Mechanism of Action
Y2 Receptor Selectivity
PYY3-36 selectively activates Y2 receptors (vs. Y1/Y4/Y5 for full-length PYY1-36). Y2 receptors are presynaptic autoreceptors on NPY/AgRP neurons in the arcuate nucleus of the hypothalamus. PYY3-36 binding reduces NPY release from arcuate neurons, decreasing the orexigenic drive. Simultaneously, anorexigenic POMC neurons are disinhibited, reducing appetite.
Vagal Signaling
PYY3-36 also acts on Y2 receptors expressed on vagal afferent neurons innervating the gastrointestinal tract. Vagal Y2 activation sends satiety signals to the nucleus tractus solitarius and hypothalamus. This peripheral-to-central mechanism is independent of the direct hypothalamic effect and may provide a longer-lasting satiety signal.
Research Summary
Satiety and Caloric Intake
ClinicalIV infusion of PYY3-36 in healthy subjects reduces food intake by approximately 33% at a buffet meal two hours post-infusion. In obese individuals, postprandial PYY levels are significantly blunted. Infusion of PYY3-36 reduces appetite scores and actual caloric intake in obese subjects comparably to lean controls.
Combination with Semaglutide
Phase 3Cagrilintide (an amylin/" class="wiki-internal-link">amylin analog) combined with semaglutide (GLP-1 agonist) and PYY3-36 analogs exploit complementary satiety pathways. The REDEFINE program for cagrisema (cagrilintide + semaglutide) showed 15-22% weight loss. Addition of a PYY analog to GLP-1/amylin combination may further enhance weight loss through Y2-mediated appetite suppression.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Appetite suppression research | 0.8 pmol/kg/min | 90-min IV infusion | Intravenous |
| SC analog (clinical trial) | 2.4 mg weekly | Once weekly | Subcutaneous |
Native PYY3-36 not approved. SC-stable analogs in Phase 3 for obesity.
Interactions
Safety Profile
PYY3-36 infusion causes nausea and headache at pharmacological doses, consistent with Y2 receptor activation in brainstem emetic circuits. These effects limit the dose that can be administered. SC-stable analogs optimized for reduced nausea are in clinical development. No significant cardiovascular or hepatic adverse effects identified.
References
- [1]Batterham RL et al. (2002). Gut hormone PYY(3-36) physiologically inhibits food intake. Nature, 418(6898), 650-654.
- [2]Batterham RL et al. (2003). Inhibition of food intake in obese subjects by peptide YY3-36. New England Journal of Medicine, 349(10), 941-948.