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Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity

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Abstract

Objective

N-acylethanolamines (NAEs) include endocannabinoid (EC) and EC-related molecules that impact the anti-obesity and anti-diabetic efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RA) in animal studies. However, the clinical relevance of these findings remains to be determined. Here, we tested whether GLP-1RA treatment affects circulating NAE levels and whether NAEs may predict the efficacy of GLP-1RA treatment in humans with obesity undergoing weight loss maintenance.

Materials and methods

We profiled plasma levels of NAEs in participants with obesity undergoing weight loss maintenance with (n = 23)/or without (n = 20) treatment with the GLP-1RA liraglutide. NAE levels were measured at three different time points: before the start of the study, at the end of the diet-induced weight loss, and after 52-weeks treatment. Linear regression analyses were used to investigate whether pharmacological responses could be predicted by NAEs levels.

Results

Liraglutide treatment reduced plasma concentrations of the NAE and oleoyl-ethanolamide (OEA), without altering arachidonoyl-ethanolamide (AEA) levels and palmitoyl-ethanolamide (PEA) levels. High pre-treatment levels of OEA were predictive of superior compound-mediated effects on fasting insulin and triglyceride levels. High pre-treatment PEA and AEA levels were also predictive of superior Liraglutide-mediated effects on triglyceride levels.

Conclusions

Our data suggests that specific NAEs such as OEA and AEA are promising biomarkers of GLP-1RA metabolic efficacy in humans with obesity during weight loss maintenance. Plasma profiling of EC-related molecules may be a promising strategy to tailor GLP-1R-based therapies to individual needs in obesity and diabetes management.

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Fig. 1

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

GLP-1R:

Glucagon-like peptide 1 receptor

GLP-1RAs:

GLP-1R Agonists

EC:

Endocannabinoids

2-AG:

2-Arachidonoylglycerol

AEA:

Arachidonoyl-ethanolamide

OEA:

Oleoyl-ethanolamide

PEA:

Palmitoyl-ethanolamide

NAEs:

N-Acylethanolamines

CB1:

Cannabinoid receptor type-1

PPARs:

Proliferator activator receptors

T2D:

Diabetes

BW:

Body weight

TRPV1:

Transient receptor potential vanilloid 1

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Acknowledgements

We acknowledge INSERM (DC and CQ), Nouvelle Aquitaine Region (DC), University of Bordeaux’s IdEx ‘Investments for the Future’ program/GPR BRAIN_2030 (DC), Agence Nationale Recherche (Labex BRAIN ANR-10-LABX-43, ANR-18-CE14-0029, ANR-21-CE14-0018, ANR-22-CE14-0016 to DC; ANR-20-CE14-0046 to CQ), French Societies of Endocrinology, Nutrition, and Diabetes (SFE, SFN, and SFD), Fyssen Foundation, and Institut Benjamin Delessert (CQ), Excellence grant (NNF16OC0019968, to ST) and Novo Nordisk Foundation.

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Authors and Affiliations

  1. University of Bordeaux, INSERM, Neurocentre Magendie, U1215, 33000, Bordeaux, France

    I. Matias, P. Zizzari, D. Cota & C. Quarta

  2. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark

    E. W. Lehmann, S. Byberg & S. S. Torekov

  3. INSERM U1215, Neurocentre Magendie, 146 Rue Léo Saignat, 33077, Bordeaux Cedex, France

    C. Quarta

Authors
  1. I. Matias
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  2. E. W. Lehmann
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  3. P. Zizzari
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  4. S. Byberg
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  5. D. Cota
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  6. S. S. Torekov
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  7. C. Quarta
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Contributions

IM and EWL performed the study, PZ analyzed the data, EWL collected the samples, DC and SB edited the manuscript and contributed to the interpretation of the data. SST and QC designed the study and co-wrote the manuscript.

Corresponding authors

Correspondence to S. S. Torekov or C. Quarta.

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Conflict of interest

SST has received research grants and speaker fees from Novo Nordisk. EWL is employed at Novo Nordisk A/S, but not at the time of preparation of this manuscript.

Ethical approval

The study was approved by the ethical committee in Copenhagen (reference number: H-4-2010-134) and was performed in accordance with the Helsinki Declaration II and with ICH-GCP practice.

Informed consent

Participation in the investigation was voluntary and the individuals could at any time retract their consent to participate. ClinicalTrials.gov Identifier: NCT02094183.

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Supplementary Information

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40618_2023_2228_MOESM1_ESM.pdf

Figure S1: Relationship between pre-treatment NAE levels and liraglutide efficacy. Relationships between pre-treatment levels of NAEs and changes in fasting insulin levels (A,E, I), fasting triglyceride levels (B,F,J), fasting glucose levels (C,G,K), and body weight (D,H,L) in Control vs Liraglutide-treated subjects. Linear regression lines are plotted separately for Liraglutide (blue line) and Control (black line) subjects (PDF 349 KB)

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Matias, I., Lehmann, E.W., Zizzari, P. et al. Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity. J Endocrinol Invest 47, 1289–1294 (2024). https://doi.org/10.1007/s40618-023-02228-8

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