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Adipocyte and Cell Biology

Canagliflozin regulates adipocyte lipolysis in vitro via a SGLT2 independent signaling pathway

International Journal of Obesity (2026)Cite this article

Subjects

Abstract

Background

Adipose lipolysis, a process involving the degradation of triglycerides and the release of fatty acids and glycerol, is an important biological event in lipid metabolism. Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter 2 (SGLT2) in renal tubules and has also been shown to improve lipid metabolism in adipocytes. This study aims to determine whether Cana directly affects adipose lipolysis and to explore the underlying mechanistic pathways.

Method

Primary mature adipocytes and differentiated preadipocytes isolated from the epididymal fat pads of Sprague-Dawley rats were used as in vitro models. The effects of Cana on glycerol release and lipase activity were evaluated using ELISA and Western blot analyses.

Results

Cana treatment directly inhibited basal glycerol release and lipase activity in both primary adipocytes and topically administered adipose tissue, achieving a dose-dependent 35% to 65% suppression of lipolysis. This was associated with a 2.3-fold decrease in the level of HSL phosphorylated at the Ser660 site. Using differentiated adipocytes derived from the human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, we found that Cana significantly attenuated glycerol release (~32% to 53% reductions) induced by lipolysis. Moreover, Cana exerted antilipolytic effects in models of both acute (isoprenaline-induced) and chronic (tumor necrosis factor-α-induced) lipolysis. Mechanistically, the antilipolytic effect of Cana was mediated through activation of the PI3K/AKT pathway and reduction of cAMP production.

Conclusion

In conclusion, Cana regulates adipocyte lipolysis via an SGLT2-independent signaling pathway, which enhances our understanding of its role in modulating lipid metabolism.

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Fig. 1: Cana treatment inhibits glycerol release in a time- and dose- dependent manner in adipocytes.
Fig. 2: Cana treatment prevents lipolysis by inhibiting lipase activity.
Fig. 3: Cana treatment activates PI3K-AKT signaling pathway.
Fig. 4: Cana directly acted on PI3K to inhibit lipolysis.
Fig. 5: Cana treatment inhibits glycerol release and lipase activity stimulated by Isop.
Fig. 6: Cana inhibits Tumor necrosis factor-α-induced chronic lipolysis.
Fig. 7: Topical application of Cana inhibits Isop-stimulated lipolysis.

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Data availability

The raw/processed data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

Materials availability

Data and materials are available upon request.

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Funding

This study was supported by Natural Science Foundation project of Sichuan Province (2024NSFSC1730); Science and Technology Strategic Cooperation Project of Luzhou Government - Southwest Medical University (2024LZXNYDJ101); Innovation Training Programme for Students in Sichuan Province (S202410632281).

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Author notes

  1. These authors contributed equally: Qiuyu Li, Mengya Li.

Authors and Affiliations

  1. Department of Pharmacy, The Affiliated Hospital, Southwest Medical University, Luzhou, China

    Qiuyu Li, Mengya Li, Jie Zhou, Xiaohui Xu, Zhongxiang Zhang, Longyang Jiang, Yilan Huang & Xuping Yang

  2. School of Pharmacy, Southwest Medical University, Luzhou, China

    Qiuyu Li, Mengya Li, Jie Zhou, Xiaohui Xu, Zhongxiang Zhang, Longyang Jiang, Yilan Huang & Xuping Yang

  3. Department of pharmacy, Naxi District People’s Hospital of Luzhou City, Luzhou, China

    Jianling Huang

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Contributions

Conceptualization: XY and YH; methodology: QL and ML; software: JZ; validation, JH and XX; formal analysis: ZZ; resources: XY; data curation: LJ; writing—original draft preparation: QL; writing—review and editing: XY and QL; supervision: XY, YH. All authors have read and agreed to the published version of the manuscript. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Yilan Huang or Xuping Yang.

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All animal care and experimental procedures complied with the National Institutes of Health guidelines and were approved by the Animal Care and Use Committee of Southwest Medical University (License No. 20221104-012).

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Li, Q., Li, M., Zhou, J. et al. Canagliflozin regulates adipocyte lipolysis in vitro via a SGLT2 independent signaling pathway. Int J Obes (2026). https://doi.org/10.1038/s41366-025-02009-8

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