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Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human jejunal samples taken perisurgically and 1 year post RYGB (\n                      <jats:italic>n<\/jats:italic>\n                      =13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL\/6j and i\n                      <jats:italic>Scd1<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice and immunohistochemistry and gene expression analyses were performed ex vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce\n                      <jats:italic>Gcg<\/jats:italic>\n                      expression and secretion of GLP-1 by GLUTag and STC-1 cells.\n                      <jats:italic>Scd1<\/jats:italic>\n                      knockdown also reduced intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signalling and membrane depolarisation. Furthermore,\n                      <jats:italic>Scd1<\/jats:italic>\n                      mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific\n                      <jats:italic>Scd1<\/jats:italic>\n                      knockout mouse model, i\n                      <jats:italic>Scd1<\/jats:italic>\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , revealed a twofold higher L cell density and a twofold increase in\n                      <jats:italic>Gcg<\/jats:italic>\n                      mRNA expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-023-06046-8","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T10:02:22Z","timestamp":1701338542000},"page":"356-370","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-5719","authenticated-orcid":false,"given":"Michael G.","family":"Miskelly","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8287-5609","authenticated-orcid":false,"given":"Andreas","family":"Lindqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6514-2689","authenticated-orcid":false,"given":"Elena","family":"Piccinin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5203-9220","authenticated-orcid":false,"given":"Alexander","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3939-8864","authenticated-orcid":false,"given":"Elaine","family":"Cowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bent-Johnny","family":"Nerg\u00e5rd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9927-9413","authenticated-orcid":false,"given":"Rita","family":"Del Giudice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5018-4387","authenticated-orcid":false,"given":"Mtakai","family":"Ngara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-414X","authenticated-orcid":false,"given":"Luis R.","family":"Cataldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6498-1977","authenticated-orcid":false,"given":"Dmytro","family":"Kryvokhyzha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Volkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1355-4964","authenticated-orcid":false,"given":"Luke","family":"Engelking","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2895-5664","authenticated-orcid":false,"given":"Isabella","family":"Artner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-2666","authenticated-orcid":false,"given":"Jens O.","family":"Lagerstedt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6467-5029","authenticated-orcid":false,"given":"Lena","family":"Eliasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6513-2384","authenticated-orcid":false,"given":"Emma","family":"Ahlqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2123-6074","authenticated-orcid":false,"given":"Antonio","family":"Moschetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-9087","authenticated-orcid":false,"given":"Jan","family":"Hedenbro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6824-4093","authenticated-orcid":false,"given":"Nils","family":"Wierup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"issue":"14","key":"6046_CR1","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1001\/jama.292.14.1724","volume":"292","author":"H Buchwald","year":"2004","unstructured":"Buchwald H, Avidor Y, Braunwald E et al (2004) Bariatric surgery: a systematic review and meta-analysis. 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Sterner and M. Neptin (Lund University Diabetes Centre [LUDC], Lund University, Sweden) for their technical assistance in performing RNA-seq. We also thank the LUDC Bioinformatics Unit (\n                      \n                      ; Lund University, Sweden) for providing bioinformatics, biostatistics and computational support, as well as access to a high-performance computing environment.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"All data are available from the corresponding author on request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Lund University. NW is supported by the Swedish Research Council (2020-01017, 2017-00862 and 521-2012-2119), regional research foundation Avtal om L\u00e4karutbildning och Forskning (ALF), Diabetes Wellness Research Foundation Sweden, Albert P\u00e5hlsson Foundation, Royal Physiographic Society in Lund and Swedish Diabetes Foundation. Lund University Diabetes Centre is supported by the Swedish Research Council, Linnaeus grant (Dnr 349-2006-237), Strategic Research Area Exodiab (Dnr 2009-1039) and the Swedish Foundation for Strategic Research (Dnr IRC15-0067). JOL is supported by the Swedish Research Council (2020-02179).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"Jens O. Lagerstedt is an employee at Novo Nordisk A\/S, Denmark. Petr Volkov is an employee at AstraZeneca AB. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"Data acquisition was performed by MGM, AL, EP, AH, EC, RDG, MN, LRC, DK and PV. Data were analysed and interpreted by MGM, AL, AH, EC, RDG, MN, DK, PV, LEn, IA, JOL, LEl, EA and NW. Study conception and design was undertaken by MGM, AL, B-JN, AM, JH and NW, EP and AM provided i<i>Scd1<\/i><sup>\u2212\/\u2212<\/sup> mice and serum and tissue samples. The original draft of this article was written and revised by MGM, AL and NW. Funding was provided by NW, who is also guarantor of the data. The manuscript was revised by all authors and all authors approved the final draft of the manuscript.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}