The Preprohormone Expression Profile of Enteroendocrine Cells following Roux-en-Y Gastric Bypass in Rats

Abstract

It is well-known that Roux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes and a marked and long-term body weight loss, but the molecular mechanisms driving these desirable effects are not fully understood. RYGB results in increased plasma levels of several gut peptidergic hormones with either anorexigenic and/or antidiabetic effects. However, the potent effects of RYGB cannot solely be ascribed to these, and it is therefore likely that additional factors play a role. To gain further insight we have characterized the mRNA expression profile in enteroendocrine cells in the gut at day 9, 22 and 60 following surgery in a RYGB rat model. The enteroendocrine cells were identified by chromogranin-A immunohistochemistry staining, and isolated by laser capture microdissection from five locations covering the full rostrocaudal extent of the gastrointestinal tract. The mRNA expression profiles were analyzed by RNAseq, and bioinformatic analyses were applied to identify known and predicted preprohormones differentially regulated following RYGB. In total 64 putative preprohormones were identified in the secretome of rat enteroendocrine cells, of which 40 were shown to be differentially regulated at one or more time-points post surgery, including several well-known preprohormone genes (GCG, CCK, GHRL, GIP, NMU, SCT, NPY, and VIP). Only six preprohormones were differentially regulated at all time-points (NMU, TAC3, FAM3D, SCT1, SCT and ADM). We present the full mRNA expression profile of the secretome of chromogranin A positive enteroendocrine cells following RYGB surgery in rats. The data provides a region-specific characterization of all preprohormone encoding genes in the rat gut, including 23 not hitherto known. This comprehensive catalogue of gut peptide hormone expression might help our understanding of hormone mediated effects of RYGB on diabetes remission and body weight lowering. Disclosure L. Biehl Rudkjaer: Employee; Self; Gubra. C. Zhang: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. K. Rigbolt: Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. S.L. Pedersen: None. M. Falkenhahn: None. T. Hübschle: Employee; Self; Sanofi-Aventis Deutschland GmbH. T. Schmidt: None. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra. J. Jelsing: Stock/Shareholder; Self; Gubra. Research Support; Self; Sanofi.