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Cited by 99Diabetes Treatment and ManagementBiochemical Analysis and Sensing TechniquesRegulation of Appetite and Obesity

Lipid derivatives activate GPR119 and trigger GLP-1 secretion in primary murine L-cells

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Hodge, Daryl, Glass, Leslie L., Diakogiannaki, Eleftheria, Pais, Ramona, Lenaghan, Carol, Smith, David M., Wedin, Marianne, Bohlooly-Y, Mohammad +2 more·2016·Peptides
DOI 10.1016/j.peptides.2015.06.012PMC PMC4788502
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Abstract

AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) is an incretin hormone derived from proglucagon, which is released from intestinal L-cells and increases insulin secretion in a glucose dependent manner. GPR119 is a lipid derivative receptor present in L-cells, believed to play a role in the detection of dietary fat. This study aimed to characterize the responses of primary murine L-cells to GPR119 agonism and assess the importance of GPR119 for the detection of ingested lipid. METHODS: GLP-1 secretion was measured from murine primary cell cultures stimulated with a panel of GPR119 ligands. Plasma GLP-1 levels were measured in mice lacking GPR119 in proglucagon-expressing cells and controls after lipid gavage. Intracellular cAMP responses to GPR119 agonists were measured in single primary L-cells using transgenic mice expressing a cAMP FRET sensor driven by the proglucagon promoter. RESULTS: L-cell specific knockout of GPR119 dramatically decreased plasma GLP-1 levels after a lipid gavage. GPR119 ligands triggered GLP-1 secretion in a GPR119 dependent manner in primary epithelial cultures from the colon, but were less effective in the upper small intestine. GPR119 agonists elevated cAMP in ∼70% of colonic L-cells and 50% of small intestinal L-cells. CONCLUSIONS/INTERPRETATION: GPR119 ligands strongly enhanced GLP-1 release from colonic cultures, reflecting the high proportion of colonic L-cells that exhibited cAMP responses to GPR119 agonists. Less GPR119-dependence could be demonstrated in the upper small intestine. In vivo, GPR119 in L-cells plays a key role in oral lipid-triggered GLP-1 secretion.

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  • NEFA may influence insulin secretion in the short term by an indirect mechanism mediated by stimulation of GLP-1 release from enteroendocrine L-cells.

    “Although there is a long delay between ingestion of triglycerides and their appearance in plasma, it is nevertheless possible that NEFA may influence insulin secretion in the short term by an indirect mechanism mediated by stimulation of GLP-1 release from enteroendocrine L-cells (463).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [463]

    The Discussion (page unavailable) says that free fatty acids released during intestinal fat digestion can be sensed through pathways that play a relatively minor role in GLP-1 secretion. The Introduction (page unavailable) says GLP-1 enhances insulin secretion. Together these support a possible indirect pathway, but the paper does not establish that circulating NEFA influence insulin secretion in the short term. (LLM, conf=0.83)

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Authors
Hodge, D., Glass, L. L., Diakogiannaki, E., Pais, R., Lenaghan, C., Smith, D. M., Wedin, M., Bohlooly-Y, M., Gribble, F. M., & Reimann, F.
Affiliations
  • Wellcome/MRC Institute of Metabolic Science (GB)
  • AstraZeneca (United Kingdom) (GB)
  • AstraZeneca (Sweden) (SE)
Corresponding author
  • Gribble, Fiona M.
  • Reimann, Frank
ORCID
Venue
Peptides
Publisher
Elsevier BV
Published
2016-03
Volume
77
Pages
16-20
ISSN
0196-9781 (ISSN-L)
DOI
10.1016/j.peptides.2015.06.012
PMC
PMC4788502
OpenAlex
W808693919
Cited by
99
References
2
Citations by year
2026: 4 · 2025: 2 · 2024: 11 · 2023: 2 · 2022: 8 · 2021: 15 · 2020: 7 · 2019: 12 · 2018: 16 · 2017: 11 · 2016: 8 · 2015: 3
FWCI
11.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Peptides (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Bedfordshire Repository (University of Bedfordshire) (submittedVersion, cc-by-nc-nd)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • AstraZeneca
  • Wellcome Trust (WT088357Z/09/Z, WT088357, #WT084210, 106263/Z/14/Z, WT084210Z/07/Z)
  • European Commission (266408)
  • Medical Research Council (MRC_MC_UU_12012/3, MC UU 12012/3)
  • Biotechnology and Biological Sciences Research Council
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
GPR119, GLP-1 secretion, L cells, proglucagon, incretins, lipid derivatives, cAMP signaling, colonic epithelium, small intestine, intestinal hormone secretion
MeSH terms
Olive Oil, Cyclic AMP, Animals, Cells, Cultured, Corn Oil, Female, Male, Mice, Transgenic, Second Messenger Systems, Enteroendocrine Cells, Receptors, G-Protein-Coupled, Glucagon-Like Peptide 1, Primary Cell Culture

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