Fullness-signaling gut peptide fragment (Peptide YY 13-36)

What this is

Peptide YY (13–36) is a 24-amino acid fragment cut from the C-terminal end of Peptide YY (PYY), a gut hormone that signals fullness after a meal. PYY itself is a 36-residue peptide first isolated by Tatemoto and Mutt in 1980 from porcine intestinal tissue and named for the tyrosine (Y) residues at both ends of the molecule. The 13–36 fragment retains the C-terminal portion responsible for activating a specific receptor subtype — the presynaptic Y2 receptor — and has been used as a key research tool to dissect how the NPY peptide family talks to the nervous system. The sequence shown here (SPEELSRYYASLRHYLNLVTRQRY) is identical across canine, mouse, porcine, and rat species, which is why this card covers all four — the stored sequence does not include the C-terminal amide (-NH₂) that the bioactive fragment carries in vivo and that is required for receptor binding.

History

Peptide YY belongs to the pancreatic polypeptide (PP) fold family, a group that also includes neuropeptide Y (NPY) and pancreatic polypeptide (PP). These three peptides share a characteristic hairpin fold and approximately 70% sequence identity between PYY and NPY, arising through ancient gene duplication events.

The 13–36 fragment came to prominence in 1986 when Wahlestedt and colleagues (Regulatory Peptides, 1986) used it as a pharmacological tool to test how much of the PYY and NPY sequence is needed for different biological effects. By showing that this C-terminal fragment reproduced the prejunctional suppression of noradrenaline release but not the direct vascular constriction of the full-length peptide, Wahlestedt, Yanaihara, and Håkanson established the first functional distinction between what they named the Y1 receptor (requiring the full peptide sequence, postjunctional) and the Y2 receptor (activated selectively by C-terminal fragments, prejunctional). That Y1/Y2 classification has since become the foundation of NPY receptor pharmacology.

What it does

In the body, PYY is released from endocrine L-cells lining the distal small intestine and colon in response to food — particularly fat — and acts as a satiety signal. Circulating PYY rises within about 15 minutes of eating and remains elevated for hours, helping to reduce appetite and slow gastric emptying (Karra, Chandarana, and Batterham, The Journal of Physiology, 2009).

The 13–36 fragment specifically activates presynaptic Y2 receptors, where it suppresses the release of noradrenaline from sympathetic nerve terminals — the effect characterized by Wahlestedt and colleagues (1986). This presynaptic Y2 activity mirrors what the larger PYY3–36 fragment (the predominant form circulating after meals) does in the hypothalamic arcuate nucleus: by binding Y2 receptors on NPY/AgRP neurons, it inhibits the "hunger-driving" NPY circuit and reduces food intake (Karra et al., 2009; Silva et al., Gut and Liver, 2012).

Because PYY(13–36) selectively engages the Y2 subtype while sparing the Y1 and Y5 receptors, it has been used in receptor characterization studies and as a reference ligand for mapping Y2 receptor distribution in tissues.

Evidence

• Human: PYY as a whole (including the 3–36 and 13–36 fragments as research tools) has been extensively studied in humans; infusion of PYY3–36 at postprandial concentrations reduced appetite and caloric intake in both lean and obese subjects in controlled trials (reviewed in Karra et al., The Journal of Physiology, 2009). PYY(13–36) itself is primarily a laboratory research fragment and has not been administered as a standalone human intervention in registered clinical trials.
• Animal: The original presynaptic Y2 activity of PYY(13–36) was characterized in smooth muscle and vas deferens preparations in vitro (Wahlestedt et al., Regulatory Peptides, 1986). Mice lacking PYY become hyperphagic and obese, and mice lacking the Y2 receptor do not respond to the anorectic effects of PYY3–36, establishing the receptor dependency of these effects in vivo (Karra et al., 2009).
• In vitro: PYY(13–36) reproduces the presynaptic suppression of electrically evoked noradrenaline release in sympathetic nerve preparations, establishing Y2 selectivity over Y1 (Wahlestedt et al., 1986).

Known effects

• Presynaptic Y2 receptor activation — Pharmacological (the defining activity of this fragment; established in vitro)
• Suppression of noradrenaline release — Demonstrated at sympathetic neuroeffector junctions (Wahlestedt et al., 1986)
• Appetite modulation (via parent peptide PYY family) — Preclinical and human evidence for the PYY/Y2 axis broadly; the 13–36 fragment is primarily a research tool rather than a clinical compound

Mechanism

PYY(13–36) binds selectively to the Y2 receptor, a Gi/o-coupled class A GPCR expressed presynaptically on NPY-containing neurons and on sympathetic nerve terminals. Activation of Y2 reduces intracellular cAMP and suppresses voltage-gated calcium channels at the presynaptic terminal, thereby inhibiting neurotransmitter (noradrenaline or NPY) release. In the hypothalamic arcuate nucleus — a region accessible to circulating gut hormones — Y2 activation on NPY/AgRP neurons dampens the orexigenic NPY signal and downstream food-seeking behavior.

The full-length PYY(1–36) activates Y1, Y2, and Y5 receptor subtypes. Cleavage of the two N-terminal residues by DPP-IV generates PYY(3–36), which is Y2-selective. PYY(13–36), lacking additional N-terminal sequence, retains this Y2 selectivity while losing residues that contribute to Y1/Y5 affinity, making it pharmacologically cleaner for dissecting presynaptic Y2 biology (Wahlestedt et al., 1986; Karra et al., 2009).

Regulatory status

• US: Not an approved drug. A research peptide and pharmacological reference compound. No registered IND for this specific fragment.
• WADA: No specific listing for PYY(13–36). The parent hormone PYY is an endogenous gut peptide; no prohibition of exogenous PYY family fragments has been listed.
• Clinical development: PYY-based therapeutics (analogs of the 3–36 form) have entered Phase I trials for obesity, but the 13–36 fragment itself is not in clinical development as a standalone compound.

Related peptides

• PYY (3–36) — The predominant circulating satiety form of peptide YY; more Y2-selective than PYY(1–36) due to DPP-IV cleavage; the form studied in human appetite trials.
• Neuropeptide Y (NPY) — The closest structural relative of PYY; 70% sequence identity; the key hunger-promoting signal in the hypothalamus that PYY(13–36) inhibits indirectly at the presynaptic Y2 level.
• Pancreatic polypeptide (PP) — Third member of the PP-fold family; primarily Y4-selective; released from the pancreas rather than gut L-cells.