In contrast to carbohydrates and proteins, which are detected by specialized taste receptors in the forms of their respective building blocks, sugars, and L-amino acids, the third macronutrient, lipids, has until now not been associated with gustatory receptors. Instead, the recognition of fat stimuli was believed to rely mostly on textural, olfactory, and postingestive cues. During the recent years, however, research done mainly in rodent models revealed an additional gustatory component for the detection of long-chain fatty acids (LCFAs), the main taste-activating component of lipids. Concomitantly, a number of candidate fat taste receptors were proposed to be involved in rodent's gustatory fatty acid perception. Compared with rodent models, much less is known about human fat taste. In order to investigate the ability of the human gustatory system to respond to fat components, we performed sensory experiments with fatty acids of different chain lengths and derivatives thereof. We found that our panelists discriminated a "fatty" and an irritant "scratchy" taste component, with the "fatty" percept restricted to LCFAs. Using functional calcium-imaging experiments with the human orthologs of mouse candidate fat receptors belonging to the G protein-coupled receptor family, we correlated human sensory data with receptor properties characterized in vitro. We demonstrated that the pharmacological activation profile of human GPR40 and GPR120, 2 LCFA-specific receptors associated with gustatory fat perception in rodents, is inconsistent with the "scratchy" sensation of human subjects and more consistent with the percept described as "fatty." Expression analysis of GPR40 and GPR120 in human gustatory tissues revealed that, while the GPR40 gene is not expressed, GPR120 is detected in gustatory and nongustatory epithelia. On a cellular level, we found GPR120 mRNA and protein in taste buds as well as in the surrounding epithelial cells. We conclude that GPR120 may indeed participate in human gustatory fatty acid perception.

Summary Human bitter taste is mediated by the hTAS2R family of G protein-coupled receptors [1-4]. The discovery of the hTAS2Rs enables the potential to develop specific bitter receptor antagonists that could be beneficial as chemical probes to examine the role of bitter receptor function in gustatory and non-gustatory tissues. In addition, they could have widespread utility in food and beverages fortified with vitamins, antioxidants and other nutraceuticals since many of these have unwanted bitter aftertastes. We employed a high-throughput screening approach to discover a novel bitter receptor antagonist (GIV3727) that inhibits activation of hTAS2R31 by saccharin and acesulfame K, two common artificial sweeteners. Pharmacological analyses revealed that GIV3727 likely acts as an orthosteric, insurmountable antagonist of hTAS2R31. Surprisingly, we also found that this compound could inhibit five additional hTAS2Rs, including the closely related receptor hTAS2R43. Molecular modeling and site-directed mutagenesis studies suggest that two residues in helix seven are important for antagonist activity in hTAS2R43/31. In human sensory trials, GIV3727 significantly reduced the bitterness associated with the two sulphonamide sweeteners, indicating that TAS2R antagonists are active in vivo. Our results demonstrate that small molecule bitter receptor antagonists can effectively reduce the bitter taste qualities of foods, beverages, and pharmaceuticals.

This article is available online at http://www.jlr.org the fi ve taste qualities, sweet, umami, salty, sour, and bitter ( 2 ). In the past, the existence of additional taste modalities such as fatty ( 3 ), metallic ( 4 ), or a taste for water ( 5 ) has been speculated. In recent years, particular attention has been paid to the potential existence of fat taste and its putative status compared with the other well-accepted taste qualities . Whereas the textural, olfactory, and postingestive recognition of fat constituents have been considered the dominant cues for fat perception in the past, several recent studies, performed mostly in rodents but also in humans, have pointed to a gustatory component in fat perception [for a recent review see ( 6 )]. The use of anosmic ( 7 ) or esophagostomized ( 8 ) rat models in combination with texture-masking buffer compositions indicated an orosensory detection mechanism for long-chain fatty acids, in particular. Moreover, a number of candidate receptors for the oral detection of lipophilic molecules were identifi ed by several independent research groups. These putative fat sensors include potassium channels ( 3 ) and scavenger receptor/fatty acid transporter CD36/FAT ( 9, 10 ), as well as G protein-coupled receptors (GPRs) such as GPR40 ( 11 ) and GPR120 ( 11-13 ). For some of the candidate receptors, knockout mouse models were analyzed and their contribution to orosensory fat perception confi rmed. Mice with a genetic ablation of CD36 exhibit no preference for the polyunsaturated long-chain fatty acid, linoleic acid, in two-bottle preference tests compared with wild-type mice. Moreover, a reduced cephalic phase response upon oral stimulation with oleic, linoleic, and linolenic acid, but not to the saturated long-chain fatty acid, stearic acid, or the medium-chain fatty acid, caprylic acid, suggests pronounced selectivity for particular lipophilic stimuli ( 10 ). Similarly, GPR40 as well as GPR120 knockout mice both show a loss of preference for linoleic acid, and The perception of taste elicited by countless chemicals present in food plays an important role for the survival of organisms. The gustatory system monitors not only the caloric content and the appropriate electrolyte supply, but also the presence of putatively harmful substances in food items ( 1 ). Detection of food constituents within the oral cavity is achieved by taste receptor molecules expressed by sensory cells specifi cally devoted to the detection of one of

Personal experience, learned eating behaviors, hormones, neurotransmitters, and genetic variations affect food consumption. The decision of what to eat is modulated by taste, olfaction, and oral textural perception. Taste, in particular, has an important input into food preference, permitting individuals to differentiate nutritive and harmful substances and to select nutrients. To be perceived as taste, gustatory stimuli have to contact specialized receptors and channels expressed in taste buds in the oral cavity. Gustatory information is then conveyed via afferent nerves to the central nervous system, which processes the gustatory information at different levels, resulting in stimulus recognition, integration with metabolic needs, and control of ingestive reflexes. This review discusses physiological factors influencing the decision of what to eat, spanning the bow from the recognition of the nutritive value of food in the oral cavity, over the feedback received after ingestion, to processing of gustatory information to the central nervous system.

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