Detection of food compounds plays a critical role in feeding behavior. Likewise, the ability to avoid harmful chemicals is essential to navigate the evaluation of suboptimal food sources that might contain toxins or are contaminated with microorganism producing harmful chemicals. Hence, animals have evolved chemoreceptors to detect and discriminate between nutritious food chemicals, and chemoreceptors that sense non-nutritious and potentially harmful chemicals. Receptors for sugars, amino acids and fatty acids have been identified in mammals (Cartoni et al., 2010; Galindo et al., 2012; Max et al., 2001; Montmayeur et al., 2001; Nelson et al., 2001; Zhao et al., 2003), and other vertebrates (Ishimaru et al., 2005), albeit in some, receptor types for certain nutritious chemicals have been lost (Baldwin et al., 2014; Jiang et al., 2012; Jin et al., 2011; Lagerström et al., 2006; Zhao et al., 2012). In mice, these various types of receptors are expressed in distinct populations of taste cells located mainly in taste buds on the tongue. For example, three different groups of cells respond to calorie-rich carbohydrates, amino acids and fatty acids, respectively, while a separate group of cells is dedicated to the detection of salt (NaCl), a modest amount of which is essential for many cellular functions. Lastly, two functionally distinct types of taste cells detect diverse organic, but repugnant chemicals (phenols, alkaloids etc.) and acids, perceived as bitter and sour, respectively (Liman et al., 2014). Thus, the intrinsic quality of different taste chemicals is initially encoded in the taste periphery, which is transmitted through dedicated sensory pathways, a concept generally referred as the labeled line hypothesis of taste coding (Dethier, 1978; Di Lorenzo, 2000; Spector and Travers, 2005).

With the exception of sugars, perception of nutritious chemicals is relatively poorly understood in insects. In Drosophila, food and other soluble chemicals are detected by taste sensilla (comparable to mammalian taste buds) located on the labial palps and the legs. Most of these sensilla harbor four Gustatory Receptor Neurons (GRNs), each of which is thought to mediate a taste quality: sweet, water, low salt, and bitter/high salt (Liman et al., 2014; Vosshall and Stocker, 2007). The only appetitive taste modality that has been studied in detail is that of sweet taste, elicited by a relative small group of dietary sugars, such as glucose, sucrose, trehalose, maltose, melizitose and raffinose, found mostly in fruits. Genetic studies, combined with behavioral analysis, electrophysiology and Ca²⁺ imaging have revealed that a group of eight sugar Gustatory receptor genes (Gr5a, Gr61a and Gr64a-f) is mostly responsible for the detection of sugars (Dahanukar et al., 2007; Fujii et al., 2015; Jiao et al., 2008; Miyamoto et al., 2013; Slone et al., 2007; Yavuz et al., 2014). With the exception of Gr5a, all sugar Gr genes are expressed at most in a single GRN per sensillum (Fujii et al., 2015; Slone et al., 2007), which is generally referred to as the sweet GRN. Indeed, electrophysiological studies on a small number of labellar taste sensilla (Dahanukar et al., 2007) and both Ca²⁺ imaging and electrophysiological recordings on tarsal sensilla of the most distal segment of the forelegs (Ling et al., 2014; Miyamoto et al., 2013; Yavuz et al., 2014) have confirmed that sweet GRNs respond specifically to sugars, but not to bitter compounds or salt. Interestingly, sweet GRNs vary in the number of expressed sugar Gr genes (Fujii et al., 2015), providing different GRNs with the potential for distinct sugar sensing specificities.

In contrast to sweet taste, little is known about the cellular and molecular basis of amino acid and fatty acid taste in insects. While both these nutrients are essential for growth and development during larval life, their relevance in adults is mainly restricted to females, which require fat and protein for the production of eggs. Evidence for appetitive taste of fatty acids in Drosophila has been demonstrated using the classical Proboscis Extension Reflex (PER) assay (Masek and Keene, 2013), but whether flies can sense amino acids through their taste sensory system is less clear and appears at least in part to depend on the internal nutrient status (Toshima and Tanimura, 2012). Regardless, no defined set of taste neurons that respond to amino acids have been described to date.

Here, we employed a genetic approach to investigate the cellular and molecular basis for fatty acid taste. Using Ca²⁺ imaging, we report that tarsal sweet GRNs are activated by fatty acids, and we show that IR25a and IR76b are expressed in numerous GRNs, including sweet GRNs, where they are required for their activation by fatty acids, but not by sugars. RNAi knock-down of a third IR transcript, IR56d, in sweet GRNs also abolished fatty acid responses both at the behavioral as well as the cellular level. In contrast to IR25a and IR76b, which are also required for sour taste and expressed in respective acid sensing GRNs (Chen and Amrein, 2017), expression of IR56d is confined to sweet GRNs, suggesting a more restricted role for this receptor in fatty acid taste.

In contrast to responses to sugars, which increase in a concentration dependent manner to reach a plateau, we observed that wild type flies show maximal PER responses at modest concentrations to one fatty acids, (hexanoic acid), while higher concentrations led to a reduction in PER responses. Interestingly, we found that hexanoic acid also activates bitter GRNs, albeit in an IR25a/IR76b independent manner, suggesting that bitter and sweet GRN activation modulate feeding response to this ligand. Consistent with this hypothesis, inhibition of neural transmission of sweet GRNs abolishes PER responses completely, while the same manipulation of bitter GRNs results in further increase in PER responses to hexanoic acid. These observations suggest a model in which activation of bitter GRNs counteract the activation of sweet GRNs to suppress feeding responses to hexanoic acid, possibly to moderate intake of this nutrient compound.

The notion that sweet GRNs are exclusively tuned to sugar has recently been challenged, as it was shown that flies exhibit sweet GRN -dependent appetitive behavioral responses to fatty acids (Masek and Keene, 2013). Thus, we first wanted to confirm these findings using flies with intact and functionally impaired, tetanus toxin (TNT) expressing sweet GRNs, respectively (Figure 1). Both sets of control flies (Gr64f-GAL4/+ and + /UAS-TNT) showed robust PER responses to fatty acids and the sugar sucrose when tarsi were stimulated, while flies with inactivated sweet GRNs (Gr64f-GAL4/UAS-TNT) lost PER responses to all these food chemicals (Figure 1A). We note that somewhat lower PER responses were elicited when the labellum was stimulated with fatty acids (Figure 1—figure supplement 1). To explore whether fatty acid taste requires the sugar Gr genes, we used a sugar Gr deficient fly strain (Gr5a^LexA; ΔGr61a ΔGr64a-f) (Fujii et al., 2015; Yavuz et al., 2014) and tested PER responses to fatty acids and sucrose (Figure 1B). While PER responses to fatty acids were unaffected or higher in these octuple mutant flies, they were severely reduced to sucrose (Figure 1B), indicating that other receptors must be expressed in sweet GRNs to detect fatty acids. Use of different taste receptors for mediating the two taste modalities is consistent with the finding that mutations in norpA, which encodes a phospholipase C, affected PER responses to fatty acids, but not to sugars (Masek and Keene, 2013). Moreover, and consistent with this behavioral phenotype, sweet taste neurons of norpA mutant flies had strongly reduced responses to fatty acids, but not sucrose, using a Ca²⁺ imaging assay (Figure 1—figure supplement 2).

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PER responses to fatty acids of flies with impaired neurons and genes.

(A) PER responses of sweet GRNs to fatty acids when inactivated by expression of UAS-TNT. (B) PER responses of octuple mutant flies lacking all sugar Gr genes (Gr5a^LexAΔGr61aΔGr64a-f) to fatty acids.

https://doi.org/10.7554/eLife.30115.007

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Broadly expressed IR25a and IR76b are required for PER responses to fatty acids

In mammals, fatty acid taste is mediated by at least two G-protein coupled receptors, GPR40 and GPR120 (Cartoni et al., 2010; Matsumura et al., 2007). However, BLAST searchers showed that no homologs for these genes are found in the Drosophila genome. To identity putative candidates for Drosophila fatty acid taste receptors, we turned our attention to members of the Ionotropic Receptor (IR) gene family. IRs are derived from ionotropic Glutamate Receptors (iGluRs) genes and expanded in number during arthropod evolution, comprising a family of 61 genes in Drosophila (Benton et al., 2009; Croset et al., 2010). The role of IR proteins has been extensively characterized in the olfactory system, where they form multimeric receptors for the detection of an array of different odorant molecules (Abuin et al., 2011; Ai et al., 2013; Benton et al., 2009; Hussain et al., 2016; Silbering et al., 2011), but IR based receptors have also been implicated in temperature sensing (Knecht et al., 2016; Ni et al., 2016), humidity sensing (Enjin et al., 2016; Knecht et al., 2017; Knecht et al., 2016) and taste perception (Croset et al., 2016; Ganguly et al., 2017; Hussain et al., 2016; Koh et al., 2014; Zhang et al., 2013). Of particular interest were IR25a and IR76b, because these two genes are enriched in taste neurons (Cameron et al., 2010). We therefore examined the expression of IR-GAL4/QF drivers for both genes and found that they were indeed expressed in multiple GRNs per sensillum (Figure 2). In tarsal sensilla, their expression largely overlapped (Figure 2F) and included the sweet and bitter GRNs that express sugar and bitter Gr genes, respectively (Figure 2B–E), thus identifying them as possible subunits of fatty acid taste receptors. Both genes were also expressed in multiple neurons per sensillum in the labial palps, albeit co-expression was incomplete in this taste organ (Figure 2—figure supplement 1). To examine a possible role for IR25a and IR76b in fatty acid taste, we conducted PER assays with flies from each mutant strain to hexanoic, octanoic and linoleic acids and found that PER responses were abolished in both IR25a^-/- and IR76b^-/- flies, a phenotype completely (hexanoic acid and octanoic acid) or partially (linoleic acid) rescued when expression was restored with UAS-IR25a or UAS-IR76b transgenes (Figure 3A and B). Additionally, IR25a^-/- and IR76b^-/- flies showed normal PER responses to sucrose, indicating that the role of these two genes is specific to fatty acid taste and not required for sweet taste to sugars. Importantly, when IR25a function was provided in sweet GRNs of IR25a^-/- flies, their PER responses were restored to levels indistinguishable from controls (Figure 3C). Likewise, expression of IR76b in sweet GRNs alone also rescued PER responses to fatty acids in IR76b^-/- flies (Figure 3D). Together, these observations indicate that the functions of IR25a and IR76b are required in sweet GRNs for robust PER responses to fatty acids, but not to sugars.

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Figure 3

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PER responses of IR25a and IR76b mutant flies to fatty acids.

(A) PER responses of IR25a mutant flies to fatty acids. (B) PER responses of IR76b mutant flies to fatty acids. (C and D) PER responses to fatty acids of IR25a (C) or IR76b (D) mutant flies with UAS-IR25a or UAS-IR76b transgenes, respectively, under the control of Gr64f-GAL4.

https://doi.org/10.7554/eLife.30115.011

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Sweet neurons require IR25a and IR76b for fatty acid sensing

To obtain direct evidence that IR25a and IR76b mediate fatty acid sensing in taste neurons, we performed Ca²⁺ imaging experiments on tarsal sensilla preparations (Miyamoto et al., 2013, 2012) of wild type control flies (w¹¹¹⁸), IR25a^-/- and IR76b^-/- flies that expressed the calcium sensor GCaMP6m in sweet GRNs (Dahanukar et al., 2007; Fujii et al., 2015) (Figure 4). We measured Ca²⁺ responses in sweet GRNs of the taste sensilla in the fifth tarsal segment of the prothoracic leg (5b, 5s and 5v; Figure 4A; the 5a sensillum is mainly dedicated to pheromone sensing, and no sugar or fatty acid responses were observed in these GRNs). In wild type flies, the sweet GRNs of 5b and 5s sensilla showed robust Ca²⁺ increases to hexanoic and octanoic acids and modest, but significant increases to linoleic acid (Figure 4B and C). Only weak Ca²⁺ responses were observed in the 5v-associated sweet GRNs. Importantly, Ca²⁺ responses were absent in 5b- and 5s-associated sweet GRNs of IR25a^-/- or IR76b^-/- flies (Figure 4D and E). IR25a or IR76b requirement for cellular fatty acid responses was confirmed by transgene rescue experiments, which restored Ca²⁺ increases to the level observed in w¹¹¹⁸ controls flies (Figure 4D and E).

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Ca²⁺ imaging results of sweet GRNs of w¹¹¹⁸, IR25a and IR76b mutant flies to fatty acids.

(C) Ca²⁺ responses of sweet GRNs associated with 5b, 5s or 5v sensilla to fatty acids. (D) Ca²⁺ responses of sweet GRNs associated with 5b, 5s or 5v sensilla of IR25a mutant flies to fatty acids. (E) Ca²⁺ responses of sweet GRNs associated with 5b, 5s or 5v sensilla of IR76b mutant flies to fatty acids.

https://doi.org/10.7554/eLife.30115.015

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The IR56d gene is sweet GRN specific and required for fatty acid taste

IR25a and IR76b are expressed in multiple GRNs per sensillum (Figure 2), including a recently characterized sour GRN where they are required to sense carboxylic acids and HCl (Chen and Amrein, 2017). This finding, together with the observation that IRs are likely to form tetrameric complexes containing three and possibly four different IR subunits (Abuin et al., 2011) led us to search for additional IR genes involved in fatty acid taste. We therefore examined seven candidate IR genes based on their expression in taste sensilla (Cameron et al., 2010; Koh et al., 2014) for effects on PER when functionally perturbed. RNAi knock-down of one of these genes, IR56d, led to a significant reduction in PER responses to all fatty acids (Figure 5A), while knock-downs of or of mutations in the other six IR genes had no effect (Figure 5—figure supplement 1). We next expressed GCaMP6m in sweet GRNs, along with the RNAi^IR56d construct and carried out Ca²⁺ imaging experiments of sweet GRNs. As expected, we observed an almost complete loss of GRN activation to hexanoic and octanoic acids (Figure 5B and C), similar as observed for IR25a or IR76b mutants (Figure 4D and E). Finally, we examined expression of an IR56d-GAL4 line in the tarsal segments of the prothoracic leg (Koh et al., 2014). Indeed, antibody staining of tarsi of flies also expressing a marker for sweet GRNs showed complete overlap between IR56d and Gr64f, while no expression was observed in bitter GRNs, labeled by Gr66a-LexA (Figure 5E and F). Taken together, these experiments imply that the fatty acid taste receptor in sweet GRNs is composed of at least three subunits, IR25a, IR76b and the more narrowly expressed IR56d subunit. However, they do not exclude the possibility of yet a fourth IR being part of a fatty acid taste receptor complex.

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PER and Ca²⁺ responses of IR56d knock-down flies to fatty acids.

(A) PER responses of flies with knockdown of IR56d in sweet GRNs to fatty acids. (B and C) Ca²⁺ responses of the sweet GRNs associated with 5b (B) or 5s (C) sensilla to fatty acids after knockdown of IR56d in sweet GRNs.

https://doi.org/10.7554/eLife.30115.019

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Bitter GRNs modulate acceptance behavior of hexanoic acid

Because IR25a and IR76b are also found in bitter GRNs, we carried out Ca²⁺ imaging experiments using Gr33a^GAL4, a bitter GRN specific marker (Moon et al., 2009). Bitter GRNs of both the s- and b-type sensilla strongly responded to denatonium, a bitter tasting compound. Intriguingly, strong Ca²⁺ increases were also observed in the 5b-associated bitter GRN to hexanoic acid, while octanoic or linoleic acid elicited no significant responses (Figure 6A and B; note that octanoic and linoleic acids could only be tested at 0.2%, due to low solubility; see Materials and methods). These observations indicate that at least hexanoic acid activates both appetitive and repulsive GRNs. However, and in contrast to sweet GRNs, bitter GRN responses to hexanoic acid did not require IR25a or IR76b (Figure 6C and D), indicating that these neurons employ a different molecular receptor.

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Ca²⁺ responses of bitter GRNs of IR25a or IR76b mutant flies to fatty acids.

(B) Ca²⁺ responses of bitter GRNs associated with 5b or 5s sensilla to fatty acids. (C) Ca²⁺ responses of bitter GRNs associated with 5b sensilla of IR25a mutant flies to hexanoic acid. (D) Ca²⁺ responses of bitter GRNs associated with 5b sensilla of IR76b mutant flies to hexanoic acid.

https://doi.org/10.7554/eLife.30115.023

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To investigate hexanoic acid response characteristics in more detail, we compared dose response profiles of sweet and bitter GRNs of 5b sensilla (Figure 7A). Interestingly, sweet GRNs reached maximal activation already at the modest concentration of 1% (Figure 7A, left). In contrast, maximal activation of bitter GRNs was reached at the highest applicable concentration (2.5%; Figure 7A, right). These observations suggest that bitter GRNs might counteract the activity of sweet GRNs above a certain concentration threshold (>1%) and possibly modulate taste behavior. Indeed, w¹¹¹⁸ flies exhibited a maximal PER response at ~1%, whereas higher concentrations of hexanoic acid led to a decrease in PER responses (Figure 7B). In contrast, when we inhibited the activity of bitter GRNs by either expressing TNT or the inward-rectifier potassium channel Kir2.1, PER responses stayed at the same high level or continued to increase with increasing hexanoic acid concentration (Figure 7C and Figure 7—figure supplement 2). Thus, activation of bitter GRNs appears to suppress PER responses at high (2.5%) hexanoic acid concentration. To test whether the decrease of sweet GRN responses was mediated through lateral inhibition, we compared Ca²⁺ responses of sweet GRNs to 2.5% hexanoic acid in the presence and absence of functional bitter GRNs. However, hexanoic acid elicited the same Ca²⁺ responses in sweet GRNs, regardless of whether functional bitter GRNs were present (Figure 7D).

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Dosage dependent Ca²⁺ and PER responses of neurons and flies to hexanoic acid.

(A) Ca²⁺ responses of the sweet or the bitter GRNs associated with 5b sensilla to different dosages of hexanoic acid. (B) PER responses of wild-type flies (w¹¹¹⁸) to different dosages of hexanoic acid. (C) PER responses of flies to different dosages of hexanoic acid when bitter GRNs are inactivated by expression of UAS-TNT. (D) Ca²⁺ responses of the sweet GRNs associated with 5b or 5s sensilla to different dosages of hexanoic acid when bitter GRNs are inactivated by expression of UAS-TNT.

https://doi.org/10.7554/eLife.30115.029

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IR genes have emerged as a second large gene family encoding chemoreceptors in insects. In the Drosophila olfactory system, IRs function as multimeric receptors in coeloconic olfactory sensory neurons (OSN) and are thought to sense volatile carboxylic acids, amines and aldehydes (Abuin et al., 2011; Benton et al., 2009; Hussain et al., 2016; Silbering et al., 2011). Expression analyses have shown that each coeloconic OSN expresses up to four IR genes, including high levels of either IR8a or IR25a (Abuin et al., 2011). IR25a and IR8a are distinct from other IRs in that they are more conserved to each other and iGluRs, and they share a long amino terminal domain absent in all other IRs (Croset et al., 2010). These observations, along with functional analyses of basiconic olfactory neurons that express combinations of IR genes, led to a model in which IR based olfactory receptors are tetrameric complexes thought to consist of up to three different subunits that contain at least one core unit (IR8a or IR25a) and two additional IRs that determine ligand binding specificity (Abuin et al., 2011; Silbering et al., 2011). The findings presented in this paper expand this concept to taste receptors that sense fatty acids through the sweet GRNs found in tarsal taste sensilla.

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Author details

1. Ji-Eun Ahn

   Department of Molecular and Cellular Medicine, Health Science Center, Texas A&M University, College Station, Texas, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3390-3578

2. Yan Chen

   Department of Molecular and Cellular Medicine, Health Science Center, Texas A&M University, College Station, Texas, United States

   Contribution

   Data curation, Yan Chen generated immunnostaining data for Figure 2 and Figure 2-figure supplement 1

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5321-3064

3. Hubert Amrein

   Department of Molecular and Cellular Medicine, Health Science Center, Texas A&M University, College Station, Texas, United States

   Contribution

   Conceptualization, Supervision, Funding acquistion, Investigation, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   amrein@tamhsc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8799-7250

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