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Untargeted Urinary Proteomics Uncovers Nephroprotective and Systemic Adaptations after Obesity Surgery Induced Weight Loss

ABSTRACT: Weight loss induced by bariatric surgery (BS) is recognized for having a profound impact on several biological systems. This study aimed to characterize the urinary proteomic profile in individuals with obesity before and after BS, to identify urinary proteins that reflect the kidney and systemic adaptations to weight loss. Urine samples from individuals with obesity (n=16) undergoing BS were collected before and two-years after surgery. Untargeted high-resolution liquid chromatography–mass spectrometry (LC-MS) with label-free quantification (LFQ) was used to assess changes in the urinary proteome. A total of 2347 proteins were identified in the urine. Among these, 1016 depicted a significantly different expression post-surgery (p<0.05). In particular, 54 proteins were identified with at least 50% change (≥1.5-fold), either upregulated (n=42) or downregulated (n=12). Functional classification of these top altered proteins revealed an association with immune function (n=17; e.g., protein S100-A9, alpha-1-acid glycoproteins 1 and 2); cytoskeleton/cell adhesion (n=11; e.g., supervillin, ezrin, periplakin) and kidney adaptation (n=11; e.g., elongation factor 1-alpha 1, cystatin-B, megalin, cubilin). A decrease in inflammation protein markers (alpha-1-acid glycoproteins), alongside an increase in proteins associated with immune modulation and oxidative stress protection (dipeptidase 1 and heat shock cognate 71 kDa protein) were also observed post-surgery. Additionally, changes in cytoskeletal and extracellular matrix proteins were identified, as well as proteins present in specific kidney cell components and tubular processes. The most significant modifications found in the urinary proteome following BS were proteins primarily associated with decreased inflammation and oxidative stress, as well as cytoskeletal and extracellular matrix proteins. Overall, our results reveal potential novel pathways contributing to systemic modifications and nephroprotective effects of BS induced weight loss.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Urine

DISEASE(S): Obesity

SUBMITTER: David Carrageta

LAB HEAD: Mariana Pereira

PROVIDER: PXD063904 | Pride | 2025-12-10

REPOSITORIES: Pride

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Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of histological findings, from simple steatosis to steatohepatitis (NASH), the latter presenting a higher risk of cardiovascular and kidney diseases, type 2 diabetes and end-stage liver disease. NAFLD is seen as the hepatic manifestation of the metabolic syndrome and affects up to 70-80% of obese patients. There are currently no approved pharmacological therapies for NASH, thus the only option is lifestyle intervention or bariatric surgery in order to lose weight and to improve insulin resistance. Although surgical intervention has allowed collections of liver biopsies, transcriptomic data from livers are still scarce and especially follow-up data to evaluate the impact of weight loss intervention on the liver. Therefore we studied hepatic transcriptomic data in a large cohort of obese patients assessed for presence of NASH at baseline and 1 year follow-up. Patients visiting the obesity clinic of the Antwerp University Hospital for a problem of being overweight (BMI above 25 to 29.9 kg/m²) or obese (BMI above 30 kg/m²) were prospectively recruited and underwent a hepatic work-up. Patients were excluded from further analysis in case of significant alcohol consumption (>20 g/day), history of bariatric surgery, diagnosis of another liver disease, pre-existing diabetes. Patients who were, however, diagnosed with de novo diabetes at baseline or at follow-up were not excluded. If NAFLD was suspected, liver biopsy was proposed. For patients undergoing bariatric surgery (BS), a liver biopsy was proposed regardless of the criteria. Patients were reassessed after 1 year. Liver biopsy was performed percutaneously (16G Menghini) or peri-operatively (14G Tru-Cut). The different histological features of NAFLD were assessed using the NASH Clinical Research Network (NASH CRN) Scoring System. The presence of NASH was defined according to Chalasani et al. necessitating the combined presence of steatosis, ballooning and lobular inflammation.

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Untargeted Urinary Proteomics Uncovers Nephroprotective and Systemic Adaptations after Obesity Surgery Induced Weight Loss

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