RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine

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RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine

Miskelly, Michael G. (författare): Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups

Lindqvist, Andreas (författare): Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups

Piccinin, Elena (författare): Department of Translational Biomedicine and Neuroscience, University of Bari 'Aldo Moro', Bari, Italy; Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy

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Hamilton, Alexander (författare): Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - molekylär metabolism,Diabetes - Islet Cell Exocytosis,Lund University Research Groups,Diabetes - Molecular Metabolism

Cowan, Elaine (författare): Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups

Nergård, Bent-Johnny (författare): Aleris Obesitas, Lund, Sweden,Aleris Obesitas Skåne

Del Giudice, Rita (författare): Malmö University,Lund University,Lunds universitet,Malmö universitet,Biofilms Research Center for Biointerfaces,Institutionen för biomedicinsk vetenskap (BMV),Department of Experimental Medical Science, Lund University, Lund, Sweden,Medicinsk proteinvetenskap,Forskargrupper vid Lunds universitet,Medical Protein Science,Lund University Research Groups

Ngara, Mtakai (författare): Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups

Cataldo, Luis R. (författare): Lund University,Lunds universitet,Diabetes - molekylär metabolism,Forskargrupper vid Lunds universitet,Diabetes - Molecular Metabolism,Lund University Research Groups,Novo Nordisk Foundation Centre for Basic Metabolic Research

Kryvokhyzha, Dmytro (författare): Lund University,Lunds universitet,Diabetiska komplikationer,Forskargrupper vid Lunds universitet,Diabetic Complications,Lund University Research Groups

Volkov, Petr (författare): Lund University,Lunds universitet,Diabetiska komplikationer,Forskargrupper vid Lunds universitet,Diabetic Complications,Lund University Research Groups

Engelking, Luke (författare): Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA

Artner, Isabella (författare): Lund University,Lunds universitet,Endokrin Celldifferentiering,Forskargrupper vid Lunds universitet,Bildbehandlingsplattformen,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Endocrine Cell Differentiation and Function,Lund University Research Groups,Imaging,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine

Lagerstedt, Jens O. (författare): Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups

Eliasson, Lena (författare): Lund University,Lunds universitet,Diabetes - öcellsexocytos,Forskargrupper vid Lunds universitet,Diabetes - Islet Cell Exocytosis,Lund University Research Groups

Ahlqvist, Emma (författare): Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups

Moschetta, Antonio (författare): Department of Interdisciplinary Medicine, University of Bari 'Aldo Moro', Bari, Italy; INBB National Institute for Biostructure and Biosystems, Rome, Italy

Hedenbro, Jan (författare): Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups

Wierup, Nils (författare): Lund University,Lunds universitet,Neuroendokrin cellbiologi,Forskargrupper vid Lunds universitet,Neuroendocrine Cell Biology,Lund University Research Groups

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Springer, 2024
2024
Engelska.
Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 67:2, s. 356-370

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://mau.diva-por... (primary) (Raw object); http://dx.doi.org/10... (free); https://urn.kb.se/re...; https://doi.org/10.1...; https://lup.lub.lu.s...; visa färre...

Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

Aims/hypothesis: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). 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.Methods: Human jejunal samples taken perisurgically and 1 year post RYGB (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 iScd1-/- mice and immunohistochemistry and gene expression analyses were performed ex vivo.Results: 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 Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 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 Scd1 knockout mouse model, iScd1-/-, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression.Conclusions/interpretation: 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

GLP-1
Gastric bypass surgery
Glucagon-like peptide-1
Intestine
Obesity
RNA sequencing
Remission
SCD
Stearoyl-CoA desaturase
Type 2 diabetes
Gastric bypass surgery
GLP-1
Glucagon-like peptide-1
Intestine
Obesity
Remission
RNA sequencing
SCD
Stearoyl-CoA desaturase
Type 2 diabetes

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Cell och molekyl ...

Artiklar i publikationen: Diabetologia

Av lärosätet: Malmö universitet; Lunds universitet

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