To identify molecular mechanisms contributing to postoperative metabolic improvements after Roux-en-Y gastric bypass (RYGB), we performed comprehensive proteomic analysis of fasting human plasma samples obtained from the SLIMM-T2D longitudinal clinical trial, which randomized obese individuals with T2D to RYGB surgery or a one-year intensive medical diabetes and weight management (DWM) program, and followed them for 3 years. Somalogic proteomic analysis was performed on plasma collected in the fasting state at baseline and during longitudinal follow-up, and proteins differentially abundant in RYGB vs. DWM at each time point were identified. The protein with highest magnitude of differential abundance at 3 years was insulin-like growth factor binding protein 2 (IGFBP2), upregulated by 2.2-fold in RYGB vs. DWM (p=4.37E-06); differences were confirmed by ELISA. IGFBP2 inversely correlated at 3 years with BMI (r=-0.74, p=5.31E-05) and HbA1c (r=-0.68, p=0.00004). Notably, IGFBP2 levels were increased at the first postoperative study visit (10% weight loss) following RYGB or at similar weight loss for the DWM group, suggesting an early weight-independent contribution.
IGFBP2 is predominantly expressed in liver and upregulated after RYGB in mice (2.8-fold at 8 weeks, GSE68812). To identify IGFBP2-dependent mechanisms contributing to improved hepatic metabolism, we overexpressed mouse IGFBP2 or control vector in mouse AML12 hepatocytes, achieving a 6-fold increase in IGFPB2 protein. qPCR revealed 15-30% downregulation of lipogenic genes (e.g., Fasn, Srebp1) with a 2-fold increase in expression of genes regulating fatty acid oxidation (e.g., Ppara, Ppargc1a). Analysis of metabolism (Seahorse flux analyzer) revealed increased fatty acid oxidation (3-fold, p<0.01 for IGFBP2 vs. control).
In conclusion, increased IGFBP2 expression may contribute to improved hepatic lipid oxidative metabolism, and thus induce systemic metabolic improvement after RYGB surgery.
Y. Yuchi: None. W. Cai: None. T. Takagi: None. H. Pan: None. J. Dreyfuss: None. K. Foster: None. A.H. Vernon: None. D.C. Simonson: Advisory Panel; Self; GI Windows, Inc.. Stock/Shareholder; Self; GI Windows, Inc.. Stock/Shareholder; Spouse/Partner; Phase V Technologies, Inc. A. Goldfine: Employee; Self; Novartis AG. A. Hoeflich: None. M.E. Patti: Research Support; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Xeris Pharmaceuticals, Inc.. Research Support; Self; Ethicon US, LLC., Coviden, MedImmune. Other Relationship; Self; Novo Nordisk Inc., XOMA Corporation, AstraZeneca, Nestlé. Research Support; Self; Dexcom, Inc.. Consultant; Self; Eiger BioPharmaceuticals.