Gut peptides including cholecystokinin, GLP-1, and peptide YY signal to the brain via the gut-brain axis to regulate food intake and energy expenditure, and gut microbiota can modulate this system.
3 key gut peptides regulate appetiteCCK, GLP-1, and PYY are released by gut cells after eating and signal to the brain via neural and hormonal pathways to control food intake and energy expenditure
What the researchers found
The review describes a comprehensive model of gut-brain energy regulation:
- Enteroendocrine cells sense ingested nutrients and release gut peptides (CCK, GLP-1, PYY)
- These peptides signal via two pathways: paracrine signaling through vagal and non-vagal neuronal relays, and endocrine signaling via the bloodstream
- Central nervous system integrates these signals to generate responses that reduce food intake and increase energy expenditure
- Gut microbiota modulate this gut-brain axis, potentially influencing the development of obesity
- Disruptions in this signaling system may contribute to impaired energy homeostasis and weight gain
Why it matters
The gut peptides reviewed here — especially GLP-1 — are now the basis of the most successful obesity drugs in history (semaglutide, tirzepatide). This review provides the foundational science explaining why these drugs work: they mimic or enhance natural gut-brain signaling that controls appetite. Understanding the microbiome's role adds another potential therapeutic target.
How the study worked
This is a comprehensive review article examining current hypotheses and recent research on nutrient sensing mechanisms of enteroendocrine cells, gut peptide signaling pathways, gut-to-brain communication, and the influence of gut microbiota on energy balance regulation.
What this study cannot tell us
As a 2016 review, it predates much of the clinical success of GLP-1 receptor agonists for obesity. The mechanisms of microbiota influence on the gut-brain axis were largely hypothetical at the time. The review does not cover dual or triple agonist approaches (GLP-1/GIP, GLP-1/GIP/glucagon) that have since emerged.
How to read the evidence
This is a narrative review article synthesizing research across molecular biology, neuroscience, and microbiome studies. It provides a conceptual framework rather than new experimental data.
When this study was published
Published in 2016, this review predates the widespread clinical use of GLP-1 drugs for obesity. The core mechanisms described remain relevant and have been validated by the success of semaglutide and tirzepatide.
The bigger picture
This review captures the scientific understanding that preceded the GLP-1 drug revolution. The gut-brain axis is now recognized as a central mechanism in energy regulation, and drugs targeting this pathway have become the most impactful obesity treatments ever developed. The review's discussion of microbiota influence foreshadowed ongoing research into how gut bacteria affect weight management and drug responses.
Questions still open
- Can manipulating gut microbiota enhance the effectiveness of GLP-1-based obesity treatments?
- Are there undiscovered gut peptides that could serve as additional therapeutic targets for obesity?
- How do individual differences in gut peptide signaling explain why some people respond better to GLP-1 drugs than others?
Common questions
How do gut peptides control hunger?
Can gut bacteria affect your weight through peptides?
Read the original research
Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.
Cellular and molecular life sciences : CMLS, 73(4), 737-55
Citation
Bauer, Paige V; Hamr, Sophie C; Duca, Frank A. (2016). Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota.. Cellular and molecular life sciences : CMLS, 73(4), 737-55. https://doi.org/10.1007/s00018-015-2083-z