Neuropeptide Y (NPY) is a 36-amino-acid peptide (MW ~4271.7 g/mol) that is one of the most abundant and widely distributed neuropeptides in the mammalian brain. It is a potent orexigenic (appetite-stimulating) peptide and plays critical roles in energy homeostasis, stress response, anxiety regulation, circadian rhythms, and cardiovascular function. NPY acts through a family of G-protein-coupled receptors (Y1, Y2, Y4, Y5). It is an endogenous reference molecule and a major drug target, not a therapeutic agent itself.
Category: Neuropeptide / Reference. Evidence rating: B (meaningful human data).
Clinical status: Endogenous neuropeptide. Not a drug. NPY receptor agonists and antagonists have been investigated for obesity, anxiety, and epilepsy but none are approved.
NPY signals through five receptor subtypes (Y1, Y2, Y4, Y5, Y6), all Gi/o-coupled GPCRs that inhibit adenylyl cyclase and reduce cAMP. Y1 receptors mediate anxiolytic effects and vasoconstriction. Y2 receptors serve as presynaptic autoreceptors regulating NPY release. Y5 receptors are the primary…
Safety considerations: Endogenous neuropeptide — not administered therapeutically; Peripheral NPY injection causes vasoconstriction and hypertension; Central NPY administration causes hyperphagia and weight gain in animal models.
Reviewed by the PeptideAtlas Editorial Team. Last reviewed: 2026-08-12.
Related peptides: Substance P, VIP (Vasoactive Intestinal Peptide), PACAP.
Compare: Neuropeptide Y vs Substance P, Neuropeptide Y vs VIP (Vasoactive Intestinal Peptide), Neuropeptide Y vs PACAP.
Yes — NPY is the most potent orexigenic (appetite-stimulating) peptide in the brain. NPY-producing neurons in the hypothalamic arcuate nucleus are activated by fasting and ghrelin, and NPY release into the paraventricular nucleus drives feeding behavior. This is an endogenous signal, not something taken as a supplement.
Yes. Higher baseline NPY levels are associated with stress resilience. Studies in military populations found that Special Forces soldiers have higher NPY levels than controls, and low NPY levels predict greater PTSD vulnerability after combat exposure.
Despite NPY being a potent appetite stimulant, Y5 receptor antagonists produced minimal weight loss in human trials (~1 kg over placebo). The redundancy of appetite-regulating systems (AgRP, ghrelin, melanocortins, GLP-1) means blocking a single orexigenic pathway is insufficient for meaningful weight loss.