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. 2024 Sep 17;14(9):500.
doi: 10.3390/metabo14090500.

Metabolomic Effects of Liraglutide Therapy on the Plasma Metabolomic Profile of Patients with Obesity

Assim A Alfadda  1   2   3 , Anas M Abdel Rahman  4 , Hicham Benabdelkamel  1 , Reem AlMalki  4 , Bashayr Alsuwayni  5 , Abdulaziz Alhossan  6 , Madhawi M Aldhwayan  7 , Ghalia N Abdeen  7 , Alexander Dimitri Miras  8   9 , Afshan Masood  1
Affiliations

Metabolomic Effects of Liraglutide Therapy on the Plasma Metabolomic Profile of Patients with Obesity

Assim A Alfadda et al. Metabolites. .

Abstract

Background: Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP1RA), is a well-established anti-diabetic drug, has also been approved for the treatment of obesity at a dose of 3 mg. There are a limited number of studies in the literature that have looked at changes in metabolite levels before and after liraglutide treatment in patients with obesity. To this end, in the present study we aimed to explore the changes in the plasma metabolomic profile, using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in patients with obesity.

Methods: A single-center prospective study was undertaken to evaluate the effectiveness of 3 mg liraglutide therapy in twenty-three patients (M/F: 8/15) with obesity, mean BMI 40.81 ± 5.04 kg/m2, and mean age of 36 ± 10.9 years, in two groups: at baseline (pre-treatment) and after 12 weeks of treatment (post-treatment). An untargeted metabolomic profiling was conducted in plasma from the pre-treatment and post-treatment groups using LC-HRMS, along with bioinformatics analysis using ingenuity pathway analysis (IPA).

Results: The metabolomics analysis revealed a significant (FDR p-value ≤ 0.05, FC 1.5) dysregulation of 161 endogenous metabolites (97 upregulated and 64 downregulated) with distinct separation between the two groups. Among the significantly dysregulated metabolites, the majority of them were identified as belonging to the class of oxidized lipids (oxylipins) that includes arachidonic acid and its derivatives, phosphorglycerophosphates, N-acylated amino acids, steroid hormones, and bile acids. The biomarker analysis conducted using MetaboAnalyst showed PGP (a21:0/PG/F1alpha), an oxidized lipid, as the first metabolite among the list of the top 15 biomarkers, followed by cysteine and estrone. The IPA analysis showed that the dysregulated metabolites impacted the pathway related to cell signaling, free radical scavenging, and molecular transport, and were focused around the dysregulation of NF-κB, ERK, MAPK, PKc, VEGF, insulin, and pro-inflammatory cytokine signaling pathways.

Conclusions: The findings suggest that liraglutide treatment reduces inflammation and modulates lipid metabolism and oxidative stress. Our study contributes to a better understanding of the drug's multifaceted impact on overall metabolism in patients with obesity.

Keywords: arachidonic acid; biomarkers; liraglutide; mass spectrometry; metabolomics; obesity; oxidized lipids.

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Conflict of interest statement

A.A.A. has received research funding from the Ministry of Education in Saudi Arabia, King Saud University, King Abdulaziz City for Science and Technology, Hevolution Foundation and Dallah Hospital. A.A.A. has received honoraria for lectures and scientific consultations from Novo Nordisk and Eli Lilly. A.A.A. has received financial support to attend scientific conferences from Novo Nordisk. A.D.M. has received research funding from the MRC, NIHR, Jon Moulton Charitable Foundation, Anabio, Fractyl, Boehringer Ingelheim, Gila, Randox, and Novo Nordisk. A.D.M. has received honoraria for lectures and presentations from Novo Nordisk, Astra Zeneca, Currax Pharmaceuticals, Boehringer Ingelheim, Screen Health, GI Dynamics, Algorithm, Eli Lilly, Ethicon, and Medtronic. ADM is a shareholder in the Beyond BMI clinic, which provides clinical obesity care. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
(A) Receiver operating characteristic (ROC) curve utilizing PLS-DA as the classification and feature ranking method. The top 15 variants had an area under the curve (AUC) of 0.852. (B) Frequency plot showing the top 15 significantly dysregulated metabolites in the pre- and post-liraglutide treatment groups. ROC curves are shown of individual metabolite biomarkers: (C) N-linoleoyl tryptophan, with an AUC of 0.881, and box plot (p ≤ 0.05 and fold change ≥ 1.5), where red represents the post-liraglutide treatment group and green represents the pre-liraglutide treatment group; and (D) epinephrine glucuronide, with an AUC of 0.849, and box plot (p ≤ 0.05 and fold change ≥ 1.5), where red represents the post-liraglutide treatment group and green represents the pre-liraglutide treatment group.
Figure 2
Figure 2
Schematic representation of the (A) highest scoring network pathways depicting the involvement of the differentially regulated metabolites between the pre- and post-liraglutide treatment groups. The dotted lines indicate indirect relationships, and the straight lines indicate direct relationships. The network pathways identified between the two groups were related to cell signalling, free radical scavenging, and molecular transport, with a score of 36 and 14 focus molecules (represented in bold Supplementary Table S4). The interaction networks were generated through IPA (QIAGEN, Aarhus, Denmark). (B) The top canonical pathways dysregulated after 12 weeks of treatment with liraglutide.
Figure 2
Figure 2
Schematic representation of the (A) highest scoring network pathways depicting the involvement of the differentially regulated metabolites between the pre- and post-liraglutide treatment groups. The dotted lines indicate indirect relationships, and the straight lines indicate direct relationships. The network pathways identified between the two groups were related to cell signalling, free radical scavenging, and molecular transport, with a score of 36 and 14 focus molecules (represented in bold Supplementary Table S4). The interaction networks were generated through IPA (QIAGEN, Aarhus, Denmark). (B) The top canonical pathways dysregulated after 12 weeks of treatment with liraglutide.
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