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Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids

Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence...

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Autores principales: Holliday, Nicholas D., Watson, Sarah-Jane, Brown, Alastair J. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Research Foundation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355945/
https://www.ncbi.nlm.nih.gov/pubmed/22649399
http://dx.doi.org/10.3389/fendo.2011.00112
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author Holliday, Nicholas D.
Watson, Sarah-Jane
Brown, Alastair J. H.
author_facet Holliday, Nicholas D.
Watson, Sarah-Jane
Brown, Alastair J. H.
author_sort Holliday, Nicholas D.
collection PubMed
description Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence from in vitro and rodent models, and an increasing number of human studies. Here we consider their promise as therapeutic targets for metabolic disease, including type 2 diabetes and obesity. FFA1 directly mediates acute FFA-induced glucose-stimulated insulin secretion in pancreatic beta-cells, while GPR120 and FFA1 trigger release of incretins from intestinal endocrine cells, and so indirectly enhance insulin secretion and promote satiety. GPR120 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects. Drug discovery has focused on agonists to replicate acute benefits of FFA receptor signaling, with promising early results for FFA1 agonists in man. Controversy surrounding chronic effects of FFA1 on beta-cells illustrates that long term benefits of antagonists also need exploring. It has proved challenging to generate highly selective potent ligands for FFA1 or GPR120 subtypes, given that both receptors have hydrophobic orthosteric binding sites, which are not completely defined and have modest ligand affinity. Structure activity relationships are also reliant on functional read outs, in the absence of robust binding assays to provide direct affinity estimates. Nevertheless synthetic ligands have already helped dissect specific contributions of FFA1 and GPR120 signaling from the many possible cellular effects of FFAs. Approaches including use of fluorescent ligand binding assays, and targeting allosteric receptor sites, may improve further pre-clinical ligand development at these receptors, to exploit their unique potential to target multiple facets of diabetes.
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spelling pubmed-33559452012-05-30 Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids Holliday, Nicholas D. Watson, Sarah-Jane Brown, Alastair J. H. Front Endocrinol (Lausanne) Endocrinology Discovery of G protein coupled receptors for long chain free fatty acids (FFAs), FFA1 (GPR40) and GPR120, has expanded our understanding of these nutrients as signaling molecules. These receptors have emerged as important sensors for FFA levels in the circulation or the gut lumen, based on evidence from in vitro and rodent models, and an increasing number of human studies. Here we consider their promise as therapeutic targets for metabolic disease, including type 2 diabetes and obesity. FFA1 directly mediates acute FFA-induced glucose-stimulated insulin secretion in pancreatic beta-cells, while GPR120 and FFA1 trigger release of incretins from intestinal endocrine cells, and so indirectly enhance insulin secretion and promote satiety. GPR120 signaling in adipocytes and macrophages also results in insulin sensitizing and beneficial anti-inflammatory effects. Drug discovery has focused on agonists to replicate acute benefits of FFA receptor signaling, with promising early results for FFA1 agonists in man. Controversy surrounding chronic effects of FFA1 on beta-cells illustrates that long term benefits of antagonists also need exploring. It has proved challenging to generate highly selective potent ligands for FFA1 or GPR120 subtypes, given that both receptors have hydrophobic orthosteric binding sites, which are not completely defined and have modest ligand affinity. Structure activity relationships are also reliant on functional read outs, in the absence of robust binding assays to provide direct affinity estimates. Nevertheless synthetic ligands have already helped dissect specific contributions of FFA1 and GPR120 signaling from the many possible cellular effects of FFAs. Approaches including use of fluorescent ligand binding assays, and targeting allosteric receptor sites, may improve further pre-clinical ligand development at these receptors, to exploit their unique potential to target multiple facets of diabetes. Frontiers Research Foundation 2012-01-03 /pmc/articles/PMC3355945/ /pubmed/22649399 http://dx.doi.org/10.3389/fendo.2011.00112 Text en Copyright © 2012 Holliday, Watson and Brown. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
spellingShingle Endocrinology
Holliday, Nicholas D.
Watson, Sarah-Jane
Brown, Alastair J. H.
Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title_full Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title_fullStr Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title_full_unstemmed Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title_short Drug Discovery Opportunities and Challenges at G Protein Coupled Receptors for Long Chain Free Fatty Acids
title_sort drug discovery opportunities and challenges at g protein coupled receptors for long chain free fatty acids
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355945/
https://www.ncbi.nlm.nih.gov/pubmed/22649399
http://dx.doi.org/10.3389/fendo.2011.00112
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