American journal of physiology. Regulatory, integrative and comparative physiologyJun 28, 2018

Oleoylethanolamide changes weight loss signals and boosts exendin-4’s effects in obese mice

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 12, 2026

Abstract

The combination of Exendin-4 and oleoylethanolamide led to greater weight loss in diet-induced obese mice compared to either treatment alone over 7 days.

Oleaoylethanolamide (OEA) enhances GLP-1 receptor signaling when combined with GLP-1, but not with Exendin-4.
Both GLP-1 and Exendin-4 activate the mTOR pathway, although OEA does not increase this effect further.
OEA synergistically boosts glycolysis when paired with GLP-1 and Exendin-4.
The combination of Exendin-4 and OEA resulted in transient reduced food intake and increased energy expenditure in diet-induced obese mice.
OEA's role appears to be complementary to Exendin-4 in promoting weight loss without enhancing the appetite-suppressing effects.

Simplified

Long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists (GLP-1RA), such as exendin-4 (Ex4), promote weight loss. On the basis of a newly discovered interaction between GLP-1 and oleoylethanolamide (OEA), we tested whether OEA enhances GLP-1RA-mediated anorectic signaling and weight loss. We analyzed the effect of GLP-1+OEA and Ex4+OEA on canonical GLP-1R signaling and other proteins/pathways that contribute to the hypophagic action of GLP-1RA (AMPK, Akt, mTOR, and glycolysis). We demonstrate that OEA enhances canonical GLP-1R signaling when combined with GLP-1 but not with Ex4. GLP-1 and Ex4 promote phosphorylation of mTOR pathway components, but OEA does not enhance this effect. OEA synergistically enhanced GLP-1- and Ex4-stimulated glycolysis but did not augment the hypophagic action of GLP-1 or Ex4 in lean or diet-induced obese (DIO) mice. However, the combination of Ex4+OEA promoted greater weight loss in DIO mice than Ex4 or OEA alone during a 7-day treatment. This was due in part to transient hypophagia and increased energy expenditure, phenotypes also observed in Ex4-treated DIO mice. Thus, OEA augments specific GLP-1RA-stimulated signaling but appears to work in parallel with Ex4 to promote weight loss in DIO mice. Elucidating cooperative mechanisms underlying Ex4+OEA-mediated weight loss could, therefore, be leveraged toward more effective obesity therapies.

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Oleoylethanolamide changes weight loss signals and boosts exendin-4’s effects in obese mice

Abstract

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