Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Kochem, Matthew; Breslin, Paul A.S.

doi:10.1093/chemse/bjw104

Cited by 11 publications

(15 citation statements)

References 43 publications

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“…It is also possible that greater doses of clofibric acid could elicit more pronounced inhibition of umami taste from MPG and ribonucleotides. The clofibrate dose of 1.4 mM was selected based on our previous work that showed it inhibits sweetness intensity across broad concentration ranges of sweeteners [ 30 ]. The difference in inhibitory efficacy suggests that clofibric acid is a superior inhibitor of sweetness intensity than umami intensity.…”

Section: Discussionmentioning

confidence: 99%

“…The MPG series was prepared in six conditions: neat, with 1.4 mM clofibric acid, with 3 mM IMP, with 3 mM GMP, with IMP + clofibric acid, and with GMP + clofibric acid. This dose of clofibric acid has been shown to inhibit sweetness intensity from high potency sweeteners and sucrose [ 30 ]. Two participants were excluded from the final analysis on the basis that they reported no difference in umami intensity between 3.16 and 316 mM MPG, indicating they were insensitive to changes in glutamate concentration over two orders of magnitude.…”

Section: Methodsmentioning

confidence: 99%

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Clofibrate inhibits the umami-savory taste of glutamate

Kochem

Breslin

2017

PLoS ONE

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In humans, umami taste can increase the palatability of foods rich in the amino acids glutamate and aspartate and the 5’-ribonucleotides IMP and GMP. Umami taste is transduced, in part, by T1R1-T1R3, a heteromeric G-protein coupled receptor. Umami perception is inhibited by sodium lactisole, which binds to the T1R3 subunit in vitro. Lactisole is structurally similar to the fibrate drugs. Clofibric acid, a lipid lowering drug, also binds the T1R3 subunit in vitro. The purpose of this study was to determine whether clofibric acid inhibits the umami taste of glutamate in human subjects. Ten participants rated the umami taste intensity elicited by 20 mM monosodium glutamate (MSG) mixed with varying concentrations of clofibric acid (0 to 16 mM). In addition, fourteen participants rated the effect of 1.4 mM clofibric acid on umami enhancement by 5’ ribonucleotides. Participants were instructed to rate perceived intensity using a general Labeled Magnitude Scale (gLMS). Each participant was tested in triplicate. Clofibric acid inhibited umami taste intensity from 20 mM MSG in a dose dependent manner. Whereas MSG neat elicited “moderate” umami taste intensity, the addition of 16 mM clofibric acid elicited only “weak” umami intensity on average, and in some subjects no umami taste was elicited. We further show that 1.4 mM clofibric acid suppressed umami enhancement from GMP, but not from IMP. This study provides in vivo evidence that clofibric acid inhibits glutamate taste perception, presumably via T1R1-T1R3 inhibition, and lends further evidence that the T1R1-T1R3 receptor is the principal umami receptor in humans. T1R receptors are expressed extra-orally throughout the alimentary tract and in regulatory organs and are known to influence glucose and lipid metabolism. Whether clofibric acid as a lipid-lowering drug affects human metabolism, in part, through T1R inhibition warrants further examination.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Clofibrate inhibits the umami-savory taste of glutamate

Kochem

Breslin

2017

PLoS ONE

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“…In addition to agonists, an inhibitor of sweet taste in humans, lactisole, has been characterized as an inverse agonist (Galindo-Cuspinera et al, 2006). Clofibrate and structurally related phenoxy herbicides also have been shown to potently antagonize TAS1R2/R3 receptor activity in cell-based assays (Maillet et al, 2009), but much higher concentrations of clofibrate were needed to achieve modest inhibition in human tests of sweet taste (Kochem and Breslin, 2017). Positive allosteric modulators of sucrose and sucralose activation of TAS1R2/R3 also have been discovered (Servant et al, 2010;Zhang et al, 2010).…”

Section: B Tas1r Receptorsmentioning

confidence: 99%

A Pharmacological Perspective on the Study of Taste

Palmer¹

2018

Pharmacol Rev

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With those discoveries a new opportunity to examine taste as a function of receptor activity has come into focus. Pharmacology is the science designed specifically for the experimental interrogation and quantitative characterization of receptor function at all levels of inquiry from molecules to behavior. This review covers the history of some of the major concepts that have shaped thinking and experimental approaches to taste, the seminal discoveries that have led to elucidation of receptors for taste, and how applying principles of receptor pharmacology can enhance understanding of the mechanisms of taste physiology and perception.

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“…Carboyxlic acid salt 5 TMD (TAS1R3) (Xu et al, 2004) Clofibric acid (4-chlorophenoxy)-2-methylpropanoic acid Herbicide acid 4 TMD (TAS1R3) (Maillet et al, 2009;Kochem and Breslin, 2017) Where VFT, Venus flytrap domain; TMD, transmembrane domain.…”

Section: Bitter Receptors Ligand Binding Domain and Amino Acid Residuesmentioning

confidence: 99%

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

2020

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Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

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Lipid-Lowering Pharmaceutical Clofibrate Inhibits Human Sweet Taste

Cited by 11 publications

References 43 publications

Clofibrate inhibits the umami-savory taste of glutamate

Clofibrate inhibits the umami-savory taste of glutamate

A Pharmacological Perspective on the Study of Taste

G Protein-Coupled Receptors in Taste Physiology and Pharmacology

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