The fatty acid receptor FFA1/GPR40 a decade later: how much do we know?

doi:10.1016/j.tem.2013.03.003

Trends in Endocrinology & Metabolism

Volume 24, Issue 8, August 2013, Pages 398-407

https://doi.org/10.1016/j.tem.2013.03.003 Get rights and content

Highlights

•
Activation of GPR40 by fatty acids potentiates glucose-induced insulin secretion.
•
GPR40 is not implicated in the toxic effects of chronic fatty acids on β-cells.
•
GPR40 couples to Gα_q/11, activation of protein kinase D1, and actin depolymerization.
•
The GPR40 agonist TAK-875 is a promising drug candidate for type 2 diabetes.
•
Our understanding of the biology and pharmacology of GPR40 remains incomplete.

Glucose homeostasis requires the highly coordinated regulation of insulin secretion by pancreatic β cells. This is primarily mediated by glucose itself, but other nutrients, including free fatty acids (FFAs), potentiate the insulinotropic capacity of glucose. A decade ago, the seven-transmembrane domain receptor (7TMR) GPR40 was demonstrated to be predominantly expressed in β cells and activated by long-chain FFAs. This discovery added a new dimension to our understanding of FFA-mediated control of glucose homeostasis. Furthermore, GPR40 has drawn considerable interest as a novel therapeutic target to enhance insulin secretion in type 2 diabetes. However, our understanding of the biology of GPR40 remains incomplete and its physiological role controversial. Here we summarize the current state of knowledge and emerging concepts regarding the role of GPR40 in regulating glucose homeostasis.

Section snippets

A β cell fatty acid receptor regulating insulin secretion

In addition to serving as essential dietary nutrients, FFAs regulate cellular signaling and metabolism in various physiological and pathophysiological states, including type 2 diabetes (T2D). FFAs have long been recognized as important regulators of glucose homeostasis via their ability to influence insulin secretion from the pancreatic β cell. Landmark studies by Crespin et al. [1], Stein et al. [2], and Dobbins et al. [3] collectively demonstrated that FFAs are essential for basal and

The GPR40 and glucolipotoxicity controversy – laid to rest?

A large number of studies have now conclusively confirmed the importance of GPR40 in mediating the acute stimulatory effects of long-chain FFAs on GSIS. GPR40 loss-of-function via small interfering RNA 7, 15, 16, 17, antisense oligonucleotides [18], pharmacological inhibition [19], or gene deletion in mice 20, 21, 22, 23 consistently resulted in a significant decrease in FFA potentiation of GSIS. Interestingly, Vettor et al. identified a low-frequency mutation in the GPR40 gene in humans that

FFAs augment the 2nd phase of insulin secretion via GPR40

Full appreciation of the mechanisms implicated in FFA amplification of GSIS through GPR40 requires knowledge of those underpinning insulin secretion. The kinetic properties of the predominant hexokinase isoform in β cells, glucokinase, are such that intracellular glucose concentrations are in rapid equilibrium with extracellular levels. Subsequent mitochondrial metabolism of glucose leads to an increase in the ATP/ADP ratio and subsequently initiates the following sequence of events: closure of

Signaling mechanisms downstream of GPR40

The mechanisms linking FFA activation of GPR40 to insulin secretion are only partially understood. GPR40 couples to the G protein subunit Gα_q/11 7, 45, which in turn is predicted to catalyze phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol triphosphate (IP₃). DAG and IP₃ subsequently serve as second messenger molecules to activate protein kinase C (PKC) and mobilize ER Ca²⁺ stores, respectively. Overall, this mechanism is

The GPR40 signaling signature: likely more complex than a linear model

The essentially linear signal-transduction pathway described above and depicted in Figure 2 likely presents a largely oversimplified model of GPR40-mediated signaling in response to FFAs. In fact, groundbreaking research by 2012 Nobel Laureate in Chemistry Robert J. Lefkowitz and his colleagues has clearly demonstrated that 7TMRs can couple to multiple heterotrimeric G proteins as well as to G protein-independent, β-arrestin-dependent pathways to promote the activation of numerous (potentially

Potential role of GPR40 in non-β cells

GPR40 was initially described as being predominantly, but not exclusively, expressed in β cells based on mRNA measurements by RT-PCR 6, 7. Its potential role in non-β cells has not been fully examined, but it has possible implications for the physiological role of the receptor as well as potential side-effects of GPR40-based drugs. GPR40 expression has been documented in several tissues (Table 1) including enteroendocrine cells, some areas of the brain, and possibly glucagon-producing α cells,

Current trends and future perspectives for GPR40-based pharmacotherapy in T2D

Of the numerous GPR40 agonists developed to date 71, 72 (Table 1), the Takeda molecule TAK-875 (currently in Phase III trials) is the most clinically advanced. TAK-875 is a highly potent GPR40 agonist (EC₅₀ in the low nM range for human GPR40) with marked selectivity for GPR40 over other members of the FFA receptor family (i.e., FFAR2, FFAR3, GPR120) [73]. In isolated rat and human islets, TAK-875 stimulated insulin secretion in a glucose-dependent manner without affecting glucagon secretion 33

Concluding remarks

The deorphanization of GPR40 as a FFA receptor in 2003 unraveled a novel mechanism of action for FFAs as extracellular signaling molecules. It also opened a new avenue for T2D drug development by identifying a relatively β cell-specific cell-surface receptor that could be targeted to enhance insulin secretion in a glucose-dependent manner. A decade later, how much do we know? Most of the available data support the notions that GPR40 (i) is responsible for approximately half of the acute,

Acknowledgments

Work performed in the authors’ laboratory was supported by the Canadian Institutes of Health Research (MOP 86545 to V.P.). A.M. is supported by a postdoctoral fellowship from the Canadian Diabetes Association. V.P. holds the Canada Research Chair in Diabetes and Pancreatic Beta-Cell Function. Figures were produced using Servier Medical Art, available from www.servier.com/Powerpoint-image-bank. We thank Dr Julien Ghislain for critical reading of the manuscript.

Glossary

Allosteric binding site: a receptor domain that is topographically distinct from the orthosteric binding pocket and binds factors that may alter the biological activity of the orthosteric ligand. Usually not subject to the same evolutionary pressure as orthosteric sites and thus more diverse.
Biased agonism (or functional selectivity): describes the ability of a 7TMR ligand to selectively signal through a subset of the classical signal transduction cascades associated with a given receptor.

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Free fatty acid receptor 1 (FFAR1 or GPR40) is a potential target for treating type 2 diabetes mellitus (T2DM) and related disorders that have been extensively researched for many years. GPR40/FFAR1 is a promising anti-diabetic target because it can activate insulin, promoting glucose metabolism. It controls T2DM by regulating glucose levels in the body through two separate mechanisms: glucose-stimulated insulin secretion and incretin production. In the last few years, various synthetic GPR40/FFAR1 agonists have been discovered that fall under several chemical classes, viz. phenylpropionic acid, phenoxyacetic acid, and dihydrobenzofuran acetic acid. However, only a few synthetic agonists have entered clinical trials due to various shortcomings like poor efficacy, low lipophilicity and toxicity issues. As a result, pharmaceutical firms and research institutions are interested in developing synthetic GPR40/FFAR1 agonists with superior effectiveness, lipophilicity, and safety profiles. This review encompasses the most recent research on synthetic GPR40/FFAR1 agonists, including their chemical classes, design strategies and structure-activity relationships. Additionally, we have emphasised the structural characteristics of the most potent GPR40/FFAR1 agonists from each chemical class of synthetic derivatives and analysed their chemico-biological interactions. This work will hopefully pave the way for developing more potent and selective synthetic GPR40/FFAR1 agonists for treating T2DM and related disorders.
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The expression of free fatty acid 1 receptors (FFA1R), activated by long chain fatty acids in human pancreatic β-cells and enhancing glucose-stimulated insulin secretion are an attractive target to treat type 2 diabetes. Yet several clinical studies with synthetic FFA1R agonists had to be discontinued due to cytotoxicity and/or so-called “liver concerns”. It is not clear whether these obstructions are FFA1R dependent. In this context we used CHO-AEQ cells expressing the bioluminescent calcium-sensitive protein aequorin to investigate calcium signaling elicited by FFA1 receptor ligands α-linolenic acid (ALA), oleic acid (OLA) and myristic acid (MYA). This study revealed complex modulation of intracellular calcium signaling by these fatty acids. First these compounds elicited a typical transient increase of intracellular calcium via binding to FFA1 receptors. Secondly slightly higher concentrations of ALA substantially reduced ATP mediated calcium responses in CHO-AEQ cells and Angiotensin II responses in CHO-AEQ cells expressing human AT₁ receptors. This effect was less pronounced with MYA and OLA and was not linked to FFA1 receptor activation nor to acute cytotoxicity as a result of plasma membrane perturbation. Yet it can be hypothesized that, in line with previous studies, unsaturated long chain fatty acids such as ALA and OLA are capable of inactivating the G-proteins involved in purinergic and Angiotensin AT₁ receptor calcium signaling. Alternatively the ability of fatty acids to deplete intracellular calcium stores might underly the observed cross-inhibition of these receptor responses in the same cells.
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Trends in Endocrinology & Metabolism

ReviewThe fatty acid receptor FFA1/GPR40 a decade later: how much do we know?

Highlights

Section snippets

A β cell fatty acid receptor regulating insulin secretion

The GPR40 and glucolipotoxicity controversy – laid to rest?

FFAs augment the 2nd phase of insulin secretion via GPR40

Signaling mechanisms downstream of GPR40

The GPR40 signaling signature: likely more complex than a linear model

Potential role of GPR40 in non-β cells

Current trends and future perspectives for GPR40-based pharmacotherapy in T2D

Concluding remarks

Acknowledgments

Glossary

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Lancet

Biochem. Biophys. Res. Commun.

Hepatol. Res.

Mol. Cell. Endocrinol.

Cell Metab.

Biochim. Biophys. Acta

Metabolism

Mol. Cell. Endocrinol.

Nutr. Metab. Cardiovasc. Dis.

J. Biol. Chem.

J. Biol. Chem.

Trends Mol. Med.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Neurosci. Res.

Brain Res.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

J. Biol. Chem.

Metabolism

J. Biol. Chem.

Stimulation of insulin secretion by infusion of free fatty acids

J. Clin. Invest.

Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat

J. Clin. Invest.

A fatty acid-dependent step is critically important for both glucose- and non-glucose-stimulated insulin secretion

J. Clin. Invest.

Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans

J. Endocrinol.

Fatty acid signaling in the β-cell and insulin secretion

Diabetes

Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40

Nature

Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120

Nat. Med.

Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes

Diabetes Care

A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes

Clin. Pharmacol. Ther.

Free fatty acid receptor 1 (FFA(1)R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion

Cell Tissue Res.

Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules

Br. J. Pharmacol.

GPR40 is necessary but not sufficient for fatty acid stimulation of insulin secretion in vivo

Diabetes

Lack of FFAR1/GPR40 does not protect mice from high-fat diet-induced metabolic disease

Diabetes

Review
The fatty acid receptor FFA1/GPR40 a decade later: how much do we know?