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Montmayeur JP, le Coutre J, editors. Fat Detection: Taste, Texture, and Post Ingestive Effects. Boca Raton (FL): CRC Press; 2010.

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Fat Detection: Taste, Texture, and Post Ingestive Effects.

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Chapter 3Gustatory Mechanisms for Fat Detection

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The incidence of obesity continues to escalate, and with it, there has been a corresponding increase in as many as 30 diseases related to the obese state, including cardiovascular disease, diabetes, and end-stage renal disease. Recent estimates place the number of overweight and obese individuals in the United States at roughly one third and two thirds of the population, respectively (CDC/DHHS, Centers for Disease Control and Prevention). While obesity is clearly a disease that has multiple etiologies, there are compelling data indicating a link between the recent surge in obesity and a corresponding increase in dietary fat intake (Bray and Popkin, 1998, 1999; Bray et al., 2004). Despite this link, there has been comparatively little attention paid to the sensory cues provided by dietary fats which might precipitate their intake over the short and long terms. Over the past decade, however, the idea that fats might provide salient cues to the gustatory system consistent with there being a “taste of fat” has gained credence. Research in this area holds great promise in understanding the role of the gustatory system in both the recognition of dietary fat and the eventual control of fat intake.

3.1.1. Taste: The Gateway to the Enteric Nervous System

The peripheral gustatory system has two primary functions. The first is the selective identification of essential nutrients the body requires to function. This appetitive property is generally reflected in the ability to respond to the primary tastes such as sweet (carbohydrates), salty (minerals), and umami (proteins/amino acids). In general, these stimuli drive ingestive behavior. The aversive role of the gustatory system, which is generally served by our bitter taste system, is meant to prevent the ingestion of potentially toxic or harmful compounds into the body and elicits an innate rejection reflex in most organisms. Interestingly, our primary taste for acidic compounds, sour, does not easily fit into one of these categories exclusively, and arguments have been made on both sides as to whether sour taste should be included in the appetitive or aversive category (Roper and Gilbertson, 1992). While there is no consensus over the direct role of taste in mediating ingestive behavior in terms of the control of food intake, it is clear that appetitive stimuli promote food intake and aversive stimuli do not.

The sense of taste is mediated by organs called taste buds situated throughout the oral cavity. The greatest density of taste buds is found in the tongue, where they reside within one of three taste papillae. In mammals, the fungiform papillae, which lie over the anterior two-thirds of the tongue, contain one, two, or four taste buds with a preponderance of single taste bud per papilla. In the posterior tongue, hundreds of taste buds lie along the sides of the deep crypts that make up the paired foliate papillae on the sides of the tongue or the circumvallate papillae just posterior to the intermolar imminence. While rodents have a single circumvallate papilla, humans may have a dozen or more. Significant numbers of taste buds are also found distributed in the soft palate, with a high density in the region between the hard and soft palate in a structure known as the geschmackstreifen (“taste stripe”). Other regions containing taste buds include the epiglottis, larynx, and nasopharynx. While these extra-lingual taste buds have been investigated to a limited degree (Gilbertson and Fontenot, 1998; Gilbertson et al., 2001; Gilbertson, 2002; Kataoka et al., 2006; Bezencon et al., 2007; Miura et al., 2007), the vast majority of taste transduction studies have been focused on signaling within the taste buds of the tongue. Although there are certainly regional differences within the taste buds of the tongue in terms of chemosensitivity, it is clear that the concept of a “tongue map” with specific areas of the tongue devoted to each modality is incorrect and that individual taste buds and, perhaps even individual cells (Gilbertson et al., 2001; Caicedo et al., 2002), may respond to multiple classes of taste primers.

An individual taste bud contains from 50 to 100 cells, and within this population, there exist multiple cell types such as cells that act as stem cells, sustentacular cells, receptor cells, and so-called output cells that release neurotransmitter onto the gustatory afferent nerves. It is generally accepted that taste buds contain at least three cells types, though the function of these cells has not been firmly established (Bartel et al., 2006; Miura et al., 2006, 2007). The most numerous cells within the taste bud, the Type I cells, have been proposed to play a supporting role in the taste bud, perhaps as a sustentacular cell that modulates the local environment of the taste bud. A recent report suggests, however, that Type I-like cells may be involved in salt taste perception (Vandenbeuch et al., 2008). Type II cells, the so-called receptor cells, are believed to represent the class of cells that contain receptors for sweet, bitter, and umami tastes as they express all the signaling components of the G protein–coupled receptors (GPCR)-mediated pathways. Type III cells have been suggested to be the output cells of the taste bud as they contain much of the synaptic machinery thought to be necessary to signal taste information to the afferent nerve. While this model is attractive, it cannot completely explain peripheral gustatory function, and the inter-cellular signaling within the taste bud remains somewhat controversial. The story of cell-to-cell communication within the taste bud is far from clear. A current empirically based model (DeFazio et al., 2006; Roper, 2006, 2007; Huang et al., 2007) favors the idea that Type II (receptor) cells communicate with Type III (output) cells via purinergic signaling mechanisms. Indeed, the loss of purinergic signaling results in rather nonspecific and widespread impairment in peripheral gustatory function (Finger et al., 2005).

3.1.2. Taste Transduction

The initial identification of chemical signals by the taste receptor cells (TRCs) has been shown to involve a series of steps culminating in the release of neurotransmitter from the TRCs onto the gustatory afferents. Initially, sapid chemicals must diffuse or be transported to interact with sites on the apical membranes of TRCs. Most taste stimuli are restricted to the apical regions due to the occlusion of tight junctions between taste cells. In most cases, taste stimuli interact either with receptors or directly with ion channels located on the apical membranes of taste cells. This interaction then leads to a conductance change and/or a release of intracellular Ca2+ within the taste cell. The conductance change activates voltage-dependent K+ and Na+ channels in the basolateral membrane leading to depolarization and generation of action potentials within the taste cell. Alternatively, release of intracellular Ca2+ may activate the nonspecific cation channel, transient receptor potential channel type M5 (TRPM5), and allow Na+ influx during chemostimulation. Membrane depolarization, in turn, activates voltage-dependent Ca2+ channels, allowing Ca2+ influx and eventually transmitter release onto gustatory afferents. As discussed above, it is unclear if this pathway from taste stimulus binding through transmitter release occurs within a single cell in the taste bud or if there is a requirement for cell-to-cell communication (Type II to Type III) within the taste bud prior to afferent nerve activation for certain subsets of taste stimuli. For more detailed information, the reader is referred to a number of excellent reviews dealing with the specifics of the taste transduction process (Herness and Gilbertson, 1999; Gilbertson et al., 2000; Gilbertson and Boughter, 2003; Chandrashekar et al., 2006; Simon et al., 2006; Sugita, 2006; Palmer, 2007; Roper, 2007).


Given the role of the taste system in recognizing those compounds needed for survival, almost a decade ago, we began to test the idea that, as is the case with other nutrients, the gustatory system should be able to detect the essential fatty acids, i.e., those that are required in the diet. At this time, however, the prevailing idea was that fat had no taste, rather, its most (only) salient cue was its texture (Raats et al., 1993; Mela et al., 1994a,b). Clearly, the textural attributes of fat have been well documented (Rolls et al., 2003; Verhagen et al., 2003; Kadohisa et al., 2005) and contribute significantly to fat perception. The texture of fat is perceived largely through activation of the somatosensory system and specifically through activation of trigeminal nerve fibers that originate in the trigeminal ganglia and send projections into the oral cavity.

Our initial work in this area was focused on trying to determine if essential fatty acids, the cis-polyunsaturated fatty acids (PUFAs), could activate taste cells in a manner analogous to other taste stimuli. The utility of fatty acids as the prototypical taste stimulus was suggested by a number of observations at the time. First, there was an emerging literature that had demonstrated that free fatty acids could act as specific and potent extracellular messengers in a variety of systems including cardiac, smooth, and skeletal muscle (Ordway et al., 1991; Honore et al., 1994; Petrou et al., 1995). These pathways appeared to be independent of the ability of some PUFAs (i.e., arachidonic acid) to activate second messenger cascades (lipoxygenase, cyclooxygenase, and 20-hydroxyeicosatetraenoic acid) within cells. Second, while there are significant free fatty acid concentrations in most, if not all, fat-containing foods (Weiss, 1983), the oral cavity contains molecules predicted to play a critical role in the generation and transport of free fatty acids within this aqueous environment. These include lingual lipase, which is released from serous glands at the base of the circumvallate and foliate papillae and can break down triglycerides into the mono- and diglycerides, free fatty acids, and the von Ebner’s gland proteins. The latter are structurally similar to the lipocalins, a family of proteins that play primary roles in the transport of lipophilic molecules (Akerstrom et al., 2000; Descalzi Cancedda et al., 2000; Flower et al., 2000; Grzyb et al., 2006). Interestingly, the von Ebner’s gland proteins, which were originally hypothesized to transport lipophilic bitter molecules, bind no known tastants other than free fatty acids (Schmale et al., 1993; Kock et al., 1994; Creuzenet and Mangroo, 1998).

3.2.1. Delayed Rectifying K+ Channels: The First Fatty Acid “Receptor”

Our original hypothesis that proposed a role for delayed rectifying K+ (DRK) channels as important players in the initial transduction of fat taste stemmed from work in the early-to-mid-1990s that demonstrated that free fatty acids were potent primary messengers in a numbers of systems (Ordway et al., 1991; Petrou et al., 1995) and their site of action was directly at the level of DRK channels (Grissmer et al., 1994; Honore et al., 1994; Poling et al., 1996). To test this idea, we began a series of electrophysiological assays to determine if free fatty acids could activate taste cells through inhibition of DRK channels. In rat TRCs, the original target in these early experiments, fatty acids could significantly inhibit current flow through DRK channels consistent with their action in other tissues. The predicted cellular consequence of this action would be the inhibition of the efflux of K+ ions, resulting in a depolarization of the TRCs during chemostimulation with free fatty acids (Gilbertson et al., 1997). Block of K+ channels, either directly or indirectly, has been shown to result in depolarization during the application of other tastants, such as sweet and sour stimuli (Kinnamon et al., 1988; Cummings and Kinnamon, 1992; Cummings et al., 1996; Herness et al., 1997). Interestingly, in the anterior tongue (i.e., fungiform taste buds), the only fatty acids that caused a significant reduction in DRK currents were the cis-PUFAs, also known as the essential fatty acids, which are required in the diet. This finding dovetailed with the role of the gustatory system in nutrient recognition (Gilbertson and Kinnamon, 1996; Herness and Gilbertson, 1999; Gilbertson et al., 2000). The effective concentration range for PUFA activation of taste cells via this mechanism was approximately 1.0 μM for each fatty acid and there was no significant effect of chain length or degree of unsaturation (Gilbertson et al., 1997). The mechanism of inhibition seemed to be a classical open channel block mechanism (Honore et al., 1994). The effective concentrations fell well within the range of free fatty acid concentrations that can be generated during fat feeding in rodents (Kawai and Fushiki, 2003) and found in most fat-containing foods (Weiss, 1983) regardless of lingual lipase activity. While the anterior tongue appeared specific for PUFAs, other areas in the oral cavity (taste buds from the foliate and circumvallate papillae and the soft palate) responded to a somewhat broader array of fatty acids, including the monounsaturated fatty acids, oleic acid, and palmitoleic acid, in a similar concentration range (Hansen et al., 2002, 2003).

3.2.2. KCNA5 Is the Major Fatty Acid-Sensitive DRK Channel in Taste Cells

Given the molecular diversity of DRK channels which exist in at least nine different forms within three different subfamilies, one of our initial goals was to identify the subtype(s) of DRK channels in the taste system that was playing the role of fatty acid “receptor.” Pharmacological, electrophysiological, and molecular biological assays are consistent with TRCs expressing a rich array of DRK channels, including members from within the three major families of DRK channels, KCNA, KCNB, and KCNC (Liu et al., 2005). Of the DRK channels expressed, the four most highly expressed channels appear to be KCNA5, KCNC2, KCNC1, and KCNC2 (Kv1.5, Kv2.2, Kv3.1, and Kv3.2, respectively). This relative expression pattern is consistent across all lingual taste bud types and the enteroendocrine cell line, STC-1, which shares many of its chemosensory pathways with mammalian taste cells, may as such be a good model for (Type II) taste cells (Wu et al., 2002, 2005; Dyer et al., 2005; Masuho et al., 2005; Chen et al., 2006; Saitoh et al., 2007; Hao et al., 2008). Heterologous expression data demonstrate that members of the KCNA family of DRK channels are highly sensitive to cis-PUFAs, while the KCNB and KCNC family members are moderately sensitive and insensitive, respectively (Shah et al., 2006). Based upon kinetics, pharmacology, and quantitative expression, the major DRK channel in taste cells appears to be the KCNA5 channel (Liu et al., 2005). Interestingly, KCNA5 (Kv1.5) is the major DRK channel expressed in the heart which exhibits similar fatty acid responsiveness as taste cells (Kim and Clapham, 1989; Kim and Duff, 1990; Wallert et al., 1991; Honore et al., 1994; Hu et al., 1998; Xu and Rozanski, 1998; Crumb et al., 1999; Doolan et al., 2002; Ogita et al., 2003; Guizy et al., 2008). KCNA5 appears to be fairly ubiquitous in its expression within the taste bud, since virtually all types of taste cells express this channel (Liu et al., 2005).

3.2.3. Implications of DRK Inhibition by Free Fatty Acids

The ability of free fatty acids to inhibit DRK channels, particularly KNCA5, in taste cells has two functional consequences. The first, already mentioned, suggests that this mechanism may act as a primary mechanism related to the transduction of fat by the peripheral gustatory system. Indeed, there is now a wealth of data from the molecular/cellular level through studies of behavior and human psychophysics to support the notion that free fatty acids are capable of being sensed by the taste system (see Chapters 4 and 7).

The other role of this mechanism has been suggested to be involved in the ability of free fatty acids to modulate the responses of taste cells to other taste stimuli (Gilbertson, 1993, 1998a,b, 1999; Gilbertson and Boughter, 2003; Mizushige et al., 2007). As mentioned above, KCNA5 shows rather broad expression patterns within the taste bud and, accordingly, might be expected to be found in cells that respond to a variety of taste primers. Because one role of DRK channels is to repolarize cells following activity, one would predict that tastant-induced activity would be altered in the presence of fatty acids. That is, a depolarization induced in a taste cell by another stimulus (sweet or salty) should be enhanced and last longer if these repolarizing DRK channels are inhibited by fatty acids, an effect we have shown at the cellular level in electrophysiological assays (Gilbertson et al., 1997). To provide support for this model at the behavioral level, we have performed 48 h preference tests in rodents, investigating the ability of free fatty acids to alter preference for a subthreshold concentration of a sweet stimulus, saccharin. In these assays, neither linoleic acid (5 and 20 μM) nor saccharin (0.5 mM) was preferred at these concentrations, but there was preference for the combination of these two stimuli (Gilbertson et al., 2005). However, this effect was limited to cis-PUFAs like linoleic acid as lauric acid at the same concentration did not affect preference for the subthreshold concentration of saccharin consistent with its inability to inhibit DRK channels. These findings were replicated in rodents using a short term behavioral paradigm (Pittman et al., 2006), which showed that linoleic and oleic acids could alter licking responses to sweet stimuli in a manner consistent with the ability of fatty acids to enhance responsiveness. However, this ability of fatty acids to enhance taste in humans appears equivocal. Some reports have suggested that linoleic acid is able to alter taste in humans (Kamphius, 2003; Kamphius et al., 2003), whereas others have reported that free fatty acids are not able to alter detection or thresholds for prototypical taste stimuli (Mattes, 2007). While the reason for these differences is unclear, the latter study used free fatty acid concentrations several orders of magnitude higher than those used in rodent studies and certain aspects of human taste performance show parabolic, not linear, relationships with concentration (Pangborn and Giovanni, 1984). Figure 3.1 summarizes the potential roles of fatty acids as a taste primer and taste modulator.

FIGURE 3.1. The ability of fatty acids to inhibit DRK channels is consistent with roles as either a taste primer or a taste modulator.


The ability of fatty acids to inhibit DRK channels is consistent with roles as either a taste primer or a taste modulator. Fatty acids (FA), like linoleic acid, inhibit DRK channels by acting as an open channel blocker. This inhibition would prohibit (more...)


In the context of the emerging “epidemic of obesity,” there has been significant interest in understanding the sensory cues for dietary fat due in part to the data suggesting a link between fat intake and obesity (Bray and Popkin, 1998, 1999; Bray et al., 2004). To this end, we compared fatty acid responsiveness in taste cells isolated from rats classified as either obesity-prone (fat-preferring) or obesity-resistant (Okada et al., 1992) to determine if the peripheral gustatory system responded differently to fatty acids. In these electrophysiological assays, DRK currents in TRCs from an obesity-prone strain (Osborne–Mendel; O–M) were significantly less responsive to cis-PUFAs than those from an obesity-resistant strain (S5B/Pl). That is, cis-PUFAs inhibited less of the total outward current through DRK channels in the O–M rats (Gilbertson et al., 1998) though the relative affinities of FAs were similar (e.g., EC50 in both strains were ~1 μM) (Gilbertson et al., 2005). From a cellular perspective, this would be predicted to exert a less robust signal from the TRC onto the gustatory afferent nerve (cf. Figure 3.1) in obesity-prone rats. Using quantitative real-time PCR (qPCR) we determined that this disparity was due to a difference in expression of DRK channels (Gilbertson et al., 2005). These expression data coupled with our functional data showing the relative sensitivity to FAs in the three families of DRK channels (Shah et al., 2006) provided a framework for a model that suggested that the difference between the obesity-prone and -resistant rats was due, at least in part, to the fact that O–M rats expressed a lower ratio of FA-sensitive DRK channels:FA-insensitive (FA-s:FA-i) DRK channels. This ratio is approximately 1.0 in O–M rats and 5.7 in S5B/Pl rats (cf. Fig. 7 in Gilbertson et al., 2005). Based solely upon the data surrounding DRK expression and peripheral responsiveness to fatty acids in obesity-prone and -resistant rats, we developed a model that predicts an “inverse correlation” between peripheral responsiveness for fatty acids and dietary fat preference (Gilbertson et al., 1998, 1999, 2005). Basically, the reduced peripheral responsiveness to FAs in obesity-prone rats provides a weaker signal to the central nervous system which, in turn, uses this information to help coordinate patterns of food intake and dietary preference. Such inverse relationships between peripheral responsiveness and dietary intake have been shown for salt in rodent models (Curtis et al., 2001, 2008), consistent with this idea.

Our behavioral assay showing the ability of linoleic acid to enhance preference for a subthreshold saccharin concentration provided additional support for this model (Gilbertson et al., 2005). In this study, the linoleic acid was significantly more effective in enhancing the preference for saccharin in S5B/Pl (obesity-resistant) rats than in O–M rats, consistent with the electrophysiological data on fatty acid responsiveness in DRK channels described above. However, a direct comparison of taste thresholds for fatty acids in O–M and S5B/Pl rats conducted using the conditioned taste aversion paradigm produced contrary results (Pittman et al., 2008). Following formation of a conditioned taste aversion to linoleic acid, S5B/Pl and O–M rats were tested for their ability to avoid (i.e., detect) fatty acids. For all effective fatty acids, the obesity-prone rats were better able to detect and avoid fatty acids than their obesity-resistant counterparts. The conclusion from this series of experiments is that O–M rats have a lower threshold for fatty acid detection than S5B/Pl rats. Interestingly, female rats of both strains were significantly better at detecting and avoiding fatty acids than were males, suggesting that gender effects are significant in the chemoreception of dietary fat. This robust gender difference has not been explored at the cellular and molecular levels to date and appears warranted.

The explanation for this incongruity is not immediately clear. Based upon the cell-based assays and the ability of linoleic acid to enhance preference for sweet compounds, it was anticipated that the obesity-prone strain should be “less” responsive to the sensory cues for fatty acids. At the minimum, since the EC50 for FA-induced inhibition of DRK channels was identical across strains (Gilbertson et al., 2005), we would expect no difference between the two strains. Yet, following formation of a conditioned taste aversion to linoleic acid, O–M rats were “more” responsive than S5B/Pl rats to fatty acids. There are two possible explanations to these apparently conflicting results. First, there may be a disconnect between the ability of fatty acids to act as taste modulators (Figure 3.1) in behavioral assays (Gilbertson et al., 2005) and those behavioral assays in which fatty acids are applied in the absence of other stimuli (Pittman et al., 2008). That is, the molecular and cellular differences reported in the taste systems between S5B/Pl and O–M rats have been at the level of DRK channels. It is plausible that the mechanisms involving fatty acid inhibition of DRK channels is more important for enhancing/modulating the response to other tastants and is less important as the primary receptive mechanism for fatty acids (see Section 3.3.1). Following this line of reasoning, a second possibility is that there may be additional mechanisms for the transduction of fatty acids that differ between S5B/Pl and O–M rats that result in the obesity-prone strain being more sensitive to dietary fatty acids. It should be noted that these two possibilities are not mutually exclusive. Contrary to our original hypothesis linking fatty acid chemosensitivity and dietary fat intake, this would imply that there is a positive relationship between taste sensitivity to fatty acids (as taste primers) and intake of dietary fat. Clearly, more research is needed to discriminate between the roles of fatty acids as primary taste stimuli and modulators of peripheral gustatory function.

3.3.1. The “Problem” with DRK Channels as Fatty Acid Receptors

As alluded to above, our data on the role of DRK channels in fatty acid transduction are consistent with there being dual roles for this pathway in the chemoreception of dietary fat. On one hand, these DRK channels play a critical role in the repolarization of taste cells following chemostimulation and their inhibition by fatty acids would inhibit the taste cell’s ability to recover from stimulus-induced depolarizations. Stimulation of taste cells in the presence of fatty acids, like linoleic acid, produces greater and longer-lasting depolarizations than in the absence of fatty acids consistent with this interpretation (Gilbertson et al., 1997). Certainly, given the widespread distribution of KCNA5 in taste cells (Liu et al., 2005), we would expect that a significant number of taste cells would express this fatty acid-sensitive DRK channel and the signaling components for other sapid molecules that impart tastes like sweet or salty. We have termed this the modulatory role of fatty acid taste, which may be thought of as being analogous to, but less specific than, the ability of 5′ nucleotides, like inosine monophosphate (IMP), to enhance umami taste (Ninomiya et al., 2000; Kawai et al., 2002).

In addition to a modulatory role, the inhibition of DRK channels by fatty acids in the absence of other tastants (i.e., fatty acids as a taste primer; Figure 3.1) should result in depolarization of taste cells in much the same manner as K+ channel block results in increased taste cell activity in response to other tastants (Kinnamon et al., 1988; Cummings and Kinnamon, 1992; Cummings et al., 1996; Herness et al., 1997). However, our electrophysiological data demonstrates that fatty acids act as open channel blockers, a finding consistent with that reported in other systems (Ordway et al., 1991; Petrou et al., 1995; Poling et al., 1996; Guizy et al., 2008). Because of this fact, for fatty acids to act as taste primers, it would require that these channels, or at least a portion of them, be open at normal taste cell resting potentials (−35 to −55 mV). We estimate that approximately 5% of DRK channels would be open within this voltage range (cf. Fig. 1B in Liu et al., 2005). While it is feasible that this proportion of open channels could depolarize a taste cell if DRK channels were inhibited by fatty acids, the modest relative number of open DRK channels at rest led us to query if there were additional receptors upstream of fatty acid-sensitive DRK channels. That is, were there other receptors that played an important role in generating the receptor potential during fatty acid stimulation that contributed to the primary receptive mechanism for fat taste?


3.4.1. CD36

At the time we began to explore the ability of fatty acids to activate mammalian TRCs, Fushiki and colleagues presented data showing the immunocytochemical localization of the fatty acid transporter CD36 in posterior taste buds in rodents (Fukuwatari et al., 1997) while it was apparently absent from nontaste epithelium. While the cellular events following fatty acid binding to CD36 were not clear at this time, it pointed out that there may be multiple mechanisms in use by the taste system to recognize and respond to components contained in dietary fat.

Since the initial identification of CD36 in the peripheral gustatory system, a number of studies have validated its expression and functional role in the chemoreception of fatty acids. Studies utilizing CD36-deficient mice have shown that CD36 plays a necessary, but not necessarily exclusive, role in the ability to discriminate fatty acids. Comparison of short- and long-term preference for linoleic acid revealed that mice lacking CD36 had no innate preference for long-chain fatty acid (LCFA) containing solutions in contrast to the normal preference found in wild-type mice (Fushiki and Kawai, 2005; Laugerette et al., 2005). Moreover, the preference for dietary fatty acids is dependent upon there being intact gustatory nerves (Gaillard et al., 2008) linking this behavioral response to activity within the gustatory system. Recent data has shown that free fatty acids are capable of generating a rise in intracellular Ca2+ in taste cells (Gaillard et al., 2008; Liu et al., 2008) at concentrations similar to those that inhibit DRK channels. Much, but certainly not all, of the LCFA-induced rise in Ca2+ is dependent upon CD36 (Gaillard et al., 2008). In an interesting study, Sclafani et al. (2007) demonstrated the required role of CD36 in preference for dilute fatty acid concentrations, but that at higher concentrations mice lacking CD36 were able to develop preferences for PUFA-rich soybean oil. The authors interpreted these data as evidence that CD36 plays a role in the taste component underlying fatty acid preference, but it was not essential for postoral conditioned fat preferences, despite the fact that CD36 is expressed throughout the enteric nervous system (Chen et al., 2001). An alternative explanation is that CD36 is not the primary receptor for fatty acids but helps facilitate the binding of fatty acids and their presentation to other fatty acid-activated proteins in the cell membrane (DRK channels, fatty acid-activated receptors). Thus, at low concentrations, CD36 may play a critical role in the presentation of fatty acids to other receptive proteins but at much higher concentrations, CD36-independent binding and activation at these other receptors can proceed.

Despite the impressive evidence that CD36 plays a critical role in the fatty acid transduction pathway (Abumrad, 2005; Calder and Deckelbaum, 2006; Mizushige et al., 2007), there is little evidence for the cellular mechanism of CD36 action in mammalian taste cells. As alluded to above, it may serve as a primary receptor for fatty acids and translocate fatty acids to the cytoplasmic domain where they may activate intracellular signaling pathways. Pathways identified in taste cells to be activated by linoleic acid/CD36 interaction include the release of Ca2+ from intracellular stores and the phosphorylation of Src-protein-tyrosine kinases which lead to activation of store-operated channels (El-Yassimi et al., 2008). Alternatively, CD36 may be playing a role as more of a chaperone protein, facilitating the binding and delivery of fatty acids (Figure 3.1). Interestingly, a CD36 homolog in Drosophila acts in just the same fashion in the binding and delivery of volatile fatty acids in their correct orientation to pheromone receptors (Benton et al., 2007). Indeed, there is mounting evidence to suggest that the CD36 may not function primarily as a transmembrane transport protein for fatty acids (Doege and Stahl, 2006). The recent development of a functional cell line expressing CD36 may help to discern the role of this important protein in fatty acid taste transduction (Inagaki et al., 2008).

3.4.2. Fatty Acid-Activated GPCR

The deorphanization of several families of GPCRs has led to a significant advance in our understanding of peripheral and central fatty acid signaling (reviewed in Hirasawa et al., 2008). The cognate ligands for these receptors are several classes of fatty acids including the long-, medium-, and short-chain free fatty acids. These receptors are expressed in a wide variety of target tissues throughout the body where they play roles in a variety of cellular processes related to fat (i.e., fatty acid) signaling. While significant progress has been made in elucidating the signaling pathways activated by these receptors, there is little information to date concerning the fatty acid–GPCR interaction in terms of ligand-binding properties. GPR40 Family

Of those previously orphan GPCRs that were identified and found to be activated by a variety of free fatty acids, three were members of a “family” of receptors, the GPR40 family which includes GPR40, GPR41, and GPR43 (Brown et al., 2003, 2005). Ligands for these GPCRs include medium- and long-chain fatty acids (GRP40 (Briscoe et al., 2003; Stewart et al., 2006)) and short-chain fatty acids (GPR41 and GPR43). Of these, GPR40 has been the best characterized to date. One of the cellular locations of GPR40 is in the pancreas where it has been functionally linked with insulin secretion (Itoh et al., 2003; Itoh and Hinuma, 2005; Tomita et al., 2005). Interestingly, a connection between GPR40 activation and DRK inhibition has been proposed to involve cAMP and protein kinase A (Feng et al., 2006). If true in TRCs, this could be a functional link between two putative fat receptors.

GPR41 and GPR43 are closely related receptors that are activated by propionate and short-chain carboxylic acids (Brown et al., 2003; Le Poul et al., 2003). Another member of this family, GPR42, appears to be a gene duplication of GPR41 (Brown et al., 2003). To date, comparatively little is known about these receptors. GPR41 has been found in adipocytes where it has been linked with the release of leptin (Xiong et al., 2004). GPR43, which has a broader distribution, has been shown to play a role, for example, in differentiation of leukocyte progenitors in hematopoietic cells (Le Poul et al., 2003) and in colon function (Karaki et al., 2008; Tazoe et al., 2008). Both GPR41 and GPR43 couple to inositol 1,4,5-trisphosphate (IP3) formation via Gi/Go (GPR41 and GPR43) or Gq (GPR43 only). GPR120

An additional fatty acid receptor has begun to be characterized in enteroendocrine cells of the small intestine. These cells (and a corresponding cell line, STC-1) share many of the same receptors and signaling components as mammalian TRC and have been called “taste cells of the gut” (Raybould, 1998; Rozengurt and Sternini, 2007; Sternini et al., 2008). Commonalities include expression of both the sweet (Dyer et al., 2005, 2007) and bitter receptor families as well as gustducin (Wu et al., 2002; Chen et al., 2006). These cells also express the receptor, GPR120, a GPCR that is activated by LCFAs. Activation of GPR120 in enteroendocrine cells has been shown to induce release of the hormone, glucagon-like peptide-1 (GLP-1) (Hirasawa et al., 2005) as well as inhibit apoptosis induced by serum deprivation (Katsuma et al., 2005). GPR84

Very recently, a novel GPCR has been deorphanized, which is activated by medium-chain fatty acids (C9–C14) and not closely related to any of the previously identified FA-activated GPCRs (Venkataraman and Kuo, 2005; Wang et al., 2006; Bouchard et al., 2007). While its tissue distribution has not been well characterized, it has been suggested that it has a role in regulation of immune cells (Venkataraman and Kuo, 2005). Like some of the other FA-activated GPCRs, GPR84 activation mobilizes Ca2+ via an activation of the pertussis toxin-sensitive Gi/Go pathway. GPR Expression in Taste Cells

Few studies have yet focused on the identification and characterization of fatty acid-activated GPCRs (FA-GPCRs) in mammalian TRCs. Matsumura et al. (2007) have identified the presence of GPR120, but not GPR40, in taste tissue using RT-PCR. Our laboratory has used RT-PCR as the first approach to try and determine the expression profile of all known FA-GPCRs in taste and trigeminal (somatosensory) tissue in rodents. Our data are consistent with a variety of FA-GPCRs being expressed in the taste system with significant differences between the anterior (fungiform papillae) and posterior (foliate and circumvallate papillae) tongue. Table 3.1 summarizes the expression of FA-GPCRs (and CD36) in the taste and somatosensory systems in rodents.



Expression of Putative Fatty Acid Receptors in Taste Cells

Preliminary studies from our laboratory are consistent with a functional role for FA-GPCRs in fatty acid-induced increase of intracellular calcium in rodent taste cells. Linoleic acid-induced changes in [Ca2+] in rodent taste cells are blocked by inhibitors of G protein activation, like GDP-β-S, a nonhydrolyzable analog of GDP (Liu et al., 2008). Despite positive preliminary evidence, it is clear that the role of FA-GPCRs in the taste transduction of fatty acids is an open question. At present, however, the only available knockout model for FA-GPCRs remains GPR40 (Latour et al., 2007; Brownlie et al., 2008; Lan et al., 2008) and there have been no published reports of the taste phenotype of these mice.


There is a general consensus that the peripheral gustatory system is responsive to the chemosensory cues for dietary fat. While the role of “fat taste” as a primary taste, like sweet, bitter, salty, sour, and umami, and/or as a taste modulator remains to be elucidated, there is solid evidence pointing to the role of free fatty acids as the prototypical fat stimulus. While early research pointed to the importance of cis-PUFAs (essential fatty acids) as gustatory stimuli (Gilbertson, 1998b, 1999; Gilbertson and Boughter, 2003), the recent identification of additional receptive proteins and cutting edge behavioral assays reveal that the taste system is likely to respond to a wider variety of fatty acids. Nonetheless, the vast majority of the current research has focused on the cis-PUFAs, particularly linoleic acid. Clearly, to further our understanding of the peripheral cues for dietary fat will require similar emphases being placed on the effects of other ligands for the various fatty acid-receptive proteins identified (cf. Table 3.1).

Our understanding of the transduction pathway for fatty acids is far from complete. While DRK channels have been implicated in this pathway, the role of these fatty acid-sensitive channels remains unclear, especially in light of the emerging data that suggests that there are FA-activated GPCRs and the fatty acid-binding protein, CD36, may also contribute to this signaling cascade. The functional role of DRK channels, like KCNA5, in fatty acid taste transduction is hampered by their ubiquitous expression in peripheral tissues and, hence, the lack of an available, viable knockout model. The generation of a taste-specific KCNA5 knockout or taste-specific knockdown of this channel using RNA interference would answer lingering questions regarding the functional importance of fatty acid-sensitive DRK channels.

Conversely, the importance of CD36 in the transduction and recognition of fatty acids is unequivocal. Data on CD36 knockout mice using a variety of approaches (Laugerette et al., 2005; Sclafani et al., 2007; El-Yassimi et al., 2008; Gaillard et al., 2008) have consistently demonstrated that this protein is important for fatty acid signaling in the gustatory system. How CD36 directly contributes to the signal transduction pathway, however, is an open question. While it may act to transport fatty acids across the taste cell membrane where they could directly affect intracellular signaling, an equally likely scenario implies that it may act as a binding or chaperone protein to facilitate fatty acid interactions with receptors or channels. Specific experiments designed to distinguish among these possibilities are critical to determine the role of this important protein.

The identification of multiple subtypes of fatty acid-activated GPCRs in the taste system, each with unique ligand profiles, promises to further expand our understanding of the mechanisms surrounding the “taste of fat.” While there has been precious little functional data to date on these receptors and their role in taste, they may provide the explanation for the ability of the taste system to respond to short- and medium-chain saturated fatty acids, such as lauric acid (Pittman et al., 2008).

In about a decade, we have gone from the generally accepted notion that fat is tasteless to one that the ability of fatty acids to elicit cellular and behavioral gustatory responses is well established. Further, there appears to be a wealth of putative fatty acid-receptive proteins including CD36, fatty acid-sensitive DRK channels and fatty acid-activated GPCRs. Given that few DRK channels are open at resting potentials in taste cells and that fatty acids act as open channel blockers, we have long proposed that there may be something upstream (other FA or taste receptors) of these FA-sensitive channels to enable their opening and subsequent inhibition by fatty acids. This fact, coupled with the distinct possibility that CD36 is playing a role as a binding protein and not as a transporter (Benton et al., 2007), leads us to hypothesize a single model for fatty acid transduction involving these three distinct fatty acid-responsive proteins based upon available data. As illustrated in Figure 3.2, our working model for fatty acid (linoleic acid) transduction involves an initial binding of free fatty acids, generated by the action of lingual lipase or available in fat-containing food, to CD36. In this scheme, the role of CD36 would be to bind and orient linoleic acid for presentation to fatty acid-activated GPCRs, such as GPR120, and fatty acid-sensitive DRK channels. It is equally plausible that CD36 facilitates the transport of linoleic acid across the membrane where it may interact with GPR120 (the binding site for fatty acids on FA-GPCRs is currently unknown). On the other hand, linoleic acid only inhibits DRK from the extracellular face of the channel (Gilbertson et al., 1997; Liu et al., 2005). The activation of GPR120, in turn, leads to the production of the second messenger, phospholipase C (Fukunaga et al., 2006; Iakoubov et al., 2007) and the eventual release of Ca2+ from intracellular stores. Matsumura and colleagues have shown that expression of GPR120 overlaps with expression of PLCβ2 and α-gustducin, lending support to this idea (Matsumura et al., 2009). As with other taste complex stimuli (Roper, 2007), this release of Ca2+ is coupled to activation of store-operated channels, like Ca-release-activated cation (CRAC) channels or TRPM channels. Interestingly, a recent paper suggests that specific cis-PUFAs can directly activate TRPM5 intracellularly (Oike et al., 2006), which may represent an additional pathway independent of FA-GPCRs, linking CD36 and TRPM5 directly. These transduction channels allow the depolarization and development of the receptor potential during fatty acid stimulation. This depolarization, in turn, would be expected to open DRK channels of the KCNA and KCNB families (i.e., fatty acid sensitive) that can be blocked by linoleic acid to enhance and prolong the depolarization. The ratio of fatty acid-sensitive:fatty acid-insensitive channels would help determine the overall magnitude of the response which could be signaled directly onto the afferent nerve or to output cells within the taste bud.

FIGURE 3.2. Putative transduction pathway for fatty acids in taste and trigeminal cells.


Putative transduction pathway for fatty acids in taste and trigeminal cells. Fatty acids (FA) delivered by the binding protein CD36 activate specific G protein–coupled receptors (like GPR120) to initiate a transduction cascade that in turn produces (more...)

While speculative, this model presents an attractive and testable synthesis of the current data surrounding fatty acid transduction in mammalian taste cells. The specific relationships between FA-GPCRs, CD36, and FA-sensitive DRK channels remain to be elucidated as do the specifics of the pathways activated by other receptor subtypes. Nonetheless, over the past decade it has become apparent that taste cells can and do respond to dietary fat and that this response is translated into the animal’s (including human’s) behavior. The understanding of how the gustatory system and the body as a whole recognizes and responds to dietary fat holds promise for not only the design of fat substitutes but also the identification of putative targets in the fight against obesity through the control of dietary fat intake.


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