GLP-1 Incretin Hormones Control Appetite and May Treat Obesity | Research

The takeaway

GLP-1, a gut-derived incretin peptide hormone, plays a key role in satiation through both peripheral and central pathways, and GLP-1 receptor agonists like exenatide and liraglutide produce weight loss even in non-diabetic overweight individuals.

GLP-1 RAs produce weight loss in non-diabetic overweight subjects
Clinical trials of exenatide and liraglutide demonstrated weight loss potential beyond their diabetes indication — foreshadowing the obesity drug revolution

What the researchers found

GLP-1 is involved in both peripheral and central pathways mediating satiation — it works through gut nerve signals and direct brain effects to reduce food intake. Studies indicate that GLP-1 levels and meal responses may be altered in obese individuals, potentially contributing to overeating.

Clinical trials showed that two GLP-1 receptor agonists, exenatide and liraglutide (both approved for type 2 diabetes), produce weight loss in overweight subjects without diabetes. This established GLP-1 RAs as potential pharmacological treatments for obesity, a direction that has since been validated with the approval of higher-dose liraglutide (Saxenda) and semaglutide (Wegovy) specifically for weight management.

Why it matters

This review, written by one of the leading GLP-1 researchers, laid out the scientific rationale for using GLP-1 receptor agonists to treat obesity — years before semaglutide (Wegovy/Ozempic) became a global phenomenon. Understanding how incretin peptides control appetite is foundational to one of the most important drug class developments in modern medicine. The insights about altered GLP-1 responses in obesity help explain why these drugs can be so effective.

How the study worked

This is a narrative review synthesizing evidence from physiological studies of GLP-1's role in appetite regulation, observational studies of GLP-1 levels in obesity, and clinical trials of GLP-1 receptor agonists for weight loss. The author, J.J. Holst, is one of the pioneers of GLP-1 research.

What this study cannot tell us

As a 2013 review, it predates much of the clinical evidence now available for obesity treatment with GLP-1 RAs. Only exenatide and liraglutide were discussed, as semaglutide and tirzepatide had not yet completed obesity trials. The abstract does not provide specific weight loss numbers from the cited clinical trials. The mechanisms of GLP-1-mediated satiation described have since been refined with newer research.

How to read the evidence

This is a narrative review by a leading expert in the field, synthesizing evidence from multiple study types including clinical trials. While the individual studies cited include randomized controlled trials, the review itself provides expert interpretation rather than systematic evidence assessment.

When this study was published

Published in 2013, this review predates the obesity-specific approvals of liraglutide (2014) and semaglutide (2021). While the specific drug landscape has evolved dramatically, the foundational GLP-1 biology described remains accurate and is valuable for understanding how these drugs work.

The bigger picture

This 2013 review was prescient in identifying GLP-1 receptor agonists as obesity treatments. Since its publication, the field has exploded: liraglutide was approved for obesity in 2014, semaglutide for obesity in 2021, and tirzepatide (a dual GLP-1/GIP agonist) followed. The GLP-1 RA market is now worth tens of billions of dollars and has transformed metabolic medicine. This review captures the foundational science that made it all possible.

Questions still open

Can GLP-1-based appetite control be maintained long-term, or does tolerance develop with chronic treatment?
What explains the altered GLP-1 responses in obesity — is it a cause or consequence of weight gain?
Could combining GLP-1 with other appetite-regulating peptides produce even greater weight loss?

Common questions

What are incretin hormones and how do they affect appetite?

Incretins are gut hormones released after eating that enhance insulin secretion. GLP-1 is the most important incretin for appetite control — it signals fullness through nerve pathways from the gut to the brain and also acts directly on brain areas that regulate hunger. When GLP-1 is impaired, as it may be in obesity, the satiation signal is weakened, potentially contributing to overeating.

How did this research lead to today's GLP-1 weight loss drugs?

This 2013 review by GLP-1 pioneer J.J. Holst highlighted early clinical trial evidence that GLP-1 receptor agonists could produce weight loss in non-diabetic overweight individuals. This evidence base led pharmaceutical companies to pursue higher-dose GLP-1 drugs specifically for obesity, resulting in approvals of liraglutide (Saxenda, 2014) and semaglutide (Wegovy, 2021), which have become some of the most prescribed medications worldwide.

Read the original research

Incretin hormones and the satiation signal.

International journal of obesity (2005), 37(9), 1161-8

View on PubMed ↗Publisher’s paper ↗

Citation

Holst, J J. (2013). Incretin hormones and the satiation signal.. International journal of obesity (2005), 37(9), 1161-8. https://doi.org/10.1038/ijo.2012.208