Original article| Volume 14, ISSUE 6, P821-832, June 2018

Jejunal long noncoding RNAs are associated with glycemic control via gut–brain axis after bariatric surgery in diabetic mice



      Metabolic and bariatric surgery is effective in ameliorating type 2 diabetes, although its underlying mechanisms are largely unknown. Our previous study indicated that the distinctly expressed duodenal long noncoding RNAs (lncRNAs) induced by the duodenal-jejunal bypass (DJB) might play a role in improving glycemic control via the enteropancreatic axis. Therefore, the physiologic role of the jejunum in metabolic regulation after DJB requires investigation.


      To investigate the alterations in the jejunal Roux limb lncRNA expression signatures after DJB and analyze the functional pathways associated with metabolic improvement on a genome-wide scale in high-fat diet–induced diabetic mice.


      University medical center.


      Diabetic mice induced by high-fat diet were randomly assigned into 2 groups undergoing either DJB or sham surgery. The lncRNA and messenger (m)RNA expression profiles of the Roux limb segment of the jejunum in both groups were investigated using microarray. To identify the functional characteristics of the distinctly expressed lncRNAs, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. The lncRNA-mRNA and lncRNA-transcription factor interaction networks were constructed based on Pearson correlation analysis.


      Compared with the sham group, 827 dysregulated (fold change ≥2.0) jejunal lncRNAs were identified in the DJB group. Both Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology enrichment analysis revealed that 601 lncRNA–co-expressed mRNAs (fold change ≥2.0) were associated with neuromodulation-related pathways or biological processes, including serotonergic, glutamatergic, and dopaminergic synapses. In addition, hormonal regulation–related pathways, especially steroid biosynthesis, were also enriched. The results were further confirmed by bioinformatic analysis of target genes or transcription factors predicted on the basis of dysregulated jejunal lncRNAs. Furthermore, the NONMMUT023781 lncRNA may simultaneously target the Adcy8 mRNA both in cis and in trans and participate in neuromodulation and hormonal regulation.


      Alterations of jejunal Roux limb lncRNA and mRNA expression profiles trigger both neuromodulation and endocrine-related pathways, which play a critical role in type 2 diabetes remission after metabolic and bariatric surgery via the gut–brain axis. NONMMTU023781 and Adcy8 were identified as potential targets, which warrant further research.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery for Obesity and Related Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Courcoulas A.P.
        • Belle S.H.
        • Neiberg R.H.
        • et al.
        Three-year outcomes of bariatric surgery vs lifestyle intervention for type 2 diabetes mellitus treatment: a randomized clinical trial.
        JAMA Surg. 2015; 150: 931-940
        • Schauer P.R.
        • Kashyap S.R.
        • Wolski K.
        • et al.
        Bariatric surgery versus intensive medical therapy in obese patients with diabetes.
        N Engl J Med. 2012; 366: 1567-1576
        • Schauer P.R.
        • Bhatt D.L.
        • Kirwan J.P.
        • et al.
        Bariatric surgery versus intensive medical therapy for diabetes–3-year outcomes.
        N Engl J Med. 2014; 370: 2002-2013
        • Schauer P.R.
        • Bhatt D.L.
        • Kirwan J.P.
        • et al.
        Bariatric surgery versus intensive medical therapy for diabetes - 5-year outcomes.
        N Engl J Med. 2017; 376: 641-651
        • Furness J.B.
        The enteric nervous system and neurogastroenterology.
        Nat Rev Gastroenterol Hepatol. 2012; 9: 286-294
        • Zhang X.
        • Yu B.
        • Yang D.
        • et al.
        Gastric volume reduction is essential for the remission of type 2 diabetes mellitus after bariatric surgery in nonobese rats.
        Surg Obes Relat Dis. 2016; 12: 1569-1576
        • Wang T.
        • Zhang P.
        • Zhang X.
        • et al.
        Duodenal-jejunal bypass attenuates progressive failure of pancreatic islets in streptozotocin-induced diabetic rats.
        Surg Obes Relat Dis. 2017; 13: 250-260
        • Liang Y.
        • Yu B.
        • Wang Y.
        • et al.
        Duodenal long noncoding RNAs are associated with glycemic control after bariatric surgery in high-fat diet-induced diabetic mice.
        Surg Obes Relat Dis. 2017; 13: 1212-1226
        • Mercer T.R.
        • Mattick J.S.
        Structure and function of long noncoding RNAs in epigenetic regulation.
        Nat Struct Mol Biol. 2013; 20: 300-307
        • Zhu X.
        • Wu Y.B.
        • Zhou J.
        • Kang D.M.
        Upregulation of lncRNA MEG3 promotes hepatic insulin resistance via increasing FoxO1 expression.
        Biochem Biophys Res Commun. 2016; 469: 319-325
        • Reddy M.A.
        • Chen Z.
        • Park J.T.
        • et al.
        Regulation of inflammatory phenotype in macrophages by a diabetes-induced long noncoding RNA.
        Diabetes. 2014; 63: 4249-4261
        • Broadbent H.M.
        • Peden J.F.
        • Lorkowski S.
        • et al.
        Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9 p.
        Hum Mol Genet. 2008; 17: 806-814
        • Messeguer X.
        • Escudero R.
        • Farre D.
        • et al.
        PROMO: detection of known transcription regulatory elements using species-tailored searches.
        Bioinformatics. 2002; 18: 333-334
        • Farre D.
        • Roset R.
        • Huerta M.
        • et al.
        Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN.
        Nucleic Acids Res. 2003; 31: 3651-3653
        • Heberle H.
        • Meirelles G.V.
        • da Silva F.R.
        • Telles G.P.
        • Minghim R.
        InteractiVenn: a web-based tool for the analysis of sets through Venn diagrams.
        BMC Bioinformatics. 2015; 16: 169
        • Bradley D.
        • Conte C.
        • Mittendorfer B.
        • et al.
        Gastric bypass and banding equally improve insulin sensitivity and beta cell function.
        J Clin Invest. 2012; 122: 4667-4674
        • Wahlstrom A.
        • Sayin S.I.
        • Marschall H.U.
        • Backhed F.
        Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism.
        Cell Metab. 2016; 24: 41-50
        • Rhee N.A.
        • Vilsboll T.
        • Knop F.K.
        Current evidence for a role of GLP-1 in Roux-en-Y gastric bypass-induced remission of type 2 diabetes.
        Diabetes Obes Metab. 2012; 14: 291-298
        • Aron-Wisnewsky J.
        • Clement K.
        The effects of gastrointestinal surgery on gut microbiota: potential contribution to improved insulin sensitivity.
        Curr Atheroscler Rep. 2014; 16: 454
        • Liu R.
        • Hong J.
        • Xu X.
        • et al.
        Gut microbiome and serum metabolome alterations in obesity and after weight-loss intervention.
        Nat Med. 2017; 23: 859-868
        • Yano J.M.
        • Yu K.
        • Donaldson G.P.
        • et al.
        Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis.
        Cell. 2015; 161: 264-276
        • Raybould H.E.
        • Glatzle J.
        • Robin C.
        • et al.
        Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying.
        Am J Physiol Gastrointest Liver Physiol. 2003; 284: G367-G372
        • Li Y.
        • Hao Y.
        • Zhu J.
        • Owyang C.
        Serotonin released from intestinal enterochromaffin cells mediates luminal non-cholecystokinin-stimulated pancreatic secretion in rats.
        Gastroenterology. 2000; 118: 1197-1207
        • Hornby P.J.
        Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis.
        Am J Physiol Gastrointest Liver Physiol. 2001; 280: G1055-G1060
        • Auteri M.
        • Zizzo M.G.
        • Serio R.
        GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation.
        Pharmacol Res. 2015; 93: 11-21
        • Yue F.
        • Cheng Y.
        • Breschi A.
        • et al.
        A comparative encyclopedia of DNA elements in the mouse genome.
        Nature. 2014; 515: 355-364
        • Chen J.
        • Liu Y.
        • Lu S.
        • et al.
        The role and possible mechanism of lncRNA U90926 in modulating 3 T3-L1 preadipocyte differentiation.
        Int J Obes (Lond). 2017; 41: 299-308
        • Moore B.D.
        • Jin R.U.
        • Lo H.
        • et al.
        Transcriptional regulation of X-box-binding protein one (XBP1) by hepatocyte nuclear factor 4 alpha (HNF4 Alpha) is vital to beta-cell function.
        J Biol Chem. 2016; 291: 6146-6157
        • Anuradha S.
        • Radha V.
        • Mohan V.
        Association of novel variants in the hepatocyte nuclear factor 4 A gene with maturity onset diabetes of the young and early onset type 2 diabetes.
        Clin Genet. 2011; 80: 541-549
        • Yamagata K.
        Roles of HNF1 alpha and HNF4 alpha in pancreatic beta-cells: lessons from a monogenic form of diabetes (MODY).
        Vitam Horm. 2014; 95: 407-423
        • Villegas V.E.
        • Zaphiropoulos P.G.
        Neighboring gene regulation by antisense long non-coding RNAs.
        Int J Mol Sci. 2015; 16: 3251-3266
        • Dou H.
        • Wang C.
        • Wu X.
        • et al.
        Calcium influx activates adenylyl cyclase 8 for sustained insulin secretion in rat pancreatic beta cells.
        Diabetologia. 2015; 58: 324-333