Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA<sub>1</sub>/GPR40), a Potential Target for the Treatment of Type II Diabetes

Christiansen, Elisabeth; Urban, Christian; Merten, Nicole; Liebscher, Kathrin; Karlsen, Kasper K.; Hamacher, Alexandra; Spinrath, Andreas; Bond, Andrew D.; Drewke, Christel; Ullrich, Susanne; Kassack, Matthias U.; Kostenis, Evi; Ulven, Trond

doi:10.1021/jm8010178

Cited by 122 publications

(127 citation statements)

References 26 publications

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“…3) (Briscoe et al, 2003;Kotarsky et al, 2003;Edfalk et al, 2008;Ma et al, 2008). This hypothesis has been substantiated by several studies using FFA1 knockout mice and selective FFA1 small-molecule agonists, showing that FFA1 regulates the FFA-mediated release of gastric inhibitory peptide and GLP-1 from the gut and the FFA-mediated enhancement of insulin release from ␤-cells of the pancreas (Itoh et al, 2003;Steneberg et al, 2005;Briscoe et al, 2006;Christiansen et al, 2008;Edfalk et al, 2008;Tan et al, 2008).…”

Section: Family a Nutrient-sensing Receptorsmentioning

confidence: 85%

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

2009

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A number of highly promiscuous seven transmembrane (7TM) receptors have been cloned and characterized within the last few years. It is noteworthy that many of these receptors are activated broadly by amino acids, proteolytic degradation products, carbohydrates, or free fatty acids and are expressed in taste tissue, the gastrointestinal tract, endocrine glands, adipose tissue, and/or kidney. These receptors thus hold the potential to act as sensors of food intake, regulating, for example, release of incretin hormones from the gut, insulin/glucagon from the pancreas, and leptin from adipose tissue. The promiscuous tendency in ligand recognition of these receptors is in contrast to the typical specific interaction with one physiological agonist seen for most receptors, which challenges the classic "lock-and-key" concept. We here review the molecular mechanisms of nutrient sensing of the calcium-sensing receptor, the G protein-coupled receptor family C, group 6, subtype A (GPRC6A), and the taste1 receptor T1R1/T1R3, which are sensing L-␣-amino acids, the carbohydrate-sensing T1R2/T1R3 receptor, the proteolytic degradation product sensor GPR93 (also termed GPR92), and the free fatty acid (FFA) sensing receptors FFA1, FFA2, FFA3, GPR84, and GPR120. The involvement of the individual receptors in sensing of food intake has been validated to different degrees because of limited availability of specific pharmacological tools and/or receptor knockout mice. However, as a group, the receptors represent potential drug targets, to treat, for example, type II diabetes by mimicking food intake by potent agonists or positive allosteric modulators. The ligand-receptor interactions of the promiscuous receptors of organic nutrients thus remain an interesting subject of emerging functional importance.In 1894, Emil Fischer published the landmark article in which he for the first time described the "lock-and-key" concept for enzyme-substrate interactions (Fischer, 1894). A few decades later, this concept was transferred to receptors by Paul Ehrlich and John Newport Langley when they studied receptors and their interactions with ligands (for review, see Limbird, 2004;Rang, 2004). A literal interpretetation of the "lock-and-key" concept suggests that each receptor only has one physiological agonist, which is also in line with the naming of the vast majority of liganded receptors by their main endogenous agonist (e.g., acetylcholine receptor, glutamate receptor). During the following decades, receptors were shown to adhere to this scheme, although some exceptions were discovered, such as the adrenergic receptor subtypes responding to both endogenous epinephrine and norepinephrine, albeit with different rank orders (Ahlquist, 1948). However, during the last few years, a number of receptors have been cloned and characterized that are highly promiscuous and thus respond to a range of natural agonists. In addition,

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Section: Family a Nutrient-sensing Receptorsmentioning

confidence: 85%

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

2009

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“…, Invitrogen) was used to generate cell lines stably expressing human FLAG-tagged FFA1 (FFA1-HEK), FFA3 (FFA3-HEK), or FFA2 (FFA2-HEK) receptors in a doxycycline-dependent manner, as described previously (17).…”

Section: Generation Of Stable Flp-in T-rex 293 Cells-the Flpmentioning

confidence: 99%

“…] i -FFA1-1321N1 and FFA1-HEK cells were seeded in poly-D-lysine-coated 96-well tissue culture plates, and intracellular Ca 2ϩ levels were quantified with the Ca 2ϩ -sensitive fluorescence dye Oregon Green 488 1,2-bis(o-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-1/AM (1.5 M, Molecular Probes, Eugene, OR) using previously published protocols (17). For desensitization assays, FFA1-1321N1 cells were preincubated with the agonist for either 100 s or 50 min at 37°C in the NOVOstar microplate reader (BMG Labtech, Offenburg, Germany) prior to injection of the test compound.…”

Section: Measurements Of Intracellular [Ca 2ϩmentioning

confidence: 99%

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

Schmidt

Liebscher

Merten

et al. 2011

Journal of Biological Chemistry

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Among dietary components, conjugated linoleic acids (CLAs) have attracted considerable attention as weight loss supplements in the Western world because they reduce fat stores and increase muscle mass. However, a number of adverse effects are also ascribed to the intake of CLAs such as aggravation of insulin resistance and the risk of developing diabetes. However, the mechanisms accounting for the effects of CLAs on glucose homeostasis are incompletely understood. Herein we provide evidence that CLAs specifically activate the cell surface receptor FFA1, an emerging therapeutic target to treat type 2 diabetes. Using different recombinant cellular systems engineered to stably express FFA1 and a set of diverse functional assays including the novel, label-free non-invasive dynamic mass redistribution technology (Corning Epic biosensor), both CLA isomers cis-9, trans-11-CLA and trans-10, cis-12-CLA were found to activate FFA1 in vitro at concentrations sufficient to also account for FFA1 activation in vivo. Each CLA isomer markedly increased glucose-stimulated insulin secretion in insulin-producing INS-1E cells that endogenously express FFA1 and in primary pancreatic ␤-cells of wild type but not FFA1 ؊/؊ knock-out mice. Our findings establish a clear mechanistic link between CLAs and insulin production and identify the cell surface receptor FFA1 as a molecular target for CLAs, explaining their acute stimulatory effects on insulin secretion in vivo. CLAs are also revealed as insulinotropic components in widely used nutraceuticals, a finding with significant implication for development of FFA1 modulators to treat type 2 diabetes.

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“…These efforts have identified many different classes of FFA1 agonist, many with relatively good potency (Fig. (3)) [19,[62][63][64][65][66][67][68], all of which have been assumed to be orthosteric. However, a recent study has demonstrated that at least two of these ligands are in fact allosteric [39], drawing into question the previously assumed orthosteric mode of action of many other FFA1 agonists.…”

Section: Allosteric Ligands For Ffa1mentioning

confidence: 99%

“…Interestingly, it has been noted that several FFA1 agonists, including 2, 3 and 4, are in fact partial agonists compared with the endogenous fatty acids [62,63,39,73]. Given that 2 (and possibly 3 and 4) is allosteric, this may suggest that allosteric agonists of FFA1 produce different functional outcomes than their orthosteric counterparts.…”

Section: Allosteric Ligands For Ffa1mentioning

confidence: 99%

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

Hudson¹,

Ulven²,

Milligan

2013

CTMC

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G protein coupled receptors (GPCRs) are the most historically successful therapeutic targets. Despite this success there are many important aspects of GPCR pharmacology and function that have yet to be exploited to their full therapeutic potential. One in particular that has been gaining attention in recent times is that of GPCR ligands that bind to allosteric sites on the receptor distinct from the orthosteric site of the endogenous ligand. As therapeutics, allosteric ligands possess many theoretical advantages over their orthosteric counterparts, including more complex modes of action, improved safety, more physiologically appropriate responses, better target selectivity, and reduced likelihood of desensitisation and tachyphylaxis. Despite these advantages, the development of allosteric ligands is often difficult from a medicinal chemistry standpoint due to the more complex challenge of identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid sensitive GPCRs.

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Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA₁/GPR40), a Potential Target for the Treatment of Type II Diabetes

Cited by 122 publications

References 26 publications

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

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Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes

Cited by 122 publications

References 26 publications

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

Molecular Pharmacology of Promiscuous Seven Transmembrane Receptors Sensing Organic Nutrients

Conjugated Linoleic Acids Mediate Insulin Release through Islet G Protein-coupled Receptor FFA1/GPR40

The Therapeutic Potential of Allosteric Ligands for Free Fatty Acid Sensitive GPCRs

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Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA₁/GPR40), a Potential Target for the Treatment of Type II Diabetes