Lidia Castagneto-Gissey, Giulia Angelini, Geltrude Mingrone, Elena Cavarretta, Leonardo Tenori, Cristina Licari, Claudio Luchinat, Anna Luise Tiepner, Nicola Basso, Stefan R. Bornstein, Deepak L. Bhatt, Giovanni Casella
| Original language | English |
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| Article number | 103864 |
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| Pages (from-to) | 103864 |
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| Journal | EBioMedicine |
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| Volume | 76 |
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| Early online date | 4 Feb 2022 |
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| DOIs | |
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| Accepted/In press | 19 Jan 2022 |
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| E-pub ahead of print | 4 Feb 2022 |
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| Published | Feb 2022 |
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Funding Information:
This study was funded by internal funds from University of Rome Sapienza which had a role in performing metabolomics analyses. The funders had no role in the study design, interpretation or writing of the report.
Publisher Copyright:
© 2022 The Authors
Introduction
Body-mass index is a major determinant of left-ventricular-mass (LVM). Bariatric-metabolic surgery (BMS) reduces cardiovascular mortality. Its mechanism of action, however, often encompasses a weight-dependent effect. In this translational study, we aimed at investigating the mechanisms by which BMS leads to LVM reduction and functional improvement.
Methods
Twenty patients (45.2 ± 8.5years) were studied with echocardiography at baseline and at 1,6,12 and 48 months after sleeve-gastrectomy (SG). Ten Wistar rats aged 10-weeks received high-fat diet ad libitum for 10 weeks before and 4 weeks after SG or sham-operation. An oral-glucose-tolerance-test was performed to measure whole-body insulin-sensitivity. Plasma metabolomics was analysed in both human and rodent samples. RNA quantitative Real-Time PCR and western blots were performed in rodent heart biopsies. The best-fitted partial-least-square discriminant-analysis model was used to explore the variable importance in the projection score of all metabolites.
Findings
Echocardiographic LVM (-12%,-23%,-28% and -43% at 1,6,12 and 48 months, respectively) and epicardial fat decreased overtime after SG in humans while insulin-sensitivity improved. In rats, SG significantly reduced LVM and epicardial fat, enhanced ejection-fraction and improved insulin-sensitivity compared to sham-operation. Metabolomics showed a progressive decline of plasma branched-chain amino-acids (BCAA), alanine, lactate, 3-OH-butyrate, acetoacetate, creatine and creatinine levels in both humans and rodents.
Hearts of SG rats had a more efficient BCAA, glucose and fatty-acid metabolism and insulin signaling than sham-operation. BCAAs in cardiomyocyte culture-medium stimulated lipogenic gene transcription and reduced mRNA levels of key mitochondrial β-oxidation enzymes promoting lipid droplet accumulation and glycolysis.
Interpretation
After SG a prompt and sustained decrease of the LVM, epicardial fat and insulin resistance was found. Animal and in vitro studies showed that SG improves cardiac BCAA metabolism with consequent amelioration of fat oxidation and insulin signaling translating into decreased intra-myocytic fat accumulation and reduced lipotoxicity.