ArticleMolecular metabolism2015
GPR40 (FFAR1) - Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo.
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed, 206 citations in OpenAlex.
- Sphinganine as a novel stimulator of GLP-1 secretion.Diabetologia · 2026Article
- Therapeutic potential of modulating endogenous PYY expression for controlling overweight and obesity: a narrative review.Frontiers in nutrition · 2026Review
- Single-cell transcriptomics of human organoid-derived enteroendocrine cell populations from the small intestine.The Journal of physiology · 2025Article
- Multicolored sequential resonance energy transfer for detection of simultaneous ligand binding at G protein-coupled receptors.Nature communications · 2025Article
- Islet hormones at the intersection of glucose and amino acid metabolism.Nature reviews. Endocrinology · 2025Review
- HD6277 Suppresses Muscle Atrophy by Promoting Myogenic Factors and Inhibiting Proteolysis in Aged Mice.Journal of cachexia, sarcopenia and muscle · 2025Article
- GPR40-full agonist AM1638 alleviates palmitate-induced oxidative damage in H9c2 cells via an AMPK-dependent pathway.BMB reports · 2025Article
- G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential.Biomolecules · 2025Review
- G Protein-Coupled Receptor 17 Inhibits Glucagon-like Peptide-1 Secretion via a Gi/o-Dependent Mechanism in Enteroendocrine Cells.Biomolecules · 2024Article
- G protein-coupled receptor 17 inhibits glucagon-like peptide-1 secretion via a Gi/o-dependent mechanism in enteroendocrine cells.bioRxiv : the preprint server for biology · 2024Article
- Activation of Gs signaling in mouse enteroendocrine K cells greatly improves obesity- and diabetes-related metabolic deficits.The Journal of clinical investigation · 2024Article
- Orphan GPCRs in Neurodegenerative Disorders: Integrating Structural Biology and Drug Discovery Approaches.Current issues in molecular biology · 2024Review
- Free Fatty Acids and Free Fatty Acid Receptors: Role in Regulating Arterial Function.International journal of molecular sciences · 2024Review
- Gut microbiota-derived metabolites tune host homeostasis fate.Seminars in immunopathology · 2024Review
- GPCRs involved in metabolic diseases: pharmacotherapeutic development updates.Acta pharmacologica Sinica · 2024Review
- Sensing of luminal contents and downstream modulation of GI function.JGH open : an open access journal of gastroenterology and hepatology · 2024Review
- Recent Developments in Drug Design of Oral Synthetic Free Fatty Acid Receptor 1 Agonists.Drug design, development and therapy · 2024Review
- AM1638, a GPR40-Full Agonist, Inhibited Palmitate- Induced ROS Production and Endoplasmic Reticulum Stress, Enhancing HUVEC Viability in an NRF2-Dependent Manner.Endocrinology and metabolism (Seoul, Korea) · 2023Article
- Identification of Crocetin as a Dual Agonist of GPR40 and GPR120 Responsible for the Antidiabetic Effect of Saffron.Nutrients · 2023Article
- Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets.Diabetologia · 2023Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesGPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins. METHODS AND
resultsHere we find that GPR40 can signal through not only Gq and IP3 but also Gs and cAMP when stimulated with certain agonists such as AM-1638 and AM-5262 in contrast to the endogenous LCFA ligands and agonists such as TAK-875 and AM-837, which only signal through Gq. In competition binding against [3H]AM-1638 and [3H]L358 the Gq + Gs and the Gq-only agonists either competed for or showed positive cooperativity by increasing the binding of the two different radio-ligands, in opposite ways. Nevertheless, both the Gq-only and the Gq + Gs agonists all docked surprisingly well into the binding site for TAK-875 in the X-ray structure of GPR40. In murine intestinal primary cell-cultures the endogenous LCFAs and the Gq-only agonists stimulated GLP-1 secretion with rather poor efficacy as compared with the high efficacy Gq + Gs GPR40 agonists and a prototype GPR119 agonist. Similarly, in fasting both male and female mice the Gq + Gs agonists showed significantly higher efficacy than the Gq-only agonists in respect of increasing plasma GLP-1 and plasma GIP in a GPR40-dependent manner.
conclusionsIt is concluded that stimulation of GPR40 by endogenous LCFAs or by Gq-only synthetic agonists result in a rather limited incretin response, whereas Gq + Gs GPR40 agonists stimulate incretin secretion robustly.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.