In Disney’s Pixar acclaimed success Ratatouille, Chef Gusteau states: “Good food is like music you can taste, color you can smell, there is excellence all around you; You only need be aware to stop and savour it!” Chef Gusteau’s extended metaphor clearly refers to the infinite combinations of flavors that delight our palate and make food intake a pleasurable experience. Flavor per se is the combined sensory impression of food, and it is determined by the five basic qualities of taste: sweet, salty, sour, bitter and umami (the “savory” taste associated with monosodium glutamate or MSG). Perception of these qualities entails the interaction of a substance from our food, or tastant, with specific taste receptor proteins residing in the taste buds of the tongue.
The discovery of taste receptor proteins, over a decade ago, represented a major milestone in taste research. Knowledge of these receptor proteins allowed scientists to unmask key components involved in taste perception, providing a deeper understanding of this convoluted process. Furthermore, this improved understanding led to the discovery that taste receptors reside in parts of the body other than the oral cavity, revealing a new role for these proteins in nutrient sensing in the gut and in the regulation of metabolic processes. This newly discovered function has given rise to the notion that taste receptor dysfunction might contribute to the development of metabolic disorders. For instance, in the United States, the increasing consumption of sweetened products, a growing concern for medical authorities, has been linked to the rising incidence of ailments such as obesity and type II diabetes. The link between sweet and bitter taste receptors and the development of these diseases has become an area of growing scientific and medical interest over the last decade. This article will explain how these taste receptors sense sweet and bitter substances and discuss their emerging potential as therapeutic targets for disease treatment.
Mechanisms of sweet and bitter taste perception
When it comes to consuming food, it all starts in the tongue! The tongue acts as a “gatekeeper” by helping us distinguish between good and noxious substances and consequently guiding our food choices. Although simple in appearance, the tongue is an intricate organ with thousands of taste buds – small structures that mostly reside on papillae (or raised bumps) on the upper surface of the tongue and on the palate . Each taste bud harbors a set of 50 to 100 specialized cells  known as taste receptor cells responsible for either sensing different tastes or mediating biological processes following taste detection (see Figure 1). Scientists have classified these cells into four subsets (called types I to IV). Type I cells, the most abundant taste cells in taste buds, act as support cells mediating biological processes following intense taste stimulation; they have also been implicated in the detection of salt taste. Type II cells, the most extensively studied taste cells, have specific receptor proteins on their surfaces that allow each cell to sense either sweet, bitter, or umami tastants [8,12]. Lastly, type III cells are responsible for detecting sour taste while the function of type IV cells is not well understood. Recognition of a tastant by its specific receptor triggers a signaling cascade that leads to the release of chemicals known as neurotransmitters that activate specific regions of the brain where taste is perceived and processed .
Figure 1. (A) The tongue, the primary organ of taste, consists of small structures known as papillae (raised bumps) where taste buds reside. Depending on their shape papillae are classified into four groups: circumvallate, fungiform, foliate and filiform  (B) Each taste bud harbors a set of elongated taste receptor cells that contain taste receptors that sense substances with different taste qualities. Upon detecting a substance, taste receptor cells transmit the information to gustatory nerves in contact with the tissue, which further transmit the information to the central nervous system, ultimately reaching the brain.
How do taste receptor cells distinguish between the sweet taste of a sugar cookie and the bitter taste of coffee? Researchers have found that distinct populations of type II taste cells contain receptors that discriminate between sweet and bitter substances. These receptors – namely, T1R2, T1R3 and T2R – belong to a family of proteins known as G-protein coupled receptors . G-protein coupled receptors are proteins that “live” on the surface of cells where they sense a wide array of substances located in the immediate vicinity of cells. The activation of a G-protein coupled receptor by a particular substance triggers a cascade of signals within the cell that results in diverse cellular responses, as is the case during taste perception. T1R2 and T1R3 receptors specifically recognize a spectrum of sweet tastants with a wide range of chemical structures, including sugars, synthetic sweeteners, and sweet-tasting proteins. Bitter compounds, on the other hand, are recognized by T2R receptors. Activation of the sweet taste receptors T1R2 and T1R3 by a sweet substance induces the activation of signaling proteins residing within the cell, namely: α-gustducin, PLC-β2, IP3R and TRPM5 . Interestingly, scientists discovered that the same repertoire of signaling proteins is required for bitter taste perception. The elimination of any of these receptors results in a decrease or complete loss of sensitivity for sweet or bitter tastes, further suggesting that these taste sensations use similar signaling pathways in the cell. Because these signaling proteins, along with the receptors themselves, are thought to be found exclusively in taste cells, scientists have designated them as “protein expression markers”, which, analogous to the fingerprint of a person, distinguish taste cells from other types of cells in the body. However, in the last decade, the observation that these “protein expression markers” are present in organs of the body other than the tongue, has led to an explosion of research on taste cells in non-taste organs.
Bitter and sweet taste receptors as potential therapeutic targets for disease
Taste receptor cells in non-taste organs? Surprisingly, taste receptor cells are not only confined to the oral cavity. The gut and pancreas are inundated with taste receptor cells [10, 2]. Unlike the taste receptor cells found in the oral cavity, the taste cells in the gut and pancreas do not convey the sensation of taste to the brain. Instead, they are responsible for sensing nutrients and maintaining the balance of hormones essential in metabolic processes. Also, like the taste cells in the tongue, these cells contain sweet and bitter taste receptors (along with other taste receptor cell “protein expression markers”). However, instead of sending a signal to the brain, activation of these receptors by their respective sweet or bitter substances triggers the release of hormones that regulate appetite and satiety and help maintain appropriate glucose levels in the bloodstream. This observation has drawn a plausible link between dysfunction of taste receptor cells and the emergence of diseases such as obesity and diabetes. As a result, the function of taste receptors in the gut and pancreas has become an active area of research due to their potential as therapeutic targets for the treatment of metabolic disorders.
I. Sweet taste receptors:
Sweet taste receptors in the enteroendocrine cells (cells that secrete hormones) of the gut and pancreas are suggested to play an important role in nutrient sensing and sugar absorption, both processes necessary for energy and maintaining a normal metabolism. When sweet taste receptors sense sugars, they elicit the release of gut hormones. One such hormone, glucagon-like peptide 1 (GLP-1), is responsible for facilitating the absorption of glucose into the bloodstream, enhancing insulin secretion in the pancreas and regulating appetite . Disruptions in any of these physiological processes can result in the development of type II diabetes. In individuals with type II diabetes, the beta cells of the pancreas are able to produce insulin in response to meals, but at relatively lower levels than those normally demanded by the body. In type I diabetes, on the other hand, the beta cells of the pancreas can no longer produce insulin because they are destroyed by the body’s immune system. In a study aiming at quantifying the levels of sweet taste receptors in the upper gut of healthy and diabetic individuals, researchers observed that the levels of sweet taste receptors were diminished in diabetic type II subjects with elevated blood glucose concentrations . This observation was consistent with previous results showing that type II diabetes patients secreted low levels of GLP-1 in response to a meal in comparison to healthy individuals . Taken together, the decrease in sweet taste receptors and GLP-1 results in decreased sugar absorption from the bloodstream which contributes to type II diabetes.
In the pancreas, beta cells release insulin in response to elevated concentrations of glucose in the bloodstream. Unlike glucose, fructose, the sugar found in fruit, does not stimulate insulin secretion . However, researchers recently found that fructose, when administered in concert with glucose to human and mice pancreatic beta cells, increased insulin release to levels higher than those observed when only glucose was used. The increase in insulin levels was mediated by the activation of sweet taste receptors in beta cells by fructose. Furthermore, inactivation of these receptors resulted in no release of insulin when exposed to fructose in the presence of glucose. Because excessive levels of insulin secretion have been implicated in the development of obesity and type II diabetes , sweet taste receptors in the pancreas are an attractive target for the treatment of these diseases. In conclusion, these studies strongly support an essential role for sweet taste receptors in maintaining an appropriate balance of glucose and insulin levels in the blood, and dysfunction of these proteins might hasten the development of type II diabetes.
What do we know about sweet taste receptors and artificial sweeteners? Sweet taste receptors in the gut and pancreas also “taste” artificial sweeteners, also known as non-nutritive sweeteners (NNS). While there is a general consensus on the contribution of regular sugars and sweet taste receptors in the release of gut and pancreas hormones, the effects reported for NNS, on the other hand, are at the center stage of much debate. Several research groups found that exposure of mouse cells to sucralose, the sweetener in Splenda, caused the release of GLP-1. Inactivation of the sweet taste receptors in these cells impaired the release of this hormone indicating that the effects of sucralose were mediated via its interaction with the receptors . These findings, nevertheless, have been challenged by other research groups that did not observe hormone release in response to oral administration of sweeteners. Hence, whether NNS themselves trigger the release of hormones or not is yet to be elucidated. In the pancreas, NNS promote insulin secretion when administered in combination with glucose . Since the body does not absorb NNS, a current hypothesis is that when NNS are taken in combination with glucose they might stimulate constant insulin secretion, which might lead to excess glucose being absorbed by the body. Rapid depletion of glucose from the blood might, in turn, hasten the development of obesity. Further research is needed to generate a more accurate conclusion on the effects of NNS in sugar metabolism and to determine whether these effects are primarily mediated by sweet taste receptors.
II. Bitter taste receptors:
Bitter taste receptors in the stomach are known to confer protection against ingested toxic substances by provoking repulsion towards bitter food . Scientists have recently found that activation of bitter taste receptors in the gut stimulates the production of hormones involved in appetite stimulation. A study in which mice were administered bitter tastants by insertion of a tube through the stomach, a procedure known as intragastric feeding, showed that bitter taste receptors induced the release of ghrelin, an appetite-stimulating hormone, resulting in short-term food intake . This short-term food intake was immediately followed by a prolonged decrease in food ingestion, correlating with an observed delay in emptying of the stomach leading to a sensation of satiety. The relationship between the ingestion of bitter compounds and a feeling of fullness suggests new potential directions for scientists to design treatments, a literal “bitter pills”, for obesity.
The future of taste receptors in medicine
The discovery of sweet and bitter taste receptors in the gut and pancreas represented a major landmark in taste research as these proteins are now known to play an important role in the regulation of metabolic processes, including nutrient sensing, the release of appetite-regulating hormones and glucose absorption. The future of taste research promises new exciting avenues in the field of drug design as these proteins have emerged as attractive therapeutic targets for the treatment and prevention of obesity and type II diabetes. For instance, scientists have proposed the selective targeting of these receptors to induce the release of satiety hormones from the pancreas that might eventually prevent overeating by fooling the body that it has eaten . Another alternative put forth has been targeting sweet taste receptors to reduce glucose absorption and thus reduce calorie uptake as a means of treating obesity . While some substances that suppress the action of sweet and taste receptors have been identified, their efficacy and safety has yet to be determined in humans. But in the future, scientists may develop substances that suppress the action of sweet and bitter taste receptors.
When it comes to experiencing flavors, Remy (the young rat gifted with a strong sense of taste in Ratatouille), enthusiastically stated: “Imagine every taste in the world being combined, discoveries to be made!” Likewise, there are many discoveries to be made in the field of taste research as scientists continue to work in the development of taste receptor suppressors with the hope of treating and preventing metabolic disorders rising from over-activation or dysfunction of these receptors. In all, taste receptors not only trigger pleasurable taste sensations, but also offer a direct path to improving our health. Medicine one day might lose the stigma of being bitter!
Luciann Cuenca is a Ph.D. candidate in the Biological and Biomedical Sciences (BBS) program.
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