PACAP and VIP neuropeptides and their three receptors regulate appetite, metabolism, and fat accumulation through both brain and gut pathways, offering potential therapeutic targets for obesity.
3 receptors across brain and gutPACAP and VIP signal through VPAC1R, VPAC2R, and PAC1R receptors distributed in both the central nervous system and gastrointestinal tract, offering multiple potential drug targets for obesity.
What the researchers found
PACAP and VIP act through three receptors (VPAC1R, VPAC2R, PAC1R) distributed in both the central nervous system and gastrointestinal tract to regulate appetite, satiety, calorie intake, energy expenditure, and fat accumulation. The review synthesizes evidence showing these peptides modulate body phenotype, metabolism, and homeostatic functions through both central (brain) and peripheral (gut, immune) pathways. Their widespread distribution and multi-organ effects position them as potential therapeutic targets for obesity and metabolic syndrome.
Why it matters
While GLP-1 drugs have transformed obesity treatment, the PACAP/VIP system represents an additional neuropeptide pathway that could complement or extend existing therapies. Understanding how these peptides regulate energy balance through parallel brain and gut mechanisms could reveal new drug targets, particularly for patients who don't respond adequately to GLP-1-based approaches.
How the study worked
Narrative review synthesizing recent data on PACAP, VIP, and their receptor subtypes' effects on appetite, satiety, metabolism, calorie intake, and fat accumulation from both central and peripheral signaling studies.
What this study cannot tell us
As a review, the paper synthesizes existing literature without presenting new data. Much of the evidence for PACAP/VIP effects on metabolism comes from animal models. The translation of receptor-specific findings to human therapeutic applications is uncertain. The review acknowledges that the mechanisms regulating appetite and energy balance through these peptides are not fully elucidated. No PACAP/VIP-targeted obesity drugs are currently in clinical development.
How to read the evidence
This is a narrative review summarizing preclinical and basic science evidence. While it identifies promising therapeutic targets, no clinical trials testing PACAP/VIP-based obesity treatments are discussed.
When this study was published
Published in 2023, this review was written during the GLP-1 drug revolution, contextualizing PACAP/VIP research within the modern landscape of peptide-based obesity therapies.
The bigger picture
The success of GLP-1 drugs has revitalized interest in gut-brain peptide signaling for obesity treatment. PACAP and VIP belong to the same peptide superfamily as GLP-1 and share evolutionary origins. Understanding these related but distinct pathways could lead to combination therapies or alternative treatments that engage complementary mechanisms — similar to how tirzepatide improved on GLP-1-only drugs by adding GIP receptor activation.
Questions still open
- Which of the three PACAP/VIP receptors would be the most effective target for obesity treatment?
- Could PACAP or VIP agonists/antagonists complement GLP-1 drugs for patients with insufficient weight loss response?
- How do PACAP and VIP signaling interact with the established GLP-1 and GIP pathways in appetite regulation?
Common questions
What are PACAP and VIP?
Could PACAP or VIP drugs be used alongside Ozempic or Wegovy?
Read the original research
PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite, Satiety and Metabolism.
Biology, 12(7)
Citation
Vu, John P; Luong, Leon; Sanford, Daniel; Oh, Suwan; Kuc, Alma; Pisegna, Rita; Lewis, Michael; Pisegna, Joseph R; Germano, Patrizia M. (2023). PACAP and VIP Neuropeptides' and Receptors' Effects on Appetite, Satiety and Metabolism.. Biology, 12(7). https://doi.org/10.3390/biology12071013