Metabolic Research
Peptide YY: A Gut Hormone with Surprising Superpowers
·Educational reference
Imagine a tiny messenger, secreted from your gut after every meal, doing far more than just signaling satiety. This is the world of Peptide YY (PYY), a remarkable gut hormone that’s capturing scientific attention for its diverse and unexpected roles. From helping to put the brakes on your appetite to potentially fighting off viruses and fungi, PYY is proving to be a true biological multitasker, hinting at exciting future applications.
What is Peptide YY
Peptide YY (PYY) is a 36-amino-acid gastrointestinal hormone, predominantly secreted by the intestinal L-cells (PMID 37666110, PMID 15960866). While originally extracted from pig intestines, it belongs to the pancreatic polypeptide (PP) family, yet has distinct functions from its relatives, PP and neuropeptide Y (NPY) (PMID 37666110). Highest concentrations of PYY are found in the distal segments of the gastrointestinal tract, though it's present throughout the gut (PMID 15960866). Following food intake, PYY is released into the bloodstream, with concentrations proportional to meal energy content and peak plasma levels appearing about an hour post-meal (PMID 15960866). PYY exists in various forms, with PYY3-36 being a major circulating variant in both gut mucosal endocrine cells and the bloodstream (PMID 15960866). Another form, PYY1-36, acts as an antimicrobial peptide (AMP) expressed by gut epithelial Paneth cells (PMID 37535745).
Why researchers are excited
Researchers are buzzing about PYY for its profound and multifaceted impact on human physiology. Its well-established role in appetite regulation and energy homeostasis makes it a prime candidate in the fight against the global obesity pandemic (PMID 15960866, PMID 18185065). The ability of PYY3-36 to curb hunger, delay gastric emptying, reduce weight, and lower blood glucose has sparked significant interest for potential treatments for type 2 diabetes mellitus (T2DM) and obesity (PMID 37666110, PMID 18185065). Beyond metabolism, the discovery of PYY's unexpected antiviral properties against Hepatitis B virus (HBV) and its selective antifungal activity against virulent *Candida albicans* hyphae has expanded its potential far beyond the digestive system (PMID 37380814, PMID 37535745). This breadth of action, from hunger pangs to fighting pathogens, positions PYY as a fascinating target for novel therapeutic strategies.
What the studies found
The research on Peptide YY paints a compelling picture of a peptide with a remarkably diverse portfolio:
| Study | Model | Key finding | PMID | | :----------------------------------------------- | :---------------------------------------------------- | :-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | :--------- | | Peptide YY inhibits transcription and replication of hepatitis B virus by suppressing promoter/enhancer activity. | HBV-expressing hepatocytes, HBV patients | PYY expression was reduced in HBV-expressing hepatocytes and HBV patients. Overexpression of PYY significantly inhibited HBV RNA, DNA levels, and HBsAg secretion in hepatocytes. PYY inhibited HBV RNA transcription by reducing activities of CP/Enh I/II, SP1, and SP2. PYY also blocked HBV replication independently of core, polymerase protein, and ε structure of pregenomic RNA in hepatocytes (PMID 37380814). | 37380814 | | Peptide YY, appetite and food intake. | Rodents, humans | Peripheral administration of PYY3-36 inhibited food intake for several hours in both rodents and humans at physiological concentrations (PMID 15960866). PYY3-36 levels are proportional to meal energy content and peak postprandially (PMID 15960866). It controls food intake by providing feedback to hypothalamic circuits, binding to the Y2 receptor to inhibit NPY neurons and potentially stimulate pro-opiomelanocortin neurons (PMID 15960866). | 15960866 | | Evolution of peptide YY analogs for the management of type 2 diabetes and obesity. | Humans | PYY has potential as a treatment for type 2 diabetes mellitus due to its ability to delay gastric emptying, reduce appetite, decrease weight, and lower blood glucose (PMID 37666110). Its clinical use is limited by rapid clearance and degradation (PMID 37666110). | 37666110 | | Peptide YY. | Obese humans, obese rodents, humans (functional imaging) | Exogenous PYY3-36 established as an anorectic agent in obese humans and rodents, showing weight loss effects in obese rodents (PMID 18185065). The NPY-Y2 receptor mediates these anorectic actions, with rodent studies implicating the hypothalamus, vagus, and brainstem (PMID 18185065). Functional imaging in humans confirmed PYY3-36 activates brainstem and hypothalamic regions, with greatest effects in the orbitofrontal cortex, involved in reward processing (PMID 18185065). Rodent studies showed PYY3-36 decreases motivation to seek high-fat food (PMID 18185065). | 18185065 | | Peptide YY: A Paneth cell antimicrobial peptide that maintains Candida gut commensalism. | *In vitro*, *Candida albicans* hyphae | PYY1-36, but not endocrine PYY3-36, acts as an antimicrobial peptide (AMP) expressed by gut epithelial Paneth cells (PMID 37535745). PC-PYY displays selective antifungal activity against virulent *Candida albicans* hyphae, but not the yeast form (PMID 37535745). PC-PYY, a cationic molecule, interacts with anionic fungal hyphae surfaces, causing membrane disruption and transcriptional reprogramming that selects for the yeast phenotype (PMID 37535745). | 37535745 | | Peptide YY and appetite control. | Animals | Peripheral administration of PYY3-36 is known to inhibit food intake (PMID 15525548). This anorexigenic effect is mediated via the hypothalamic Y2 receptor (PMID 15525548). Levels of PYY3-36 are low in overweight volunteers (PMID 15525548). | 15525548 | | Peptide YY3-36 concentration in acute- and long-term recovered anorexia nervosa. | Young patients with acute anorexia nervosa (n=47), long-term recovered (n=35), healthy controls (n=58) | No significant group difference in fasting plasma PYY3-36 concentration among young acutely underweight anorexia nervosa patients, long-term recovered anorexia nervosa patients, and healthy control participants (PMID 32166384). No change in PYY3-36 concentration after short-term weight rehabilitation (PMID 32166384). A negative correlation between PYY3-36 concentration and body mass index was observed for acute anorexia nervosa patients at admission (PMID 32166384). | 32166384 |
How it's thought to work
PYY’s mechanisms of action are as varied as its effects. For appetite control, the PYY3-36 form binds to the Y2 receptor, which leads to an inhibition of the NPY neurons and a possible reciprocal stimulation of the pro-opiomelanocortin neurons in the hypothalamus (PMID 15960866). This powerful feedback mechanism regulates food intake (PMID 15960866). Studies in rodents suggest the hypothalamus, vagus, and brainstem are key target sites, and functional imaging in humans shows PYY3-36 activates brainstem and hypothalamic regions, with notable effects in the orbitofrontal cortex, an area involved in reward processing (PMID 18185065).
In its antiviral capacity, PYY acts as a restriction factor against Hepatitis B virus (HBV). *In vitro* studies in HBV-expressing hepatocytes show that PYY can inhibit HBV RNA and DNA levels, as well as the secretion of HBsAg (PMID 37380814). It achieves this by suppressing viral promoters/enhancers, specifically reducing the activities of CP/Enh I/II, SP1, and SP2, thereby blocking HBV RNA transcription (PMID 37380814). PYY also independently blocks HBV replication (PMID 37380814).
As an antimicrobial peptide (AMP), the PYY1-36 form, specifically from Paneth cells (PC-PYY), functions by interacting with fungal surfaces. This cationic molecule selectively targets virulent *Candida albicans* hyphae (but not the yeast form) (PMID 37535745). It causes membrane disruption and transcriptional reprogramming, which shifts the fungus towards a less harmful yeast phenotype, helping to maintain gut fungal commensalism (PMID 37535745).
The catch: what we still don't know
While the findings on PYY are certainly exciting, the journey from laboratory discovery to widespread application is often long and winding. A significant hurdle for PYY as a potential therapeutic is its rapid clearance by the kidneys and degradation by enzymes, which limits its clinical use (PMID 37666110). Researchers are actively working on structural modifications, such as amino acid substitutions, PEGylation, lipidation, and fusion with other proteins, to prolong its half-life and boost its biological activity (PMID 37666110).
Furthermore, while PYY3-36 has shown promising anorectic effects in obese individuals and rodents, research on its concentrations in conditions like anorexia nervosa suggests a more complex picture. One study found no significant difference in fasting plasma PYY3-36 concentrations between young acutely underweight anorexia nervosa patients, long-term recovered patients, and healthy controls (PMID 32166384). This suggests that PYY's role in appetite regulation is part of a larger, intricate network of appetite-regulating peptides, whose complex interplay requires further investigation, potentially using food challenge designs (PMID 32166384).
Finally, while the antiviral and antifungal properties are groundbreaking, these studies are currently in early stages, primarily in cells or *in vitro* (PMID 37380814, PMID 37535745). Much more research is needed to understand their full implications and potential for human health. The multifaceted nature of PYY demands continued exploration to fully unlock its secrets.
Keep exploring
Peptide YY is clearly more than just a gut hormone; it's a dynamic player in metabolic health and immune defense. As research progresses, we look forward to seeing how this peptide's remarkable versatility could lead to new avenues in medicine. Keep exploring the exciting world of peptides by browsing our A–Z protocols and comparing compounds. Don't forget to share this article with fellow science enthusiasts!