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Animal Models

Curcumin enhances the anti-obesogenic activity of orlistat through SKN-1/NRF2-dependent regulation of nutrient metabolism in Caenorhabditis elegans

International Journal of Obesity volume 49, pages 516–526 (2025)Cite this article

Subjects

Abstract

Background

Metabolic dysregulation, a defining feature of obesity, disrupts essential signalling pathways involved in nutrient sensing and mitochondria homeostasis. The nuclear factor erythroid 2-related factor 2 (NRF-2) serves as a pivotal regulator of the cellular stress response, and recent studies have implicated it in the pathogenesis of obesity, diabetes, and metabolic syndrome. Curcumin, a polyphenolic compound derived from turmeric, has been identified as a potent activator of NRF-2. Evidence suggests curcumin impacts obesity and metabolic disorders by modulating gut microbiota composition, increasing energy expenditure, and regulating lipid metabolism. Orlistat, an anti-obesity drug, inhibits fat absorption in the gastrointestinal tract, but its side effects limits its broader use.

Objectives

The present study aims to investigate the potential synergetic effect of a hybrid combination between orlistat and curcumin. Additionally, we provide a detailed understanding of the molecular mechanisms through which this combination mitigates glucose-induced lipid accumulation in Caenorhabditis elegans, with a focus on the role of the skinhead 1 (SKN-1) transcription factor, an orthologue of NRF2.

Methods

We assessed the lipid accumulation and the changes in skn-1 transcriptional activity in C. elegans using confocal GFP-based detection, alongside mRNA expression analysis of genes from lipid metabolism and oxidative stress response in wild-type, QV225 and LD1 strains. Furthermore, we evaluated locomotion, chemotaxis and mitochondrial dynamics to enhance our understanding of the proposed molecular-based model.

Results

Our findings reveal that the orlistat/curcumin combination exerts an anti-obesogenic effect through SKN-1/NRF2-dependent regulation of conserved genes involved in carbohydrate and lipid metabolism in C. elegans. Moreover, the combination stimulates mitochondrial potential, further contributing to the observed synergistic effects.

Conclusion

The hybrid combination of orlistat and curcumin demonstrates significant anti-obesity activity by regulating nutrient-sensing pathways through SKN-1/NRF-2 modulation. This approach may allow for the reduction of orlistat dosage, thereby minimizing its adverse effects while maintaining its therapeutic efficacy.

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Fig. 1: Curcumin and orlistat combination stimulates the chemosensory system and body bending in glucose-fed C. elegans.
Fig. 2: Curcumin and orlistat combination potently suppressed glucose-associated lipid accumulation in C. elegans.
Fig. 3: Curcumin and orlistat combination upregulates SKN-1 expression in glucose-supplemented C. elegans.
Fig. 4: Curcumin and orlistat modulate genes related to the nutrient-sensing network in C. elegans-based obesity model.
Fig. 5: Curcumin and orlistat either alone or in combination stimulate mitochondrial potential in glucose-supplemented C. elegans.
Fig. 6: Orlistat/curcumin combination regulates lipid metabolism and mitochondria activity through skn-1 activation in C. elegans.

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Data availability

All relevant data are within the manuscript. The data set generated and analysed during the current study also available from the corresponding author upon request.

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Acknowledgements

This research received funding from the Bulgarian National Science Fund under BG-175467353-2023-03 programme for project Natural NRF2 activators modulating obesity mechanisms: molecular pharmacology-based in vivo study (contract number КП-06-КОСТ/4), the European Union’s Horizon 2020 research and innovation programme, project PlantaSYST (SGA No 739582 under FPA No. 664620) and by the European Regional Development Fund through the Bulgarian “Science and Education for Smart Growth” Operational Programme (project BG05M2OP001-1.003-0001-C01) and Programme Research Innovation and Digitalisation for Smart Transformation. This article is based upon work from COST Action CA20121 BenBedPhar, supported by COST (European Cooperation in Science and Technology).

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Author notes

  1. These authors contributed equally: Martina S. Savova, Monika N. Todorova.

Authors and Affiliations

  1. Laboratory of Metabolomics, Department of Biotechnology, Institute of Microbiology, Bulgarian Academy of Sciences, 139 Ruski Blvd., 4000, Plovdiv, Bulgaria

    Martina S. Savova, Monika N. Todorova, Biser K. Binev, Milen I. Georgiev & Liliya V. Mihaylova

  2. Department of Plant Cell Biotechnology, Center of Plant Systems Biology and Biotechnology, 4000, Plovdiv, Bulgaria

    Martina S. Savova, Monika N. Todorova, Biser K. Binev, Milen I. Georgiev & Liliya V. Mihaylova

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  1. Martina S. Savova
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Contributions

Martina S. Savova: Conceptualization, Methodology, Formal analysis, Data curation, Writing – original draft, review and editing. Monika N. Todorova: Conceptualization, Methodology, Data curation, Writing – original draft, Visualization, Investigation. Biser K. Binev: Methodology. Milen I. Georgiev: Conceptualization, Methodology, Supervision, Funding acquisition, Writing – review and editing. Liliya V. Mihaylova: Conceptualization, Methodology, Formal analysis, Writing – review and editing, Funding acquisition, Supervision.

Corresponding author

Correspondence to Liliya V. Mihaylova.

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This study does not involve human participants, human material, or live vertebrates. The research was conducted using C. elegans as a model organism, which aligns with the Replacement principle of the 3 R’s (Replacement, Reduction and Refinement) philosophy. Therefore, ethics approval or consent to participate were not required.

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Savova, M.S., Todorova, M.N., Binev, B.K. et al. Curcumin enhances the anti-obesogenic activity of orlistat through SKN-1/NRF2-dependent regulation of nutrient metabolism in Caenorhabditis elegans. Int J Obes 49, 516–526 (2025). https://doi.org/10.1038/s41366-025-01724-6

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