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Cited by 587Pancreatic function and diabetesDiabetes Treatment and ManagementReceptor Mechanisms and Signaling

Gpr40 Is Expressed in Enteroendocrine Cells and Mediates Free Fatty Acid Stimulation of Incretin Secretion

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Edfalk, Sara, Steneberg, Pär, Edlund, Helena·2008·Diabetes
DOI 10.2337/db08-0307PMC PMC2518478
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Abstract

OBJECTIVE—The G-protein–coupled receptor Gpr40 is expressed in β-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion (1–4). However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5′-flanking region of Gpr40 (5), implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS—In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1-null and β-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS—Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in β-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS—Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from β-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.

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  • L cells can sense carbohydrates via SLC5A1, long-chain fatty acids via FFAR1 and FFAR4 receptors, and monoacylglycerols via the GPR119 receptor.

    “L cells can sense carbohydrates via the sodium-coupled glucose transporter (SLC5A1) (Gorboulev et al., 2012;Reimann et al., 2008), long-chain fatty acids via FFAR1 and FFAR4 receptors (Edfalk et al., 2008;Hirasawa et al., 2004), and monoacylglycerols via the GPR119 receptor (Reimann et al., 2008).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Edfalk et al., 2008

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Authors
Edfalk, S., Steneberg, P., & Edlund, H.
Affiliations
  • Umeå University (SE)
  • From the Umeå Center for Molecular Medicine, University of Umeå, Umeå, Sweden
Corresponding author
Edlund, Helena
ORCID
Edlund, Helena
Venue
Diabetes
Publisher
American Diabetes Association
Published
2008-09-01
Volume
57
Issue
9
Pages
2280-2287
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db08-0307
PMC
PMC2518478
OpenAlex
W2077936393
Cited by
587
References
2
Citations by year
2026: 24 · 2025: 17 · 2024: 15 · 2023: 18 · 2022: 29 · 2021: 27 · 2020: 23 · 2019: 35 · 2018: 45 · 2017: 40 · 2016: 44 · 2015: 43 · 2014: 40 · 2013: 45 · 2012: 51
FWCI
32.40
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Kempe Foundation
  • European Commission (LSHM-CT-2006-518153)
  • Vetenskapsrådet
  • Kempestiftelserna
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
GPR40, free fatty acids, enteroendocrine cells, incretin secretion, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pancreatic beta cells, insulin secretion, energy homeostasis
MeSH terms
Insulin Secretion, Animals, Duodenum, Fatty Acids, Nonesterified, Gastric Inhibitory Polypeptide, Insulin, Mice, Mutant Strains, Pylorus, Trans-Activators, Gene Expression, Genes, Reporter, Homeodomain Proteins, Enteroendocrine Cells, Receptors, G-Protein-Coupled, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1

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