The calorie-burning effect of oxyntomodulin comes specifically from glucagon receptor activation, while GLP-1 receptor activation handles appetite suppression — explaining why dual agonist drugs aim to balance both.
Glucagon = essentialBlocking the GLP-1 receptor didn't prevent oxyntomodulin's energy expenditure boost, but eliminating glucagon receptor activity completely abolished it
What the researchers found
Using a sustained-release oxyntomodulin analogue (OX-SR) in rats, researchers definitively showed that the energy expenditure (calorie-burning) effect of oxyntomodulin occurs through the glucagon receptor, not the GLP-1 receptor. When the GLP-1 receptor was blocked with Exendin 9-39, OX-SR still increased oxygen consumption (energy burning). But when glucagon receptor activity was eliminated, the energy expenditure boost completely disappeared.
This resolves a key controversy about how oxyntomodulin works: its appetite-suppressing effects come mainly through GLP-1 receptor activation, while its calorie-burning effects require glucagon receptor activation. Both receptor activities are needed for optimal weight loss.
Why it matters
Oxyntomodulin is a natural gut hormone that activates both GLP-1 and glucagon receptors — making it a natural 'dual agonist.' This study is critical for drug design because it shows that the two receptors contribute different benefits: GLP-1 for appetite suppression, glucagon for increased energy expenditure. Drugs like survodutide and other GLP-1/glucagon dual agonists in development are designed based on this principle, and this study provides the mechanistic proof for why balancing both receptor activities matters.
The numbers in context
Sustained-release OXM analogue (OX-SR) · Significant increase in energy expenditure · Glucagon receptor: essential for energy expenditure · GLP-1 receptor blockade: did not prevent energy increase · Indirect calorimetry measurement
How the study worked
Animal study in rats using a sustained-release oxyntomodulin analogue (OX-SR). Energy expenditure was measured by indirect calorimetry (oxygen consumption). The GLP-1 receptor was blocked using Exendin 9-39 to test whether energy expenditure still occurred. Separately, glucagon receptor activity was eliminated to test whether it was required. This receptor-specific blocking approach allowed researchers to dissect which receptor drives each metabolic effect.
Who was studied
Male Wistar rats treated with sustained-release oxyntomodulin analogue
What this study cannot tell us
Rat study — the receptor pharmacology may not translate identically to humans. The specific OX-SR analogue used is a research tool, not a clinical drug candidate. The study focused on energy expenditure and did not measure appetite or food intake effects in parallel. Glucagon receptor activation also carries risks (e.g., hepatic glucose output), which were not assessed in this short-term study.
How to read the evidence
This is a well-designed mechanistic animal study using specific receptor blockade to isolate which receptor drives each metabolic effect. It provides strong preclinical evidence for the dual agonist mechanism, but results are in rats and may not translate identically to humans.
When this study was published
Published in 2018. The findings remain highly relevant as they underpin the design of dual and triple agonist drugs (survodutide, retatrutide) currently in late-stage clinical trials.
The bigger picture
This study provides the scientific rationale for the 'dual agonist' drug development strategy that has produced some of the most promising obesity drugs in the pipeline — including survodutide (GLP-1/glucagon) and retatrutide (GLP-1/GIP/glucagon). By understanding that GLP-1 and glucagon receptors contribute different weight-loss mechanisms, drug developers can fine-tune the ratio of receptor activities to maximize both appetite suppression and calorie burning while minimizing glucagon's side effects (like raising blood sugar).
Questions still open
- What is the optimal GLP-1-to-glucagon receptor activity ratio for maximizing weight loss while avoiding glucagon-driven blood sugar spikes?
- Does the glucagon receptor's role in energy expenditure explain why dual GLP-1/glucagon agonists show greater weight loss than pure GLP-1 drugs in clinical trials?
- Could selective glucagon receptor agonism alone boost metabolism in people who are already on GLP-1 drugs for appetite suppression?
Common questions
What is oxyntomodulin?
Why does it matter which receptor burns the calories?
Read the original research
Oxyntomodulin analogue increases energy expenditure via the glucagon receptor.
Peptides, 104, 70-77
Citation
Scott, R; Minnion, J; Tan, T; Bloom, S R. (2018). Oxyntomodulin analogue increases energy expenditure via the glucagon receptor.. Peptides, 104, 70-77. https://doi.org/10.1016/j.peptides.2018.04.008