Roux-en-Y gastric bypass surgery (RYGB) has been effective for inducing weight-loss and remission of diabetes in obese persons. Nonetheless, the response to RYGB and resulting improvements in glycemic control are heterogeneous and not well understood. To gain molecular insights into how individuals respond to RYGB, we monitored the longitudinal effects of RYGB surgery via circulating proteins. We quantified 368 proteins using multiplexed and sensitive immunoassays (Olink) in sera collected from 146 obese persons with T2D (BMI > 35 kg/m2) prior to, and at one and three months after surgery. We observed an overall longitudinal change in circulating levels for ∼50% of the proteins (FDR < 0.01). This included a post-RYGB increase in levels of GH, IGFBP-2, NT-proBNP, REGA1 and MMP-3, as well as a decrease in levels of SSC4D, SERPINA12, GIF, FBP1, CES1. To deconvolute the inter-individual heterogeneity of the circulating proteomes and protein-related longitudinal dynamics, we clustered the total of ∼44,000 protein profiles into 10 response patterns. Just 8% (28/368) of the proteins’ levels changed in a common manner across the majority of individuals, as these were grouped into 3 or fewer clusters. Among these were proteins related to adipogenesis (LEP, DLK1, GH), white adipocyte differentiation (LEP, FABP4), as well as innate immunity (CHIT1, PTX3, CSTB). However, out of these 28 proteins, only levels of VSIG2 were significantly associated (FDR < 0.01) with diabetes remission at 12 months (HbA1c < 6.5%, no diabetes medication). Overall, our results suggest a wide-reaching, individual-specific, but predominantly short-term impact of RYGB surgery on the circulating proteome. Current investigations examine how genetic variance and mRNA expression in adipose and liver tissue influence the donors’ circulating proteomes in order to explain the observed heterogeneity and its impact on a person’s molecular homeostasis.

Disclosure

C.E. Thomas: None. R.S. Häussler: None. M. Hong: None. V. Raverdy: None. M. Dale: None. M. Canouil: None. G. Mazzoni: None. A. Viñuela: None. P. Froguel: None. S. Brunak: Board Member; Self; Intomics A/S, Proscion A/S. Research Support; Self; Novo Nordisk Foundation. Stock/Shareholder; Self; Lundbeck, Novo Nordisk A/S. J.M. Schwenk: None.

Funding

Innovative Medicines Initiative Joint Undertaking (115317); European Union’s Seventh Framework Programme (FP7/2007-2013); Conseil Regional Nord-Pas-de-Calais; European Commission (FEDER 12003944); European Genomic Institute for Diabetes (ANR-10-LABX-46); Foundation Coeur et Arteres (R15112EE); Fonds hospitalier d’aide a l’emergence et a la structuration des activities et des equipes de recherche 2015 (CHRU Lille, France)

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