Neuropeptide Y: brain chemical that drives hunger and stress responses
A natural signaling peptide found throughout the brain and nervous system that stimulates appetite, regulates stress, and controls blood vessel tone; this is the sheep version, used as a lab research tool.
- Class
- Endogenous neuropeptide — ovine (sheep) form
- Status
- No approved therapeutic status identified in attached sources
- Main caveat
- Source file provides the ovine amino-acid sequence and a single 1989 structural characterization reference only. No efficacy, safety, mechanism, or clinical data are attached to this card.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Neuropeptide Y (NPY) is a 36-amino acid signaling peptide that is one of the most abundant neuropeptides in the mammalian brain and peripheral nervous system. Found in virtually all vertebrates, it acts as a chemical messenger that regulates hunger, stress responses, sleep, and blood vessel tone. The sequence stored here is the sheep (Ovis aries) form of NPY; sheep NPY differs from human and rat NPY at position 10 (Asp instead of Glu) and shares Leu at position 17 with pig and bovine NPY, making it one of three distinct mammalian structural variants (Sillard and colleagues, 1989).
History
NPY was first isolated and characterized in the early 1980s as part of a broader effort to describe the neuropeptide Y peptide family, which also includes peptide YY (PYY) and pancreatic polypeptide (PP). The sheep-specific sequence was characterized by Sillard and colleagues (1989, FEBS Letters), who found it differed from the six previously described mammalian forms at position 10, establishing three structural classes of mammalian NPY. Interest in NPY's receptor system expanded substantially after the deorphanization of GPR7 and GPR8 as the receptors for the related neuropeptides B (NPB) and W (NPW) — receptors now designated NPBWR1 and NPBWR2 (Singh and colleagues, 2006, British Journal of Pharmacology).
What it does
NPY acts as a potent orexigenic (appetite-stimulating) signal in the hypothalamus, promoting food intake and contributing to energy balance regulation. It also functions as an endogenous "anti-stress" peptide: central NPY signaling is recruited in response to stressors to help restore homeostasis, suppressing the HPA axis and inhibiting the release of stress hormones ACTH and cortisol. Beyond hunger and stress, NPY participates in regulating sleep and in sympathetic control of blood vessel tone — NPY released from sympathetic nerves contributes to vasoconstriction in the skin. NPY has five recognized receptor subtypes across the central and peripheral nervous system (Y1R–Y5R).
Evidence
- Human: NPY is an endogenous peptide well-established in human physiology. Genetic variation in the NPBWR1 receptor — the receptor family this card links NPY to — has been associated with individual differences in social cognition; a single nucleotide polymorphism of NPBWR1 influenced evaluation of facial expressions in a human study (Watanabe and colleagues, 2012, PLoS ONE). No human clinical trials using exogenous NPY as a therapeutic have been identified in the dossier.
- Animal: Animal studies have established NPY as a key hypothalamic regulator of food intake and stress responses. NPY's roles in circadian regulation, sleep promotion, and HPA axis suppression are supported by rodent and other vertebrate models.
- In vitro: Structural-activity relationship (SAR) work on non-peptidic NPBWR1 (GPR7) antagonists has characterized receptor binding properties at the NPBWR1 target (Guerrero and colleagues, 2013, Bioorganic & Medicinal Chemistry Letters).
Known effects
- Appetite stimulation (orexigenic) — Well-established in animal models; central NPY signaling promotes food intake.
- HPA axis suppression / anti-stress — Preclinical models; NPY inhibits ACTH and cortisol release.
- Sleep promotion — NPY promotes sleep in animal models.
- Sympathetic vasoconstriction — NPY participates in reflex cutaneous vasoconstriction; established across animal and human studies.
- Social cognition modulation — NPBWR1 SNP association with facial expression evaluation in humans (Watanabe and colleagues, 2012).
Mechanism
NPY's classical actions are mediated through five G protein-coupled receptor subtypes — Y1R, Y2R, Y3R, Y4R, and Y5R — distributed throughout the central and peripheral nervous system. This card's platform target assignment is NPBWR1 (GPR7), a class A GPCR originally deorphanized as the receptor for the structurally related neuropeptides B and W (NPB/NPW). NPB and NPW were identified as the cognate endogenous ligands for GPR7/NPBWR1; NPW mRNA is highly expressed in the substantia nigra and at moderate levels in the amygdala and hippocampus in humans (Singh and colleagues, 2006). The NPBWR1 system modulates energy homeostasis, inflammatory pain, and emotional processing (Sakurai, 2013, Frontiers in Endocrinology). A second receptor, NPBWR2 (GPR8), is present in humans but absent in rodents (Wojciechowicz and colleagues, 2021, International Journal of Molecular Sciences). The Chottova Dvorakova (2018, Frontiers in Physiology) review maps the full distribution and functional scope of the NPB/W signaling network.
Safety signals
NPY is an endogenous peptide present throughout the nervous system in all mammalian species examined. No adverse safety signals from exogenous administration are documented in the dossier sources. The opioid receptor evolution context provided by Dreborg and colleagues (2008, PNAS) situates the NPBWR1 receptor within a broader GPCR family context; no safety-relevant off-target interactions at opioid receptors are characterized for NPY specifically in the dossier.
Related peptides
The NPY family includes structurally related peptides that share the PP-fold motif and act at overlapping receptor sets:
- Peptide YY (PYY) — a 36-amino acid gut hormone co-expressed with GLP-1 in intestinal L-cells; anorexigenic counterpart to NPY's orexigenic action.
- Neuropeptide B (NPB) — primary endogenous ligand for NPBWR1 (GPR7), the platform target assigned to this card (Singh and colleagues, 2006).
- Neuropeptide W (NPW) — co-ligand at NPBWR1 and NPBWR2 alongside NPB (Singh and colleagues, 2006).
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could the tiny difference between sheep and human NPY change how strongly it sticks to the NPBWR1 receptor?
If true, drug developers would know that animal model choice matters for NPY-related drugs, and they could design peptides that selectively favor human or sheep-like binding for better therapeutic control.
Could the same peptide that makes us hungry also prevent the adrenal gland from pumping out too much adrenaline?
If true, doctors could explore NPY-like drugs for high blood pressure or panic disorders by targeting the adrenal gland, using a well-known peptide in an entirely new way.
Could a single shorter side chain at position 10 change the bend angle of NPY and alter how its back half meets the receptor?
If true, scientists could redesign NPY-like drugs by tweaking hinge residues far from the binding surface, creating new variants with better receptor fit and fewer side effects.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8876509666442871 | boltz-2 |
| ranking score | 0.8559975028038025 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10715,
sequence = {YPSKPDNPGDDAPAEDLARYYSALRHYINLITRQRY},
target = {npbwr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}