Peptide YY

Most Common Uses

Peptide YY is primarily studied for its role in appetite regulation and energy balance. Postprandial release of PYY, especially PYY3-36, inhibits food intake by acting on Y2 receptors in the hypothalamic arcuate nucleus, reducing neuropeptide Y release and promoting satiety.

Preclinical and human studies demonstrate that PYY3-36 infusions reduce short-term food intake by approximately 30% in some trials, though results vary. It also slows down how quickly food moves through the stomach and intestines, which helps people feel fuller longer. Because of this, researchers are looking into PYY as a possible treatment for obesity, using things like injections or nasal sprays. PYY may also help keep gut fungi like Candida albicans in balance, thanks to its ability to fight off certain harmful forms.

Since PYY helps regulate energy intake and digestion, it is also of interest in the management of metabolic diseases such as type 2 diabetes and metabolic syndrome. PYY may help in maintaining blood glucose levels and improving insulin sensitivity with its appetite suppressive effects that lead to reduced caloric intake. 

Warnings and Cautions

Peptide YY is not approved for clinical use, and its administration is limited to research settings. Potential risks include gastrointestinal side effects, such as nausea, observed in some human studies at supraphysiological doses. Its effects on Y2 receptors may influence other physiological processes, including mood and stress responses, due to the gut–brain axis, although this isn’t well understood yet. Low PYY levels are linked to obesity and type 2 diabetes, but it’s unclear if one causes the other. While giving PYY from outside sources might help, the long-term effects are unknown. 

Its ability to fight microbes could also upset the natural balance of gut bacteria. Because of limited safety data and risks of overstimulating receptors, using PYY without medical supervision is not recommended.

Mechanism of Action:

Appetite Regulation

PYY exerts its anorexigenic effects primarily through the Y2 receptor, a G-protein-coupled receptor in the hypothalamic arcuate nucleus. PYY3-36, formed by dipeptidyl peptidase IV (DPP4) cleavage of PYY1-36, selectively binds Y2 receptors, inhibiting neuropeptide Y (NPY) neurons and stimulating pro-opiomelanocortin (POMC) neurons, which reduce appetite. This action modulates both homeostatic and hedonic brain circuits, as shown in functional brain imaging studies. PYY also acts via the vagus nerve and brainstem to reinforce satiety signals.

Gastrointestinal Effects

PYY slows gastric emptying and intestinal motility by inhibiting cholinergic pathways, contributing to the “ileal brake” effect. It reduces pancreatic exocrine secretion and gallbladder contraction, optimizing nutrient absorption. In the colon, PYY enhances water and electrolyte absorption, influencing gut homeostasis.

Antimicrobial Activity

Full-length PYY1-36, secreted by Paneth cells, functions as an antimicrobial peptide. It selectively targets Candida albicans hyphae, disrupting fungal membranes and promoting the commensal yeast form, thus maintaining gut microbial balance. This action is independent of Y-receptor signaling and relies on PYY’s cationic structure.

Structure and Pharmacology

Peptide YY is a 36-amino-acid peptide with tyrosine residues at both N- and C-terminals, hence its name (Y for tyrosine). It adopts a PP-fold structure, a U-shaped tertiary conformation with a pyroproline helix and α-helix linked by β-turns, conferring enzymatic stability. PYY1-36 is cleaved by DPP4 to form PYY3-36, a 34-amino-acid peptide with high Y2 receptor selectivity. The C-terminal is amidated, enhancing receptor binding.

PYY is synthesized in enteroendocrine L-cells and co-secreted with glucagon-like peptide-1 (GLP-1). PYY3-36 has a plasma half-life of approximately 10–15 minutes due to rapid DPP4 cleavage and renal clearance. It binds Y2 receptors with high affinity but has lower affinity for Y1 and Y5 receptors. Pharmacological studies show PYY3-36 crosses the blood–brain barrier to act centrally, though peripheral vagal signaling also contributes to its effects. Its short half-life poses challenges for therapeutic development, prompting research into stable analogs and alternative delivery systems.

History

Peptide YY was isolated in 1980 by Tatemoto and Mutt at the Karolinska Institute in Stockholm, Sweden, using a chemical assay targeting C-terminal amide structures. Identified in porcine small intestine, it was named for its tyrosine residues. Early research in the 1980s established its role in inhibiting pancreatic and gastric secretions.

By the 1990s, its anorexigenic properties were recognized, with pivotal studies in the early 2000s demonstrating PYY3-36’s ability to reduce food intake in rodents and humans. The discovery of its antimicrobial role in 2023 expanded its functional scope. Despite decades of research, PYY’s therapeutic potential remains unrealized due to challenges in delivery and long-term efficacy.

Clinical Trials & Research

Peptide YY and Obesity

Phase 1 clinical trial tested an extended-release peptide YY analogue called Y14, developed as a potential treatment for obesity. Conducted in the United Kingdom, the trial involved overweight and obese participants and was divided into two parts. Part A assessed single ascending doses up to 36 mg, while Part B tested multiple ascending doses over 28 days, administered at 7- to 14-day intervals.

The study found that Y14 was generally well tolerated. The most common side effects, nausea, vomiting, and injection site reactions, were mostly mild and resolved over time.

Participants who received multiple doses of Y14 experienced a significant reduction in body weight, losing between 2.87 and 3.58 kg compared to placebo. Food intake also dropped by 38% to 55%, with no evidence of the body becoming resistant to the effects. [1]

Weight Loss and Glucose Control

One study explored how modifying PYY3-36, a peptide known for regulating appetite and blood sugar, could lead to better obesity and diabetes treatments. The native form of PYY3-36 strongly targets the Y2 receptor, but it breaks down quickly in the body and isn’t ideal for long-term use. Researchers screened different versions of the peptide to pinpoint which amino acids are crucial for Y2 receptor selectivity, strength, and stability. By combining these optimized variants with a fatty diacid, they created long-acting PYY analogs that worked better and lasted longer.

These new analogs not only improved blood sugar levels in diabetic mice but ,when paired with a GLP-1 agonist, they outperformed GLP-1 treatment alone, leading to greater weight loss and stronger glucose control in animal models. [2]

Appetite Suppression

A 2003 study tested whether obese individuals respond to the appetite-suppressing hormone PYY3–36. In a double-blind crossover trial with 12 obese and 12 lean subjects, both groups experienced a ~30% reduction in food intake after PYY infusion. Despite lower baseline PYY levels in obese individuals, they remained sensitive to its effects. This suggests PYY deficiency, not resistance, may play a role in obesity, and that PYY-based treatments could help reduce appetite in both lean and obese individuals. [3]

Gastric Emptying

This study looked at how two similar peptides, Peptide YY (PYY) and Neuropeptide Y (NPY), affect how quickly food leaves the stomach in humans. Both peptides are found in the digestive system, but in different locations: PYY is produced by endocrine cells in the gut, while NPY is stored in nerve endings. The researchers wanted to see if either of these peptides could influence gastric emptying, a process closely tied to digestion, satiety, and blood sugar regulation.

PYY significantly slowed gastric emptying, meaning it delayed how fast food left the stomach. This effect was observed even at low plasma concentrations. On the other hand, NPY, despite reaching similar levels in the bloodstream, had no meaningful impact on gastric emptying.

According to the study, PYY plays a direct role in slowing digestion, which can contribute to feelings of fullness and potentially reduce food intake. [4]