Peptide YY and Satiety: The Gut Hormone That Complements GLP-1

Written by Adam Maggio | Medically reviewed by Dr. Sarah Chen, PharmD, BCPS

Peptide YY (PYY) works synergistically with GLP-1 to suppress appetite and slow gastric emptying, making it a key target for future obesity therapies.

The intricate regulation of appetite and energy balance involves a complex interplay of gut hormones, neuropeptides, and central nervous system signaling. Among these, glucagon-like peptide-1 (GLP-1) has garnered significant attention for its role in satiety and glucose homeostasis. However, GLP-1 does not act in isolation; it is complemented by other potent gut-derived signals, notably Peptide YY (PYY), which synergistically contribute to appetite suppression and metabolic regulation.

Understanding Peptide YY (PYY)

Peptide YY is a 36-amino acid peptide hormone released by L-cells in the ileum and colon in proportion to caloric intake, particularly in response to fat and protein [1]. There are two main forms: PYY(1-36) and PYY(3-36). PYY(3-36) is the predominant circulating form and is considered the active anorexigenic (appetite-suppressing) agent, acting primarily on Y2 receptors in the brainstem and hypothalamus [2].

Mechanisms of Action: How PYY Promotes Satiety

PYY exerts its appetite-suppressing effects through several key mechanisms:

  • Central Nervous System Modulation: PYY(3-36) crosses the blood-brain barrier and activates Y2 receptors in the arcuate nucleus of the hypothalamus. This activation inhibits neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons, which are potent stimulators of appetite, while simultaneously stimulating pro-opiomelanocortin (POMC) neurons, which promote satiety [3].
  • Slowing Gastric Emptying: Similar to GLP-1, PYY slows the rate at which food leaves the stomach. This prolongs the feeling of fullness and reduces the rate of nutrient absorption, contributing to reduced food intake [4].
  • Reduced Gut Motility: PYY also decreases overall gastrointestinal motility, further enhancing satiety and nutrient processing.

    • PYY and GLP-1: A Synergistic Partnership

    Both PYY and GLP-1 are secreted from intestinal L-cells in response to food intake and share overlapping roles in metabolic regulation. Their combined action creates a more potent and sustained effect on satiety and glucose homeostasis than either hormone alone:

    Complementary Satiety Signals: While both contribute to satiety, they may act through distinct or partially overlapping neural pathways, leading to an additive or synergistic reduction in appetite.

    Integrated Glucose Control: Both hormones enhance glucose-dependent insulin secretion and suppress glucagon, contributing to improved glycemic control. PYY's effect on gastric emptying further aids in blunting post-prandial glucose excursions.

    Therapeutic Potential: The synergistic relationship between PYY and GLP-1 has led to interest in developing co-agonists or combination therapies that target both pathways for enhanced weight loss and metabolic benefits. For instance, some GLP-1 receptor agonists also have indirect effects on PYY release, or future drugs may directly combine their actions.

    Clinical Evidence and Therapeutic Implications

    Exogenous administration of PYY(3-36) has been shown to reduce food intake in both lean and obese individuals. Studies have demonstrated that intravenous infusion of PYY(3-36) significantly reduces calorie consumption over a 24-hour period [5]. While PYY monotherapy has faced challenges related to short half-life and route of administration, its role in combination therapies or as a target for novel drug development remains promising.

    Research into PYY analogs or strategies to enhance endogenous PYY release (e.g., through dietary interventions or gut microbiome modulation) is ongoing. The goal is to leverage PYY's natural satiety-inducing properties to develop effective and well-tolerated treatments for obesity and related metabolic disorders.

    Conclusion

    Peptide YY is a crucial gut hormone that plays a significant role in regulating satiety, gastric emptying, and overall energy balance. Its synergistic relationship with GLP-1 underscores the complexity and redundancy of the body's appetite control systems. By understanding and harnessing the power of PYY, particularly in combination with other incretins, the future of obesity pharmacotherapy can move towards more comprehensive and effective strategies that address the multifaceted nature of weight regulation. This gut-brain axis communication is vital for maintaining metabolic health and combating the global obesity epidemic.

    References

    [1] Batterham, R. L., et al. (2002). Inhibition of food intake in obese subjects by peptide YY3-36. New England Journal of Medicine, 346(15), 923–930. https://www.nejm.org/doi/full/10.1056/NEJMoa020143

    [2] Ueno, N., et al. (1999). Peptide YY(3-36) is a physiological anorectic hormone. Nature Medicine, 5(10), 1125–1129. https://www.nature.com/articles/nm1099_1125

    [3] Chelikani, P. K., et al. (2006). A role for peptide YY in the control of food intake. Physiology & Behavior, 87(2), 361–369. https://pubmed.ncbi.nlm.nih.gov/16406082/

    [4] Adrian, T. E., et al. (1985). Effect of peptide YY on gastric, pancreatic, and biliary function in humans. Gastroenterology, 89(3), 494–499. https://pubmed.ncbi.nlm.nih.gov/3875143/

    [5] Batterham, R. L., et al. (2003). PYY(3-36) reduces food intake in obese subjects. Journal of Clinical Endocrinology & Metabolism, 88*(8), 3989–3992. https://pubmed.ncbi.nlm.nih.gov/12915684/