

Central Nervous System

• Hypothalamus: Arcuate nucleus (AgRP/NPY neurons), paraventricular nucleus
• Brainstem: Nucleus tractus solitarius, locus coeruleus
• Cortex: Widespread cortical expression
• Hippocampus: Memory and learning circuits

Peripheral Nervous System

• Sympathetic neurons: Co-localized with norepinephrine
• Enteric neurons: GI motility regulation
• Adrenal medulla: Co-secreted with epinephrine

Receptors

Receptor	Gene	Distribution	Primary Effects
Y1 (NPY1R)	NPY1R	Hypothalamus, cortex, hippocampus	Appetite stimulation, anxiety
Y2 (NPY2R)	NPY2R	Hypothalamus, hippocampus, GI	Appetite suppression, memory
Y4 (NPY4R)	NPY4R	Pancreas, intestine	Satiety, pancreatic secretion
Y5 (NPY5R)	NPY5R	Hypothalamus	Potent appetite stimulation
Y6 (NPY6R)	Pseudo-gene	Non-functional in humans	—

Physiological Functions

Appetite Regulation

Fasting → ↑ AgRP/NPY neurons (arcuate nucleus)
    → NPY release → Y1/Y5 receptors (hypothalamus)
    → ↑ Appetite, ↑ Food intake
    → ↓ Energy expenditure

Feeding → ↓ NPY release
    → Leptin, CCK, PYY signal satiety
    → ↓ Appetite

Stress Response

• Co-released with norepinephrine from sympathetic neurons
• Anxiolytic: Central NPY reduces anxiety
• Stress resilience: High NPY expression correlates with stress resilience
• PTSD: Low CSF NPY levels in PTSD patients

Other Functions

• Circadian rhythms: NPY in suprachiasmatic nucleus
• Memory: Hippocampal NPY modulates learning
• Cardiovascular: Vasoconstriction (peripheral)
• GI motility: Modulates enteric nervous system

Clinical Significance

Obesity

• NPY is the most potent known appetite stimulant
• AgRP/NPY neurons are inhibited by leptin
• Therapeutic target: Y5 receptor antagonists (investigational)

Eating Disorders

• Anorexia nervosa: Elevated CSF NPY levels
• Bulimia nervosa: Altered NPY signaling
• Prader-Willi syndrome: Dysregulated NPY/AgRP pathway

Stress-Related Disorders

• PTSD: Low CSF NPY, high NPY may be protective
• Depression: Altered NPY receptor expression
• Anxiety: Y1/Y5 receptor polymorphisms

Therapeutic Approaches

Target	Drug/Strategy	Status
Y5 antagonist	Velneperit	Phase II (discontinued)
Y5 antagonist	L-152,804	Preclinical
Y1 agonist	NPY analogs	Research
AgRP antagonist	Anti-AgRP antibodies	Research

Biosynthesis

1. Gene: NPY (chromosome 7p15.3)
2. Prepro-NPY (97 aa) → Signal peptide cleavage
3. Pro-NPY (69 aa) → Prohormone convertases
4. NPY (36 aa) + Peptide YY (36 aa) — co-derived from PYY gene? No, separate genes
5. Storage: Large dense-core vesicles
6. Release: Activity-dependent exocytosis

Manufacturing

• SPPS (Fmoc): Standard solid-phase synthesis
• C-terminal amidation: Required for biological activity
• Purification: RP-HPLC
• Characterization: Mass spectrometry, NMR

References

1. Lecklin A, et al. “Neuropeptide Y and feeding.” Pharmacology & Therapeutics 70:151-202, 1996. doi:10.1016/S0163-7258(97)00059-4
2. Kalra SP, Kalra PS. “NPY and energy homeostasis.” Peptides 25:407-412, 2004.
3. Heilig M. “The NPY system in stress, anxiety, and depression.” Neuropeptides 38:213-224, 2004.
4. Batterham RL, et al. “PYY modulation of feeding.” Journal of Clinical Investigation 112:1674-1681, 2003.
5. Kuo LE, et al. “Neuropeptide Y acts directly in the periphery to affect blood pressure.” Hypertension 49:1399-1404, 2007.