Neuropeptide Y: the brain's hunger & stress signal
A natural brain chemical that drives appetite, regulates the body's stress response, and controls energy use; used mainly as a lab research tool.
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 one of the most abundant neuropeptides in the mammalian brain and peripheral nervous system. It is a 36-amino-acid signaling peptide produced naturally by the body, found in particularly high concentrations in the hypothalamus, where it plays a central role in regulating hunger, energy use, and the brain's response to stress. The same 36-residue sequence is shared between the human and rat forms, and the sequence stored here carries a C-terminal amide group (–NH₂) that is not represented in the raw letters — this modification is characteristic of the active peptide and is required for receptor binding.
History
NPY belongs to the pancreatic polypeptide (PP) family alongside Peptide YY (PYY) and pancreatic polypeptide (PP). The family name reflects the peptides' shared C-terminal tyrosine amide and structural similarity. Receptor nomenclature for this family was standardized by the International Union of Pharmacology (IUPHAR), which designated the NPY/PYY/PP receptor subtypes Y1 through Y5 (Michel and colleagues, Pharmacological Reviews, 1998). NPY neurons in the arcuate nucleus of the hypothalamus emerge early in fetal development — work in rhesus macaques, a primate model closely resembling human neurodevelopment, documented their appearance around day 44 of gestation (Rønnekleiv and colleagues, eNeuro, 2025).
What it does
NPY acts broadly as an appetite-stimulating and stress-buffering signal in the brain. In the hypothalamus it promotes food intake and adjusts energy balance; in limbic areas including the amygdala it modulates the emotional and hormonal response to stress. Beyond the brain, NPY participates in gut-brain communication alongside related peptides PYY and pancreatic polypeptide — all three circulate as post-meal satiety signals and coordinate digestive function (Holzer and colleagues, Neuropeptides, 2012). A substantial body of work links NPY signaling to mood regulation, with reduced NPY tone associated with depressive and stress-related states in animal models (Morales-Medina and colleagues, Brain Research, 2010).
Evidence
- Human: NPY is an established endogenous peptide with well-characterized expression in human brain and peripheral tissues. Genetic variation at the NPBWR1 receptor locus — one of the receptors NPY can engage — has been associated with differences in facial-expression evaluation in humans, pointing to a role in emotional processing (Watanabe and colleagues, PLoS ONE, 2012). No registered clinical trials targeting NPY itself were identified in the dossier.
- Animal: NPY neurons in the arcuate hypothalamus of fetal rhesus macaques are documented to develop by gestational day 44 (Rønnekleiv and colleagues, eNeuro, 2025). Reduced hippocampal NPY signaling has been reported in animal models of depression and chronic stress (Morales-Medina and colleagues, Brain Research, 2010).
- In vitro: NPY's sequence YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY was confirmed by mass spectrometry in a proteomics characterization of the Tupaia belangeri (treeshrew) neuropeptidome, a species relevant to evolutionary studies of mammalian neuropeptide systems (Petruzziello and colleagues, Journal of Proteome Research, 2012).
Known effects
- Appetite and energy balance — Mechanistic / extensive preclinical; NPY is one of the most potent orexigenic (hunger-promoting) signals known from hypothalamic studies
- Stress resilience and HPA axis modulation — Preclinical; animal models link NPY tone to anxiety, depression-like behavior, and HPA reactivity (Morales-Medina and colleagues, 2010)
- Gut-brain signaling — Mechanistic; NPY participates in the enteric-hypothalamic axis alongside PYY and pancreatic polypeptide (Holzer and colleagues, 2012)
- Emotional processing — Human genetic association; NPBWR1 SNP associated with facial-expression evaluation differences (Watanabe and colleagues, 2012)
Mechanism
NPY acts through a family of G protein-coupled receptors, Y1 through Y5, whose nomenclature was formalized by IUPHAR (Michel and colleagues, 1998). The primary target assigned to this card is NPBWR1 (also known as GPR7), a class A GPCR expressed in the hypothalamus and amygdala. NPBWR1 was originally deorphanized using Neuropeptide B and Neuropeptide W as its principal cognate ligands (Singh and colleagues, British Journal of Pharmacology, 2006), and its roles span energy homeostasis, pain modulation, and emotional regulation (Sakurai, Frontiers in Endocrinology, 2013; Wojciechowicz and colleagues, International Journal of Molecular Sciences, 2021). The distribution and function of the NPB/W signaling system — the broader context in which NPBWR1 operates — has been reviewed in detail (Chottova Dvorakova, Frontiers in Physiology, 2018). In rodents only NPBWR1 is expressed, while humans also express the related receptor NPBWR2 (GPR8) (Wojciechowicz and colleagues, 2021).
Related peptides
- Peptide YY (PYY) — structurally related member of the PP-fold family; shares Y-receptor pharmacology with NPY and functions as a post-meal satiety signal released from gut L-cells
- Pancreatic polypeptide (PP) — third member of the PP-fold family; co-regulates energy balance and gut motility alongside NPY and PYY (Holzer and colleagues, Neuropeptides, 2012)
- Neuropeptide B (NPB) — primary cognate ligand of NPBWR1; modulates appetite, pain, and emotion through the same receptor this card is assigned to (Wojciechowicz and colleagues, 2021)
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.
Is NPY incorrectly matched to the NPBWR1 receptor, and should it instead point to the Y1/Y2 receptors that actually mediate its hunger and stress effects?
Fixing this annotation protects the integrity of any research or drug-discovery pipeline using this database, ensuring that hypotheses about NPY's biology actually target the receptors responsible for hunger, anxiety, and stress responses.
Could inhaled NPY reach the amygdala quickly enough to calm fear-circuit overactivation in PTSD, while bypassing the rest of the body to avoid side effects?
A nasal NPY spray could offer PTSD patients a rapid, side-effect-limited option for calming acute fear responses, filling a major gap in a disorder where current medicines are inadequate for many people.
Does the early appearance of NPY neurons in the fetal primate brain create a critical window where nutrition permanently programs how strongly hunger signals operate throughout life?
If early-life programming of NPY circuits explains why some adults resist even the best current obesity drugs, it would shift the focus of obesity prevention toward pregnancy and infancy, the phase when the biological set-point for hunger is first established.
Could swapping the natural amide cap at the end of NPY for a chemically similar but more durable synthetic group extend its lifetime in the body without losing receptor activity?
A longer-lasting NPY analog could finally make this well-studied stress and hunger hormone into a practical drug candidate for PTSD, anxiety, or obesity, where rapid degradation has historically blocked therapeutic development.
Does this particular form of NPY activate the Y5 receptor less strongly than standard NPY, making it a natural tool for studying which receptor is really responsible for NPY-driven overeating?
Having a natural NPY variant that skips one receptor would let researchers precisely map which NPY receptor causes which type of hunger, informing the design of targeted drugs that suppress appetite without the broad effects of blocking all NPY receptors.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.90739506483078 | boltz-2 |
| ranking score | 0.8561233878135681 | 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{pep10716,
sequence = {YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY},
target = {npbwr1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}