NPY

Neuropeptide Y (NPY) is a 36-amino acid neuropeptide and one of the most abundant neuropeptides in the mammalian central nervous system. It is the most potent known appetite-stimulating (orexigenic) peptide, acting predominantly in the hypothalamus. NPY also regulates stress responses, anxiety, circadian rhythms, cardiovascular function, pain perception, and bone metabolism, making it a broadly important neuromodulator.

NPY signals through five GPCRs (Y1–Y5 in humans). Y1 and Y5 receptors in the arcuate and paraventricular nuclei of the hypothalamus mediate the primary orexigenic effects, increasing food intake and energy storage in white adipose tissue. Y2 and Y4 receptors have appetite-inhibiting roles, creating a complex regulatory balance. NPY is co-released with norepinephrine from sympathetic nerve terminals, modulating vasoconstriction and blood pressure. Chronic NPY elevation promotes adipogenesis, suppresses brown adipose tissue activation, and contributes to obesity maintenance.

NPY knockout mice on high-fat diets show reduced obesity, validating it as an obesity target. However, Y1 and Y5 receptor antagonists have largely failed in clinical trials due to off-target effects and limited efficacy. NPY's role in resilience to stress-induced depression and its anti-anxiety effects via Y1R have generated interest in NPY-based PTSD treatments. Intranasal NPY delivery has been explored in Phase 1 PTSD studies with preliminary positive results.