In Vivo Gastric Expression of FTO and MC4R in Sleeve Gastrectomy Patients: Diagnostic Utility Without Predictive Value for Weight Loss

TL;DR

The study finds that FTO and MC4R gene expression in the stomach can distinguish obese from non-obese individuals but does not predict weight loss after surgery.

Contribution

This is the first study to demonstrate the diagnostic utility of gastric FTO and MC4R expression in obesity classification without predictive value for post-surgery weight loss.

Findings

FTO expression was significantly upregulated in obese patients compared to controls.

MC4R expression was significantly downregulated in obese patients compared to controls.

No correlation was found between preoperative gene expression and weight loss outcomes after sleeve gastrectomy.

Abstract

The fat mass and obesity-associated (FTO) and melanocortin-4 receptor (MC4R) genes have been implicated in the pathophysiology of obesity. However, their regulatory behavior in human gastric tissue and association with postoperative weight loss following metabolic and bariatric surgery (MBS) remain unclear.

In this prospective case–control study, gastric tissue from 50 patients with obesity undergoing laparoscopic sleeve gastrectomy and 48 non-obese controls was analyzed for FTO and MC4R mRNA expression using quantitative PCR. Adjusted Inverse propensity score weighting (IPSW-adjusted) and age-/sex-adjusted linear regression were applied. Receiver operating characteristic (ROC) curves were used to evaluate discriminatory thresholds. Correlation with 12-month percent total weight loss (%TWL) was assessed.

FTO expression was significantly upregulated (mean fold-change: 4.68, p < 0.001) and MC4R downregulated (mean fold-change: − 0.91, p < 0.001) in patients with obesity. ROC analysis identified thresholds of > 1.515 for FTO (AUC = 1.00) and < 0.525 for MC4R (AUC = 1.00), both with high sensitivity and specificity. No significant correlation was observed between gene expression and %TWL at 12-month follow-up.

Gastric expression of FTO and MC4R accurately discriminates between individuals with and without obesity but does not predict postoperative weight loss outcomes after sleeve gastrectomy. These findings indicate diagnostic potential, whereas prognostic value remains unsubstantial.

The online version contains supplementary material available at 10.1007/s11695-025-08399-y.

Gastric expression of FTO and MC4R was significantly different between patients with and without obesity.

FTO > 1.515-fold and MC4R < 0.525-fold thresholds effectively discriminated obesity status (AUC 1.00 for both).

No significant correlation was found between preoperative gene expression and %TWL at 12 months after sleeve gastrectomy.

FTO and MC4R may serve as diagnostic biomarkers for obesity classification, but not predictors for weight loss response.

Further studies with larger and sex-stratified cohorts are needed to validate mechanistic and prognostic roles.

The online version contains supplementary material available at 10.1007/s11695-025-08399-y.

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