Alterations of lipid homeostasis in serum and white adipose tissue in morbid obese patients are partly reversed by the bariatric surgery

Gastric Bypass surgery (GBS) represents a well-established approach to counteract human morbid obesity and its related comorbidities in modern countries. Beside its beneficial effect on weight loss and glucose homeostasis, emerging evidence suggests that GBS impacts on the circulating levels of phospho- and sphingolipids. However, long-term effects of GBS on lipid metabolism have not been explored. Thereby, we aimed to unveil to what extent GBS improves lipid homeostasis in serum and tissues from morbid obese individuals. To investigate alterations in lipidomic signatures associated with massive weight loss following GBS in morbid obese patients, we employed direct infusion tandem mass spectrometry (MS) allowing to quantify a wide range of lipid metabolites in serum and subcutaneous adipose tissue (SAT) samples. Systematic lipidomic analyses were conducted in samples collected in a longitudinal cohort of patients (cohort 1, n = 11) prior to GBS, and one year following the surgery. These novel data were cross compared with our recent lipidomic analyses conducted by the same approach in an independent cohort of morbid obese patients and lean controls, where serum and visceral adipose tissue (VAT) lipids were analysed (cohort 2, n = 39). Over 400 phospholipid and sphingolipid species have been quantified in serum and SAT (cohort 1), allowing to establish detailed lipidomic signatures associated with morbid obesity in a tissue-specific manner. Concomitant with weight loss and improvement of metabolic parameters, a massive rearrangement of lipid metabolites was observed one year following GBS. Strikingly, a substantial reduction of ceramide levels and increased amount of hexosylceramides were detected in both serum and SAT. The comparison of these new lipidomic profiles with the serum and VAT lipidomes established from lean and morbid obese subjects (cohort 2) revealed that GBS partly restored the lipid alterations associated with morbid obesity. Our study provides the first systematic analysis of the long-term lipid homeostasis modifications upon GBS in humans SAT and serum and demonstrates that lipid metabolism alterations associated with morbid obesity might be partly reversed by GBS. The research protocol was registered with the Protocol Registration and Results System at [ClinicalTrial.gov][1] [[NCT03029572][2]]. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by Swiss National Science Foundation grant 310030_184708/1, the Vontobel Foundation, the Novartis Consumer Health Foundation, EFSD/Novo Nordisk Programme for Diabetes Research in Europe, the Olga Mayenfisch Foundation, Fondation pour l'innovation sur le cancer et la biologie, Ligue Pulmonaire Genevoise, Swiss Cancer League KFS-5266-02-2021-R, Velux Foundation, Leenaards Foundation, Swiss Life Foundation, the ISREC Foundation, and the Gertrude von Meissner Foundation attributed to CD. FS was supported by the Swiss Life Foundation and the Young Independent Investigator Grant from SGED/SSED. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics committee of the University Hospital of Geneva gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data generated or analysed during this study are included in this published article (and its supplementary information files). [1]: https://ClinicalTrial.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03029572&atom=%2Fmedrxiv%2Fearly%2F2023%2F08%2F11%2F2023.06.12.23291122.atom