PYY(3-36): gut hormone that tells the brain you're full (animal form)

What this is

Peptide YY (3-36) — commonly abbreviated PYY(3-36) — is a gut hormone fragment that tells the brain a meal has been eaten. It is released by L-cells lining the lower small intestine and colon in proportion to the caloric content of a meal, and it suppresses appetite for several hours afterward. This card carries the canine, mouse, porcine, and rat sequence, which differs from the human form at two amino acid positions; the biological activity and receptor pharmacology are otherwise conserved across these species (Karra and colleagues, 2009). The stored 34-residue sequence ends in a free arginine-tyrosine dipeptide, but the active form carries a C-terminal amide on the terminal tyrosine (–NH₂) that is not represented in the raw sequence shown here.

History

The parent peptide, PYY(1-36), was first isolated from porcine upper intestinal tissue by Tatemoto in 1982. Its name reflects its two terminal tyrosine residues: "peptide YY," where Y is the single-letter code for tyrosine. PYY belongs to the PP-fold family alongside neuropeptide Y (NPY) and pancreatic polypeptide (PP), sharing characteristic secondary structure and receptor pharmacology with both (Ballantyne, 2006). The shorter 3-36 fragment arises naturally in circulation: the enzyme dipeptidyl peptidase IV (DPP-IV) cleaves the first two residues from PYY(1-36) rapidly after secretion, making PYY(3-36) the dominant circulating form postprandially (Vincent and le Roux, 2008). The key role of this fragment in appetite suppression was established by Batterham and colleagues in a landmark 2002 paper in Nature and confirmed in obese humans the following year (Batterham and colleagues, 2003).

What it does

After a meal, rising blood levels of PYY(3-36) act as a satiety signal that crosses into the brain and reduces the drive to eat. In a controlled human infusion study, peripheral administration of PYY(3-36) at concentrations matching normal postprandial levels reduced food intake by approximately 33% over 24 hours compared with placebo (Batterham and colleagues, 2002). A follow-up study in obese individuals found a comparable ~30% reduction in caloric intake at a subsequent buffet meal (Batterham and colleagues, 2003). Beyond acute meal termination, obese individuals have been found to have attenuated postprandial PYY release and lower fasting PYY levels compared with lean controls, suggesting that a blunted PYY response may contribute to difficulty maintaining satiety in obesity (le Roux and colleagues, 2006). PYY(3-36) also appears relevant to protein-mediated satiation specifically; dietary protein is among the strongest triggers for PYY secretion, and PYY-knockout mice are resistant to the satiating effect of high-protein diets (Batterham and colleagues, 2006).

Evidence

• Human: Intravenous infusion of PYY(3-36) at postprandial concentrations reduced 24-hour food intake by ~33% in lean volunteers and ~30% in obese subjects (Batterham and colleagues, 2002; Batterham and colleagues, 2003). An intranasal formulation trialed in 133 obese adults did not achieve significant weight loss over 12 weeks and was poorly tolerated at the highest dose, with 59% of participants in the 600 µg three-times-daily group discontinuing due to nausea and vomiting (Gantz and colleagues, 2007).
• Animal: Peripheral injection of PYY(3-36) reduced food intake dose-dependently in rats and mice; this effect was absent in Y2 receptor-knockout mice, establishing Y2R as necessary for the anorectic response (Batterham and colleagues, 2002). Non-human primates showed similar acute appetite suppression (Karra and colleagues, 2009).
• In vitro / mechanistic: PYY(3-36) selectively activates the Y2 receptor subtype, in contrast to the full-length PYY(1-36), which also binds Y1 and Y5 receptors. Y2 receptor expression is highest in the arcuate nucleus of the hypothalamus, where PYY(3-36) acts to inhibit NPY/AgRP neurons (orexigenic) while indirectly promoting POMC neuron activity (anorexigenic) (Batterham and colleagues, 2002; Karra and colleagues, 2009).

Known effects

• Appetite suppression / reduced food intake — Demonstrated in controlled human infusion studies (Batterham and colleagues, 2002; 2003)
• Satiety signaling proportional to caloric load — Postprandial PYY(3-36) release correlates with meal calorie content (Vincent and le Roux, 2008)
• Protein-driven satiation — PYY appears required for the satiating effect of high-protein diets in rodent models (Batterham and colleagues, 2006)
• Attenuated in obesity — Blunted postprandial PYY release and lower fasting levels observed in obese versus lean individuals (le Roux and colleagues, 2006)
• Rapid in vivo degradation — PYY(3-36) is further cleaved at the C-terminus in circulation, producing an inactive PYY(3-34) fragment; this short half-life limits the duration of appetite suppression (Toräng and colleagues, 2015)

Safety signals

The main tolerability concern identified in human studies is gastrointestinal: nausea was dose-limiting in the intranasal trial by Gantz and colleagues (2007), with more than half of participants at the highest intranasal dose discontinuing treatment due to nausea and vomiting. No serious adverse safety signals beyond GI side effects were reported in published intervention studies reviewed by Silva and Bloom (2012) and Karra and colleagues (2009). The peptide's rapid degradation in vivo limits systemic exposure, which may constrain both therapeutic duration and off-target risk.

Regulatory status

• US: Not approved by the FDA. Investigated as a potential anti-obesity therapeutic but no approved product exists. Research tool compound.
• EU: Not approved by the EMA.
• WADA: Not listed as a prohibited substance at the time of the most recent sources reviewed.

Mechanism

PYY(3-36) is a selective Y2 receptor (NPY2R) agonist. The Y2 receptor is a Gi-coupled class A GPCR; its activation inhibits adenylyl cyclase, reducing intracellular cAMP and suppressing neuronal excitability. In the arcuate nucleus of the hypothalamus — where Y2 receptor expression is densest — PYY(3-36) binding inhibits the orexigenic NPY/AgRP neurons that would otherwise promote hunger, and secondarily disinhibits pro-opiomelanocortin (POMC) neurons that generate satiety signals. This hypothalamic arc represents the primary central mechanism for PYY(3-36)'s food intake effect (Batterham and colleagues, 2002; Karra and colleagues, 2009). Peripheral Y2 receptors on vagal afferents in the gut wall may contribute an additional satiety relay to the brainstem (Silva and Bloom, 2012).

The non-human sequence stored in this card (canine, mouse, porcine, rat) differs from human PYY at position 3 (Ala here vs. Ile in human) and position 18 (Ser here vs. Asn in human). Rat, mouse, dog, and pig share this identical sequence. Because most rodent pharmacology studies use endogenous PYY matching this non-human form, the animal evidence for appetite suppression maps directly to this card's sequence.

Open questions

• No oral or long-acting formulation of PYY(3-36) has been validated in humans; the rapid degradation to inactive PYY(3-34) (Toräng and colleagues, 2015) is a central development challenge.
• Whether chronic PYY(3-36) administration preserves its anorectic potency or induces receptor desensitization has not been established in long-term human trials.
• The relative contribution of central (arcuate) versus peripheral (vagal) Y2 receptor signaling to the observed food intake reduction remains incompletely characterized.
• Combination with GLP-1 receptor agonists has shown additive effects in preclinical models; clinical translation has not been published for the non-human-sequence form specifically.

Related peptides

• PYY(1-36) — the full-length parent peptide, non-selective across Y1, Y2, and Y5 receptors; the circulating precursor that DPP-IV converts to PYY(3-36).
• Neuropeptide Y (NPY) — shares ~70% sequence identity and the PP-fold structure with PYY; a central orexigenic neuropeptide whose arcuate NPY/AgRP neurons are the direct target of PYY(3-36)'s inhibitory action.
• See also: GLP-1 — the other major L-cell satiety hormone co-released with PYY(3-36) after meals.