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Treatment with dapagliflozin increases FGF-21 gene expression and reduces triglycerides content in myocardial tissue of genetically obese mice

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Abstract

Background

The association between obesity and some cardiovascular complications such as heart failure (HF) is well established, and drugs affecting adiposity are supposed to be promising treatments for these conditions. The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antidiabetic drugs showing benefits in patients with HF, despite the underlying mechanisms have not been completely understood yet. SGLT2i are supposed to promote systemic effects, such as triglycerides mobilization, through the enhancement of fibroblast growth factor-21 (FGF-21) activity. So, in this study, we evaluated the effects of dapagliflozin treatment on FGF-21 and related receptors (FGF-Rs) gene expression and on lipid content in myocardial tissue in an animal model of genetically induced obesity to unravel possible metabolic mechanisms accounting for the cardioprotection of SGLT2i.

Methods

Six-week-old C57BL/6J wild-type mice and B6.V-LEP (ob/ob) mice were randomly assigned to the control or treatment group (14 animals/group). Treatment was based on the administration of dapagliflozin 0.15 mg/kg/day for 4 weeks. The gene expression of FGF-21 and related receptors (FGF-R1, FGF-R3, FGF-R4, and β-klotho co-receptor) was assessed at baseline and after treatment by real-time PCR. Similarly, cardiac triglycerides concentration was measured in the control group and treated animals.

Results

At baseline, FGF-21 mRNA expression in the heart did not differ between lean and obese ob/ob mice. Dapagliflozin administration significantly increased heart FGF-21 gene expression, but only in ob/ob mice (p < 0.005). Consistently, when measuring the amount of triglycerides in the cardiac tissue, SGLT2i treatment reduced the lipid content in obese ob/ob mice, while no significant effects were observed in treated lean animals (p < 0.001). The overall expression of the FGF-21 receptors was only minimally affected by dapagliflozin treatment both in obese ob/ob mice and in lean controls.

Conclusions

Dapagliflozin administration increases FGF-21gene expression and reduces triglyceride content in myocardial tissue of ob/ob mice, while no significant effect was observed in lean controls. These results might help understand the cardiometabolic effects of SGLT2i inducing increased FGF-21 synthesis while reducing lipid content in cardiomyocytes as a possible expression of the switch to different energy substrates. This mechanism could represent a potential target of SGLT2i in obesity-related heart diseases.

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Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

T2DM:

Type 2 diabetes mellitus

NAFLD:

Non-alcoholic fatty liver disease

HFpEF:

Heart failure with preserved ejection fraction

GLP-1:

Glucagon-like peptide 1

SGLT2i:

Sodium-glucose cotransporter-2 inhibitors

FGF-21:

Fibroblast growth factor-21

NIH:

National Institute of Health

FGF-R(s):

Fibroblast growth factor-21 receptor(s)

BMI:

Body mass index

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Funding

Research relating to this abstract was funded by a non-conditioning grant from AstraZeneca (476/2016), in charge to R.V.

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Authors and Affiliations

  1. Internal Medicine 3, Department of Medicine, University-Hospital of Padova, Padua, Italy

    A. Di Vincenzo, M. Crescenzi, M. Granzotto, P. Fioretto, R. Vettor & M. Rossato

  2. Sports and Exercise Medicine Division, Department of Medicine, University-Hospital of Padova, Padua, Italy

    M. Vecchiato

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Contributions

ADV, MR, and RV designed the study and wrote the manuscript; MC and MG performed the experiments and the statistics; MV and PF proofread and checked the entire manuscript. All authors read and approved the final manuscript.

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Correspondence to A. Di Vincenzo.

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P.F. is involved as advisory board member and speaker for AstraZeneca, Eli Lilly, Boehringer Ingelheim, Novo, and Bayer.

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As reported in the Methods section, the procedures involving animal care followed institutional guidelines that comply with national and international laws and policies (European Economic Community Council Directive 86/609, OJ L 358, 1 Dec.2012, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication no. 85–23, 1985). The study design was approved by the Ethics Committee of the University of Padova for the care and use of laboratory animals (CEASA protocol number 58/2018-PR, approved by the Ethics Committee of the University of Padova, Italy). All experiments followed committee guidelines and the institutional protocol for animal care that was approved by the Italian Ministry of Health (58/2018-PR).

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Di Vincenzo, A., Crescenzi, M., Granzotto, M. et al. Treatment with dapagliflozin increases FGF-21 gene expression and reduces triglycerides content in myocardial tissue of genetically obese mice. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-023-02273-3

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