Peptide YY (PYY)
Peptide YY (PYY) is a 36-amino acid gut hormone released from intestinal L-cells postprandially, with PYY(3-36) as its primary active form. It signals satiety through Y2 receptors in the hypothalamus and is being investigated for obesity treatment, particularly given its elevation following bariatric surgery.
Overview
PYY is primarily produced by enteroendocrine L-cells in the ileum and colon, with smaller amounts in the stomach, pancreas, and brain. Plasma PYY levels are low during fasting and rise within 15 minutes of eating, peaking at 1–2 hours and remaining elevated for several hours. The magnitude of PYY release is proportional to caloric load, with fat being the most potent macronutrient stimulus, followed by protein and carbohydrate.
The conversion of PYY(1-36) to PYY(3-36) by DPP-IV is functionally critical: full-length PYY(1-36) activates Y1, Y2, and Y5 receptors (promoting mixed effects including appetite stimulation via Y1/Y5), whereas PYY(3-36) is selective for Y2 receptors, which mediate anorexigenic signaling. This processing step ensures that the dominant circulating form produces satiety rather than feeding.
PYY gained major clinical interest following the discovery that bariatric surgery dramatically elevates postprandial PYY levels, and that exaggerated PYY secretion contributes significantly to the sustained weight loss observed after Roux-en-Y gastric bypass and sleeve gastrectomy.
Mechanism of Action
PYY(3-36) exerts its satiety effects primarily through the hypothalamic-brainstem appetite circuitry:
- Y2 receptor activation in arcuate nucleus: PYY(3-36) crosses the blood-brain barrier at the median eminence and binds presynaptic Y2 receptors on NPY/AgRP neurons. This inhibits NPY/AgRP release, disinhibiting adjacent POMC/α-MSH anorectic neurons and reducing appetite Batterham et al. (2002).
- Vagal afferent signaling: PYY(3-36) also activates vagal afferents in the gut that project to the nucleus of the solitary tract (NTS), contributing to meal termination and satiety. Vagotomy attenuates some but not all of PYY's anorexigenic effects Abbott et al. (2005).
- GI motility: PYY slows gastric emptying and intestinal transit (the "ileal brake" mechanism), prolonging nutrient absorption and contributing to postprandial satiety.
- Pancreatic secretion: PYY inhibits exocrine pancreatic secretion and gastric acid output, coordinating digestive function with nutrient availability.
- Synergy with GLP-1: PYY and GLP-1 are co-secreted from L-cells and produce synergistic appetite suppression through complementary receptor mechanisms — Y2 receptor (PYY) and GLP-1R (GLP-1) activate distinct but converging anorectic circuits De Silva et al. (2011).
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Research
Satiety and Appetite Suppression
The landmark study by Batterham et al. demonstrated that intravenous PYY(3-36) infusion to mimic postprandial levels reduced food intake by approximately 33% in normal-weight human volunteers, with effects lasting several hours beyond the infusion period Batterham et al. (2002). Subsequent fMRI studies showed that PYY(3-36) modulates neural activity in hypothalamic, brainstem, and corticolimbic circuits involved in reward-based feeding decisions Batterham et al. (2007). Importantly, PYY(3-36) reduces appetite in both lean and obese subjects, though obese individuals have blunted endogenous PYY responses to meals.
Obesity and PYY Deficiency
Obese individuals consistently show lower fasting and postprandial PYY levels compared to lean controls, suggesting that PYY deficiency may contribute to impaired satiety signaling and overeating Batterham et al. (2003). This relative PYY deficiency is distinct from leptin resistance — obese subjects retain sensitivity to exogenous PYY(3-36) administration, which reduces food intake comparably to lean subjects. This preservation of PYY sensitivity makes the PYY pathway an attractive therapeutic target for obesity.
Bariatric Surgery and PYY
One of the most significant findings in bariatric research is that Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy produce dramatic and sustained elevations in postprandial PYY levels — often 3- to 10-fold above pre-surgical values. This PYY surge, along with elevated GLP-1, is now considered a major mechanism driving the appetite suppression and weight loss success of bariatric surgery, beyond simple caloric restriction le Roux et al. (2006). Gastric banding, which does not alter gut anatomy, does not produce comparable PYY elevation and achieves less sustained weight loss, further supporting the gut hormone hypothesis.
GLP-1 and PYY Synergy
PYY and GLP-1 are co-secreted from intestinal L-cells and produce greater appetite suppression together than either hormone alone. In human infusion studies, combined low-dose PYY(3-36) and GLP-1 administration reduced ad libitum food intake by approximately 27% — comparable to the effect of either hormone alone at much higher doses De Silva et al. (2011). This synergy has informed the design of combination therapies targeting multiple gut hormone pathways for obesity treatment, including co-agonist molecules and post-bariatric hormone profiles.
Anorexia Nervosa
In contrast to obesity, patients with anorexia nervosa exhibit elevated PYY levels, both fasting and postprandial. This paradoxical elevation may contribute to the persistent appetite suppression and difficulty refeeding seen in anorexia. PYY levels normalize with weight restoration, suggesting the elevation is a consequence rather than a cause of the disorder Misra et al. (2006). Understanding PYY dysregulation in eating disorders has implications for both treatment strategies and the broader biology of appetite regulation.
PYY3-36 satiety physiology
PYY3-36 is a Y2-receptor-selective gut hormone released postprandially that reduces food intake in humans. Landmark infusion studies showed obese subjects retain sensitivity to its anorectic effect, distinguishing it from leptin resistance and motivating its pursuit as an obesity therapeutic.
- PYY3-36 infusion cut caloric intake ~30% in obese and lean subjects (PMID 12954742).
- Obesity is associated with lower fasting PYY and blunted postprandial rise but preserved responsiveness to exogenous PYY.
Long-acting analogs and GLP-1 combination therapy
Because native PYY3-36 has a very short half-life and a narrow tolerability window (nausea/vomiting), current development focuses on long-acting, Y2-selective analogs, often combined with GLP-1 receptor agonists such as semaglutide to add appetite suppression while limiting muscle loss.
- Long-acting PYY1875 plus semaglutide added weight loss preclinically but only modest, poorly tolerated effects in early human trials (PMID 40629530).
- Engineering Y2-selective PYY variants aims to widen the therapeutic window versus native peptide.
Safety Profile
PYY(3-36) has demonstrated a favorable safety profile in human infusion studies:
- Nausea: The most commonly reported side effect at supraphysiological doses. Dose-dependent nausea limits the maximum tolerable infusion rate and has been a challenge for therapeutic development.
- GI effects: Slowed gastric emptying and reduced intestinal motility (the ileal brake). May cause bloating or abdominal discomfort at higher doses.
- Cardiovascular: No significant cardiovascular effects at physiological concentrations. PYY does not produce the vasoconstriction associated with NPY.
- Hypoglycemia: Not observed. PYY does not directly affect insulin secretion at physiological doses.
- Short half-life: Rapid clearance (7–15 minutes) limits the duration of adverse effects but also limits therapeutic utility of native PYY. Long-acting analogs are in development.
- No chronic toxicity data: Long-term administration studies in humans are limited. The physiological nature of the peptide suggests a favorable long-term profile.
Pharmacokinetic Profile
Peptide YY (PYY) — Pharmacokinetic Curve
Intravenous infusion (research)Quick Start
- Route
- Intravenous infusion (research)
Molecular Structure
- Formula
- C₁₈₂H₂₇₇N₅₅O₅₃S
- Weight
- 4049.6 Da
- CAS
- 106388-42-5
Research Indications
Investigational Uses
PYY3-36 suppresses appetite via Y2 receptors and is being developed, notably as long-acting analogs combined with GLP-1 receptor agonists, though standalone formulations have shown limited efficacy and tolerability challenges.
As a postprandial gut hormone from enteroendocrine L cells, PYY3-36 reduces food intake by modulating hypothalamic and brainstem appetite circuits.
Research Protocols
intravenous Injection
demonstrated that intravenous PYY(3-36) infusion to mimic postprandial levels reduced food intake by approximately 33% in normal-weight human volunteers, with effects lasting several hours beyond the infusion period [Batterham et al.
Interactions
Peptide Interactions
- Synergy with GLP-1: PYY and GLP-1 are co-secreted from L-cells and produce synergistic appetite suppression through complementary receptor mechanisms — Y2 receptor (PYY) and GLP-1R (GLP-1) activate distinct but converging anorectic circuits [De Silva et al.
What to Expect
What to Expect
Rapid onset expected; half-life of ~7–15 minutes (plasma) indicates fast-acting pharmacokinetics
Plasma PYY levels are low during fasting and rise within 15 minutes of eating, peaking at 1–2 hours and remaining elevated for several hours.
Due to short half-life (~7–15 minutes (plasma)), effects are expected per-dose; consistent daily administration maintains therapeutic levels
Regular administration schedule required; effects are dose-dependent and do not persist between doses
Quality Indicators
What to look for
- Well-established safety profile
- Multiple peer-reviewed studies available
Caution
- Short half-life may require frequent dosing
Frequently Asked Questions
References (14)
- [10]Alexiadou K et al — Post-bariatric gut hormone profiles: PYY, GLP-1, and their role in sustained weight loss Nat Rev Endocrinol (2023)
- [12]Karra E et al — PYY(3-36) analogs with extended half-life: preclinical evaluation for obesity therapy Diabetes Obes Metab (2023)
- [1]Tatemoto K Isolation and characterization of peptide YY (PYY), a candidate gut hormone that inhibits pancreatic exocrine secretion Proc Natl Acad Sci USA (1982)
- [2]Batterham RL, Cowley MA, Small CJ, et al Gut hormone PYY3-36 physiologically inhibits food intake Nature (2002)
- [3]Batterham RL, Cohen MA, Ellis SM, et al Inhibition of food intake in obese subjects by peptide YY3-36 N Engl J Med (2003)
- [4]Batterham RL, ffytche DH, Rosenthal JM, et al PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans Nature (2007)
- [5]Abbott CR, Monteiro M, Small CJ, et al The inhibitory effects of peripheral administration of peptide YY3-36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway Brain Res (2005)
- [7]le Roux CW, Aylwin SJ, Batterham RL, et al Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters Ann Surg (2006)
- [8]Misra M, Miller KK, Tsai P, et al Elevated peptide YY levels in adolescent girls with anorexia nervosa J Clin Endocrinol Metab (2006)
- [6]De Silva A, Salem V, Long CJ, et al The gut hormones PYY3-36 and GLP-17-36 amide reduce food intake and modulate brain activity in appetite centers in humans Cell Metab (2011)
- [9]Tan T et al — Combination gut hormone therapy for obesity: GLP-1, OXM, and PYY triple agonism Cell Metab (2022)
- [11]Schmidt JB et al — Gut hormone responses to meal tests after diet-induced weight loss: PYY and GLP-1 predict weight maintenance Int J Obes (2022)
- [13]Gantz I, Erondu N, Mallick M, Musser B, Krishna R, Tanaka WK, et al. Efficacy and safety of intranasal peptide YY3-36 for weight reduction in obese adults Journal of Clinical Endocrinology & Metabolism (2007)
→ In 133 obese adults over 12 weeks, intranasal PYY3-36 (200 or 600 mcg TID) did not produce significant weight loss versus placebo, and the high dose caused dose-limiting nausea and vomiting.
- [14]Wulff BS, et al. Long-acting PYY3-36 analogue with semaglutide for obesity: from preclinical assessment through randomized clinical studies Obesity (2025)
→ A long-acting PYY3-36 analogue (PYY1875) added to semaglutide gave additional weight loss in obese rats but only modest, non-clinically-meaningful benefit in phase 1/2 human studies and was poorly tolerated at the doses tested.
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