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Extra-oral bitter taste receptors: New targets against obesity?
Abstract
Taste perception on the tongue is essential to help us to identify nutritious or potential toxic food substances. Emerging evidence has demonstrated the expression and function of bitter taste receptors (TAS2Rs) in a wide range of extra-oral tissues. In particular, TAS2Rs in gastrointestinal enteroendocrine cells control the secretion of appetite regulating gut hormones and influence hunger and food intake. Furthermore, these effects may be reinforced by the presence of TAS2Rs on intestinal smooth muscle cells, adipocytes and the brain. This review summarises how activation of extra-oral TAS2Rs can influence appetite and body weight control and how obesity impacts the expression and function of TAS2Rs. Region-selective targeting of bitter taste receptors may be promising targets for the treatment of obesity.
... Although T2R expression outside oral tissues was already known in one of the earliest studies [3], subsequent studies have revealed that T2R expression is widely distributed in various extra-oral tissues such as the brain, muscles, cardiovascular system, skin, adipose tissues, immune cells, respiratory tract, gastrointestinal tract, and reproductive organs [108][109][110][111]. Human and rodent studies have revealed that the extra-oral receptors act as local chemoreceptors and are involved in important physiological functions, including not only protection from pathogens and harmful substances similar to their role in the oral cavity but also in metabolic regulatory pathways and the reproductive system. ...
... T2R-expressing cell types, T2R subtypes, and functions in extra-oral tissues of humans and rodents are summarized in the tables of several recent review articles [109][110][111]186]. Please see the recent specific reviews for more details on the extra-oral functions of T2Rs and their inter-and intra-cellular mechanisms (e.g., overall review [109,174], smooth muscle and cardiovascular system [186,187], respiratory tract [124,139], gastrointestinal tract [111,151,188], and reproductive system [184,189]). ...
... T2R-expressing cell types, T2R subtypes, and functions in extra-oral tissues of humans and rodents are summarized in the tables of several recent review articles [109][110][111]186]. Please see the recent specific reviews for more details on the extra-oral functions of T2Rs and their inter-and intra-cellular mechanisms (e.g., overall review [109,174], smooth muscle and cardiovascular system [186,187], respiratory tract [124,139], gastrointestinal tract [111,151,188], and reproductive system [184,189]). ...
Bitter taste perception is crucial for animal survival. By detecting potentially harmful substances, such as plant secondary metabolites, as bitter, animals can avoid ingesting toxic compounds. In vertebrates, this function is mediated by taste receptors type 2 (T2Rs), a family of G protein-coupled receptors (GPCRs) expressed on taste buds. Given their vital roles, T2Rs have undergone significant selective pressures throughout vertebrate evolution, leading to frequent gene duplications and deletions, functional changes, and intrapopulation differentiation across various lineages. Recent advancements in genomic and functional research have uncovered the repertoires and functions of bitter taste receptors in a wide range of vertebrate species, shedding light on their evolution in relation to dietary habits and other ecological factors. This review summarizes recent research on bitter taste receptors and explores the mechanisms driving the diversity of these receptors from the perspective of vertebrate ecology and evolution.
... Germane to humans, about 25 functional TAS2Rs are expressed in many tissues besides the lingual epithelium (Q. L. Wang, Liszt, & Depoortere, 2020). The expression of TAS2Rs in non-taste sensing districts was deemed ectopic for a long time, though specialized, testingunrelated and tissue-dependent roles have been described in recent years (Lu, Zhang, Lifshitz, & ZhuGe, 2017). ...
... anism of action eventually improving their risk assessment, and more in general their toxicological understanding. In this respect, recent advances in understanding the toxicity of trichothecenes have described mechanisms which might be consistent with the extra-oral involvement of bitter receptors (Flannery, Clark, & Pestka, 2012;Jia et al., 2022;Q. L. Wang et al., 2020). However, to the best of our knowledge, direct evidence is still missing. Therefore, the interaction with TAS2R46 and trichothecolone and a series of type B trichothecenes relevant to food safety was studied through docking studies and molecular dynamics to gain a thorough analysis from a molecular viewing angle. Specifically, the set u ...
... 2012;Holanda & Kim, 2021). Moreover, although there are no clear and unique connections between the decrease of food intake and TAS2Rs activation, it has been demonstrated that the release of peptide YY and GLP-1, which are involved in the mechanisms of food acceptance, is in part under the control of TAS2Rs (Flannery et al., 2012;Jia et al., 2022;Q. L. Wang et al., 2020). Further analysis are needed to provide final proofs, however a possible functional corelation between the DONdependent food rejection and its capability to activate TAS2R46 is meaningful, also considered the expression of TAS2R46 in enteroendocrine cells which are inherently exposed to DON (K. S. Kim, Egan, & Jang, 2014). On this basis ...
... One is that low levels of background tastes/odors in the recycled water could create "noise" somewhere in the flavor-signaling pathway and change the perceived flavor of foods, as has been described in published studies (Oleszkiewicz, Rambacher, Whitcroft, & Hummel, 2018;Proserpio, de Graaf, Laureati, Pagliarini, & Boesveldt, 2017). Another phenomenon is that a background aversive taste may not be consciously detected, but can nevertheless lead to a decrease in food intake in some situations (Wang, Liszt, & Depoortere, 2020). ...
... In contrast to the effects of background tastes/flavors on food intake, aversive tastes, especially bitterness, have been studied in more detail. A recent review (Wang et al., 2020) highlighted that bitter receptors are located in oral and intestinal tissues and are in close contact with parts of the food-intake control system (Wang et al., 2020). Some studies indicate that bitter compounds can affect specific parts of the food-intake control mechanism (e.g., changes in hormone levels or gut motility) (Avau et al., 2015;Bitarafan et al., 2020), whereas other studies have focused on the overall effect of bitter compounds on food intake compared to a control diet (Andreozzi et al., 2015;Mennella et al., 2016;Walker et al., 2019). ...
... In contrast to the effects of background tastes/flavors on food intake, aversive tastes, especially bitterness, have been studied in more detail. A recent review (Wang et al., 2020) highlighted that bitter receptors are located in oral and intestinal tissues and are in close contact with parts of the food-intake control system (Wang et al., 2020). Some studies indicate that bitter compounds can affect specific parts of the food-intake control mechanism (e.g., changes in hormone levels or gut motility) (Avau et al., 2015;Bitarafan et al., 2020), whereas other studies have focused on the overall effect of bitter compounds on food intake compared to a control diet (Andreozzi et al., 2015;Mennella et al., 2016;Walker et al., 2019). ...
The intention to send a crewed mission to Mars involves a huge amount of planning to ensure a safe and successful mission. Providing adequate amounts of food for the crew is a major task, but 20 years of feeding astronauts on the International Space Station (ISS) have resulted in a good knowledge base. A crucial observation from the ISS is that astronauts typically consume only 80% of their daily calorie requirements when in space. This is despite daily exercise regimes that keep energy usage at very similar levels to those found on Earth. This calorie deficit seems to have little effect on astronauts who spend up to 12 months on the ISS, but given that a mission to Mars would take 30 to 36 months to complete, there is concern that a calorie deficit over this period may lead to adverse effects in crew members. The key question is why astronauts undereat when they have a supply of food designed to fully deliver their nutritional needs. This review focuses on evidence from astronauts that foods taste different in space, compared to on Earth. The underlying hypothesis is that conditions in space may change the perceived flavor of the food, and this flavor change may, in turn, lead to underconsumption by astronauts. The key areas investigated in this review for their potential impact on food intake are the effects of food shelf life, physiological changes, noise, air and water quality on the perception of food flavor, as well as the link between food flavor and food intake.
... One is that low levels of background tastes/odors in the recycled water could create "noise" somewhere in the flavor-signaling pathway and change the perceived flavor of foods, as has been described in published studies (Oleszkiewicz, Rambacher, Whitcroft, & Hummel, 2018;Proserpio, de Graaf, Laureati, Pagliarini, & Boesveldt, 2017). Another phenomenon is that a background aversive taste may not be consciously detected, but can nevertheless lead to a decrease in food intake in some situations (Wang, Liszt, & Depoortere, 2020). ...
... In contrast to the effects of background tastes/flavors on food intake, aversive tastes, especially bitterness, have been studied in more detail. A recent review (Wang et al., 2020) highlighted that bitter receptors are located in oral and intestinal tissues and are in close contact with parts of the food-intake control system (Wang et al., 2020). Some studies indicate that bitter compounds can affect specific parts of the food-intake control mechanism (e.g., changes in hormone levels or gut motility) (Avau et al., 2015;Bitarafan et al., 2020), whereas other studies have focused on the overall effect of bitter compounds on food intake compared to a control diet (Andreozzi et al., 2015;Mennella et al., 2016;Walker et al., 2019). ...
... In contrast to the effects of background tastes/flavors on food intake, aversive tastes, especially bitterness, have been studied in more detail. A recent review (Wang et al., 2020) highlighted that bitter receptors are located in oral and intestinal tissues and are in close contact with parts of the food-intake control system (Wang et al., 2020). Some studies indicate that bitter compounds can affect specific parts of the food-intake control mechanism (e.g., changes in hormone levels or gut motility) (Avau et al., 2015;Bitarafan et al., 2020), whereas other studies have focused on the overall effect of bitter compounds on food intake compared to a control diet (Andreozzi et al., 2015;Mennella et al., 2016;Walker et al., 2019). ...
Andrew Taylor, Jonathan Beauchamp, Loic Briand, Victor Demaria Pesce, Martina Heer, Thomas Hummel, Scott McGrane, Christian Margot, Serge Pieters, Paola Pittia and Charles Spence consider the role of food flavour in combatting under-consumption of nutrients by astronauts on the Mars expedition.
... These receptors signal information to the brain about the nutritive value or toxicity of ingested foods and beverages (16,17). Aside from their role in chemosensory cells, these receptors are expressed in an extensive range of tissues and perform varied functions (18). A recent study conducted by Grassin-Delyle et al. (19) suggested that TAS2Rs 3, 4, 5, 9, 10, 14, 30, 39, and 40 were involved in the inhibition of cytokine production. ...
... Interestingly, extra-oral TAS2R expression could be reduced in obese subjects compared to non-obese individuals (18). This may result in a decreased sensitivity to bitter taste, which is often observed in obese individuals, and may affect food choices (18). ...
... Interestingly, extra-oral TAS2R expression could be reduced in obese subjects compared to non-obese individuals (18). This may result in a decreased sensitivity to bitter taste, which is often observed in obese individuals, and may affect food choices (18). Considering the role of TAS2R and its agonists on immune responses, and the fact that CQ is a TAS2R agonist, we hypothesized that COVID-19-infected obese patients could respond differently to pharmacological treatment with CQ and side effects could occur more frequently due to overdosage in this population. ...
The coronavirus disease 2019, referred to as COVID-19 by the World Health Organization (WHO), is an ongoing viral pandemic caused by the influenza-like virus strain SARS-CoV-2 (1). According to WHO (2020), SARS-CoV-2 infection has been responsible for approximately 10,185,374 confirmed cases of COVID-19 and more than 500,000 deaths worldwide (2). In Brazil, 1,368,195 cases have been confirmed, and 58,314 deaths have occurred as of June 30, 2020 (3).
The coronaviruses are one of the primary pathogens that target the human respiratory system. These viruses often cause pneumonia-like symptoms that can develop into Severe Acute Respiratory Syndrome (SARS), causing higher leukocyte production, abnormal respiratory findings, and increased levels of plasma pro-inflammatory cytokines (4). COVID-19 may manifest either as an asymptomatic infection or as a mild to severe pneumonia (5). The most common initial symptoms at the onset of COVID-19 are fever, cough, and fatigue, while sputum production, headache, hemoptysis, diarrhea, dyspnea, and lymphopenia are less frequent (6).
The severity of the COVID-19 infection varies among individuals and may relate to several reported risk factors, such as aging, diabetes mellitus, cardiovascular risk (including hypertension), and respiratory or kidney disease. Moreover, an increasing number of studies have linked obesity to more severe COVID-19 symptoms and, ultimately, increased mortality (7-9).
Recently, a retrospective analysis of 3,615 patients with COVID-19 at the New York academic hospital system reported that approximately 38% of these patients were obese (Body Mass Index, BMI >30 kg/m2). Moreover, obese patients under 60 years of age had twofold susceptibility to being admitted in critical care compared to non-obese individuals (8).
Obesity-related conditions worsen the impact of COVID-19 symptoms due to complications associated with excessive body weight, metabolic dysfunction, cardiovascular risk, sleep apnea, vitamin D deficiency, dysregulation of the renin-angiotensin-aldosterone system, and sarcopenia (10). Furthermore, obese patients have altered levels of circulating cytokines. Notably, these individuals exhibit higher concentrations of TNF-alpha, MCP-1, and IL-6, which are generated by visceral and subcutaneous adipose tissue (11). This alteration in inflammatory profile appears to predict the severity and prognosis of obese patients and COVID-19 (11,12). Thus, special attention should be considered for this population.
In the absence of efficient pharmacotherapy, and due to the public health emergency, a significant number of potential drugs was proposed, such as antiviral agents, chloroquine and hydroxychloroquine, and corticosteroids (13,14).
... For example: sweet and bitter taste receptors expressed in the sinonasal epithelium are involved in regulating the innate immune pathways. 8 Bitter taste receptors expressed in gastrointestinal enteroendocrine cells, influence hunger and satiety by controlling the secretion of appetite regulating gut hormones, 9 and monitor potential toxins and xenobiotics derived from the ingested food, 10 while bitter receptors expressed in the respiratory tract have an important role in protecting the airways against pathogens and conditions such as bronchoconstriction. 11,12 Elucidation of the physiological roles of taste GPCRs in extra-oral tissues requires identification of their ligands. ...
... Recent reviews provided insight and overview on taste receptor signal transduction, vast physiological importance in the body and therapeutic potential. 9,14,18,19 Ahmad and Dalziel 20 summarized the physiology and pharmacology of taste GPCRs, as well as their signal transduction pathways and conformational changes upon ligand binding. ...
Taste GPCRs are expressed in taste buds on the tongue and play a key role in food choice and consumption. They are also expressed extra-orally, with various physiological roles that are currently under study. Unraveling the roles of these receptors relies on the knowledge of their ligands. Combining sensory, cell-based and computational approaches enabled the discovery of numerous agonists and several antagonists. Here we provide a short overview of taste receptor families, main recent methods for ligands discovery, and current sources of information about known ligands. The future directions that are likely to impact the taste GPCR field include focus on ligand interactions with naturally occurring polymorphisms, as well as harnessing the power of CryoEM and of multiple signaling readout techniques. https://authors.elsevier.com/a/1fW-56gpflBVb5
... However, recent evidence has suggested that, in addition to being found in the oral cavity, some taste-related G protein-coupled receptors (GPCRs) and taste signal transduction molecules are found in extraoral locations, such as in the pancreas, adipose tissue, gastrointestinal tract (GI), and respiratory tract. [10][11][12] These types of taste GPCRs may exert functions that are beyond taste detection and may regulate metabolism of the host. 10,11,13 The potential role of taste GPCRs in inflammation has been supported by evidence that type 2 taste receptors (T2Rs) in the upper airway epithelium can detect bitter components and regulate respiratory innate immunity. ...
... [10][11][12] These types of taste GPCRs may exert functions that are beyond taste detection and may regulate metabolism of the host. 10,11,13 The potential role of taste GPCRs in inflammation has been supported by evidence that type 2 taste receptors (T2Rs) in the upper airway epithelium can detect bitter components and regulate respiratory innate immunity. [14][15][16][17] This has prompted us to evaluate the possible role of taste GPCRs in obesity and their impact on obesity-induced inflammation, a condition that can dictate the morbidity and mortality rate among obese individuals. ...
Obesity is characterized by chronic low-grade inflammation that could lead to other health complications, such as cardiovascular disease, diabetes, and various forms of cancer. Emerging evidence has shown that taste perception is altered during the development of obesity. Moreover, suppression of taste receptor or taste signaling molecules potentiate the inflammatory response, and the progression of inflammation attenuates the expression of taste receptors in vivo. Together, these findings suggest a possible interplay between taste signaling and inflammation. This review summarizes the interactions between type 1 (T1Rs) and type 2 taste receptors (T2Rs) and inflammation, as well as the impact of obesity on T1R- and T2R-mediated signaling. Furthermore, we evaluate the possible role that taste receptors play in regulating the inflammatory response during obesity as a therapeutic target to prevent the progression of comorbidities associated with obesity.
... The finding that TAS2Rs are expressed in multiple organs outside the oral cavity has prompted studies on their physiological function (4,5). In particular, the gastrointestinal tract, which forms a critical interface between the exterior and the human body, continuously monitors the presence of possible toxic bitter compounds derived from ingested food, drinks, pharmaceuticals, or bacterial sources. ...
... Indeed, the supernatant of crypts treated with 0.1 mM DB reduced the growth of E. coli, but a higher dose (1 mM) of DB had crypt-independent effects and reduced E. coli growth by itself. Similar effects were observed with the synthetic bitter compound 1,10-phenanthro-reduced hunger scores after intragastric administration of DB to healthy volunteers and the reduction in food intake induced by administration of bitter compounds to mice and humans (5,9,52,53). The FC in GDF15 expression after treatment with DB correlated with the FCs in expression of ADM2 and the LDLR, indicating that DB treatment induced mRNA expression of genes that are involved in food intake and triglyceride metabolism. ...
Bitter taste receptors (TAS2R) serve as warning sensors in the lingual system against ingestion of potential poisonous food. Here, we investigated the functional role of TAS2Rs in the human gut and focused on their potential to trigger an additional host defense pathway in the intestine. Human jejunal crypts, especially from obese subjects, responded to bitter agonists by inducing the release of antimicrobial peptides (α-defensin 5 and REG3A) but also regulated the expression of other innate immune factors (mucins, chemokines) that affected E. coli growth. The effect of aloin on E. coli growth and on the release of the mucus glycoprotein CLCA1, identified via proteomics, was affected by TAS2R43 amino acid/deletion polymorphisms and thus confirmed a role for TAS2R43. RNA sequencing uncovered that denatonium benzoate induced an NRF2-mediated nutrient stress response and an unfolded protein response that increased the expression of the mitokine GDF15 but also ADM2 and the LDLR, genes that are involved in anorectic signaling and lipid homeostasis. To conclude, TAS2Rs in the intestine provide a promising target for treating diseases that involve disturbances in the innate immune system and in body weight control. Polymorphisms in TAS2Rs may be valuable genetic markers to predict therapeutic responses.
... Bitter taste receptors are G protein-coupled receptors (GPCRs) that belong to the taste two receptor family (TAS2Rs) [19], of which roughly 25 subtypes exist in humans [20]. However, TAS2Rs are also present outside the oral cavity, such as the gastrointestinal tract and adipose tissue, and have been suggested as possible therapeutic targets to treat obesity [21,22]. In the gut activation of TAS2Rs on enteroendocrine cells by bitter compounds regulates the release of appetite regulating hormones, such as ghrelin [23] and glucagon-like peptide 1 (GLP-1), [24] in humans. ...
Objective
Growth differentiation factor 15 (GDF15), a stress related cytokine, was recently identified as a novel satiety signal acting via the GFRAL receptor located in the hindbrain. Bitter compounds are known to induce satiety via the release of glucagon-like peptide 1 (GLP-1) through activation of bitter taste receptors (TAS2Rs, 25 subtypes) on enteroendocrine cells in the gut. This study aimed to investigate whether and how bitter compounds induce a stress response in intestinal epithelial cells to affect GDF15 expression in patients with obesity, thereby facilitating satiety signaling from the gut.
Methods
The acute effect of oral intake of the bitter-containing medication Plaquenil (hydroxychloroquine sulfate) on plasma GDF15 levels was evaluated in a placebo-controlled, double-blind, randomized, two-visit crossover study in healthy volunteers. Primary crypts isolated from the jejunal mucosa from patients with obesity were stimulated with vehicle or bitter compounds, and the effect on GDF15 expression was evaluated using RT-qPCR or ELISA. Immunofluorescence colocalization studies were performed between GDF15, epithelial cell type markers and TAS2Rs. The role of TAS2Rs was tested by 1) pretreatment with a TAS2R antagonist, GIV3727; 2) determining TAS2R4/43 polymorphisms that affect taste sensitivity to TAS2R4/43 agonists.
Results
Acute intake of hydroxychloroquine sulfate increased GDF15 plasma levels, which correlated with reduced hunger scores and plasma ghrelin levels in healthy volunteers. This effect was mimicked in primary jejunal cultures from patients with obesity. GDF15 was expressed in enteroendocrine and goblet cells with higher expression levels in patients with obesity. Various bitter-tasting compounds (medicinal, plant extracts, bacterial) either increased or decreased GDF15 expression, with some also affecting GLP-1. The effect was mediated by specific intestinal TAS2R subtypes and the unfolded protein response pathway. The bitter-induced effect on GDF15/GLP-1 expression was influenced by the existence of TAS2R4 amino acid polymorphisms and TAS2R43 deletion polymorphisms that may predict patient's therapeutic responsiveness. However, the effect of the bitter-tasting antibiotic azithromycin on GDF15 release was mediated via the motilin receptor, possibly explaining some of its aversive side effects.
Conclusions
Bitter chemosensory and pharmacological receptors regulate the release of GDF15 from human gut epithelial cells and represent potential targets for modulating metabolic disorders or cachexia.
... Variation in bitter taste sensitivity may influence individual preferences for foods with bitter sensory qualities (i.e., cruciferous vegetables) and consequently impact health status [38]. In particular, T2Rs activation can influence appetite and body weight control, identifying T2Rs as promising targets for the treatment of obesity [39]. However, it has not been suggested that CAP bitterness is a barrier to chili intake, given that the amount of burn is much greater [40]. ...
Introduction: It has been suggested that capsaicin (CAP), a major pungent component in chili peppers, can be used as an anti-obesity ingredient due to effects on energy metabolism, but evidence is not consistent. Genetics may account for differences in CAP tolerance and its impact on adiposity status. The aim of this study was to systematically review current evidence concerning the role of genetic polymorphisms influencing CAP tolerance. Methods: The present systematic review analyzed and synthesized available evidence concerning associations between genetic polymorphisms and CAP tolerance following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines. Databases such as PubMed/Medline, Cochrane, Scopus, Google Scholar, Scielo and Lilacs were screened. Out of 228 publications identified, only 6 meet inclusion criteria and were finally included in the final report. Results: Overall, a total of 28 single nucleotide polymorphisms were associated with several CAP tolerance traits including sensitivity to burning/stinging, heat pain, and cough reactions, and detection of bitter taste thresholds. These genetic variants were located within 6 genes involved in key physiological processes such synthesis of tetrahydrobiopterin and nitric oxide production (GCH1), CAP uptake and transduction of thermal stimuli (TRPV1), and bitter taste perception (TAS2R38, TAS2R3, TAS2R4, and TAS2R5). Conclusion: There is evidence about the influence of genetic polymorphisms on CAP tolerance by affecting nociceptive signaling, CAP binding, and bitter tasting. This knowledge may facilitate the design and implementation of innovative CAP-based nutrigenetic strategies for a more precise clinical management of obesity.
... As a result, the lingual detection of bitterness through taste 2 receptors (TAS2Rs) elicits an aversive response, reducing the intake of potentially noxious agents [2,3]. TAS2Rs are expressed in several other tissues throughout the body, including in enteroendocrine cells (EECs), goblet cells and the Paneth cells of the gastrointestinal (GI) tract [4][5][6][7][8]. These TAS2Rs detect bitter compounds in the lumen derived from ingested food or medical drugs or released by bacteria to elicit an appropriate functional response. ...
The direct infusion of bitter solutions in the gastrointestinal tract can reduce the secretion of orexigenic hormones and influence appetite and food intake. We aimed to explore whether oral ingestion of the bitter tastant hydroxychloroquine sulfate can exert similar effects. Ten lean adult women were included in this double-blind, randomized, two-visit, crossover study. After an overnight fast, each volunteer received film-coated tablets containing 400 mg of hydroxychloroquine sulfate (Plaquenil®) or placebo. Plasma-ghrelin, -motilin, -insulin and blood-glucose concentrations were determined every 10 min before and 30 min after feeding; appetite was scored every 10 min. Hunger scores were investigated with a special interest 50–60 min after the ingestion of hydroxychloroquine sulfate, right before a rewarding chocolate milkshake was offered to drink ad libitum. Compared with the placebo, hydroxychloroquine sulfate tended to reduce hunger at the time of interest (p = 0.10). No effect was found upon subsequent milkshake intake. Motilin plasma concentrations were unaltered, but acyl-ghrelin plasma concentrations decreased after the ingestion of hydroxychloroquine sulfate (t = 40–50; p < 0.05). These data suggest that the oral intake of hydroxychloroquine sulfate tablets reduces subjective hunger via a ghrelin-dependent mechanism but does not affect motilin release, hedonic food intake or insulin levels in healthy women.
... The various taste receptor genes are expressed in the oral cavity in specialized cells, which are combined to taste buds (Chaudhari and Roper, 2021). Apart from the oral cavity, taste receptor gene expression has been reported in numerous non-gustatory tissues such as the gastrointestinal tract and the respiratory system (Wang et al., 2020;Martens et al., 2021;Behrens and Lang, 2022). Although in general five basic taste modalities act in concert to assess the nutritional quality of food, a considerable number of animals have lost some taste modalities (Antinucci and Risso, 2017). ...
Despite the important role of bitter taste for the rejection of potentially harmful food sources, birds have long been suspected to exhibit inferior bitter tasting abilities. Although more recent reports on the bitter recognition spectra of several bird species have cast doubt about the validity of this assumption, the bitter taste of avian species is still an understudied field. Previously, we reported the bitter activation profiles of three zebra finch receptors Tas2r5, -r6, and –r7, which represent orthologs of a single chicken bitter taste receptor, Tas2r1. In order to get a better understanding of the bitter tasting capabilities of zebra finches, we selected another Tas2r gene of this species that is similar to another chicken Tas2r. Using functional calcium mobilization experiments, we screened zebra finch Tas2r1 with 72 bitter compounds and observed responses for 7 substances. Interestingly, all but one of the newly identified bitter agonists were different from those previously identified for Tas2r5, -r6, and –r7 suggesting that the newly investigated receptor fills important gaps in the zebra finch bitter recognition profile. The most potent bitter agonist found in our study is cucurbitacin I, a highly toxic natural bitter substance. We conclude that zebra finch exhibits an exquisitely developed bitter taste with pronounced cucurbitacin I sensitivity suggesting a prominent ecological role of this compound for zebra finch.
... The results of the current study showing upregulation of Tas2r138 and Tas2r116 in the large intestine of mice fed a long-term HFD and association with different bacteria strengthen the proposal that taste receptors are "sensors" of luminal bacteria [24,29]. Sensory receptors on EEC cells are critical for the integration of inputs from nutrients and non-nutrients, toxins, and bacteria within the body and are proposed as novel therapeutic targets for feeding disorders and metabolic diseases [13,25,33,70,71]. Though many questions remain to be addressed and further studies are required to establish causality in addition to association, the findings of this study provide support for a role of Tas2r138 and Tas2r116 in gut chemosensing and suggest that these bitter taste receptors could be explored as potential targets for treating diseases with microbiome disturbances. ...
Bitter taste receptors (Tas2rs in mice) detect bitterness, a warning signal for toxins and poisons, and are expressed in enteroendocrine cells. We tested the hypothesis that Tas2r138 and Tas2r116 mRNAs are modulated by microbiota alterations induced by a long-term high-fat diet (HFD) and antibiotics (ABX) (ampicillin and neomycin) administered in drinking water. Cecum and colon specimens and luminal contents were collected from C57BL/6 female and male mice for qRT-PCR and microbial luminal 16S sequencing. HFD with/without ABX significantly increased body weight and fat mass at 4, 6, and 8 weeks. Tas2r138 and Tas2r116 mRNAs were significantly increased in mice fed HFD for 8 weeks vs. normal diet, and this increase was prevented by ABX. There was a distinct microbiota separation in each experimental group and significant changes in the composition and diversity of microbiome in mice fed a HFD with/without ABX. Tas2r mRNA expression in HFD was associated with several genera, particularly with Akkermansia, a Gram-negative mucus-resident bacterium. These studies indicate that luminal bacterial composition is affected by sex, diet, and ABX and support a microbial dependent upregulation of Tas2rs in HFD-induced obesity, suggesting an adaptive host response to specific diet-induced dysbiosis.
... Mechanism of action of TAS2R in the weight loss process. Copyright 2020, Elsevier[145] ...
Taste is one of the basic senses of living organisms and can recognize sour, bitter, salty, sweet and umami tastes. Bitter taste receptor is a class of G protein-coupled receptors capable of sensing bitterness. Initially, bitter taste receptor was thought to be only found in the taste buds of the tongue, palate and throat. Recent research has shown that in addition to the oral cavity, the bitter taste receptor is also present in the intestinal tract, respiratory tract, urinary tract, vascular smooth muscle, nervous system, thyroid gland and other tissues and organs to regulate body homeostasis and resist disorders . In this review, we focus on the effects of the bitter taste receptor outside the oral cavity to lay the groundwork for future research.
... These findings suggest that, in vivo, the secretion of other circulating hormones or neural reflexes may mask the local stimulatory effect of bitter agonists on GHR secretion. Therefore, care should be taken to directly extrapolate findings from in vitro studies to clinical applications in vivo [28]. ...
The worldwide prevalence of gastrointestinal diseases is about 40%, with standard pharmacotherapy being long-lasting and economically challenging. Of the dozens of diseases listed by the Rome IV Foundation criteria, for five of them (heartburn, dyspepsia, nausea and vomiting disorder, constipation, and diarrhoea), treatment with herbals is an official alternative, legislatively supported by the European Medicines Agency (EMA). However, for most plants, the Directive does not require a description of the mechanisms of action, which should be related to the therapeutic effect of the European plant in question. This review article, therefore, summarizes the basic pharmacological knowledge of synthetic drugs used in selected functional gastrointestinal disorders (FGIDs) and correlates them with the constituents of medicinal plants. Therefore, the information presented here is intended as a starting point to support the claim that both empirical folk medicine and current and decades-old treatments with official herbal remedies have a rational basis in modern pharmacology.
... However, there are also plenty of bitter tasting food products with clear benefits, such as olive oil, coffee, vegetables and medicines, such as ancient Chinese herbal medicines 32 . In addition, extraoral expression of bitter taste receptor throughout the body mediate diverse nontasting roles through various mechanisms [33][34][35] . ...
Extra-virgin olive oil (EVOO) is a critical component of the Mediterranean diet, which has been found beneficial to human health. Bitterness is often positively associated with the presence of phenolic compounds in EVOO. There are twenty-five bitter taste receptors (TAS2Rs) in humans, each of which responds to specific bitter tastants. The identity of phenolic compounds and the bitter taste receptors they stimulate remain unknown. In this study, we isolated 12 phenolic and secoiridoid compounds from the olive fruit and the oil extracted from it, and tested their ability to stimulate bitter taste receptor activity, using a calcium mobilization functional assay. Our results showed that seven out of twelve studied compounds activated TAS2R8, and five of them activated TAS2R1, TAS2R8, and TAS2R14. The phenolic compounds oleuropein aglycon and ligstroside aglycon were the most potent bitter tastants in olive oil. TAS2R1 and TAS2R8 were the major bitter taste receptors activated most potently by these phenolic compounds. The results obtained here could be utilized to predict and control the bitterness of olive oil based on the concentration of specific bitter phenolics produced during the milling process of olives.
... suggested that bitter compounds intake may lead to weight loss by several mechanisms, and the gastrointestinal enteroendocrine cell, gastrointestinal smooth muscle cells, gut-brain axis and adipose tissue may play important roles (Wang, Liszt, & Depoortere, 2020). Instead, individuals with impaired bitter identification may decrease bitter compounds intake and increase carbohydrate intake, leading to weight gain (Duffy, 2004). ...
Chemosensory (gustatory and olfactory) dysfunction contributes to obesity, but the association between body mass index (BMI) and chemosensory dysfunction are inconsistently reported. The present study included 4,390 subjects at a Smell and Taste Clinic. Results suggested that both the obesity class II group (BMI ≥ 35) and underweight group (BMI < 18.5) exhibited impaired taste function compared with the normal weight group (p < .05). Comparing with the other groups, the obesity class II group exhibited a higher proportion of impaired bitter identification (8.6%), and the underweight group showed a higher proportion of impaired salty identification (7.9%). When investigating differences for individual tastes, subjects with impaired bitter identification had higher BMI (t = 2.79, p = .005) and lower olfactory scores (p < .05) compared with those with intact bitter identification. Finally, reduced taste scores are associated with an increased BMI (r = −.04, p = .022). This correlation becomes more pronounced with age (F = 1.42, p < .001).
Practical Application
The nonlinear association between chemosensory dysfunction and BMI suggested that maintaining the gustatory and olfactory function is of significance for normal metabolism. In obesity regulating bitter taste appears to be more important than the other tastes.
... Nutrient taste receptors have been fully described in the oral cavity [32], but recent studies have demonstrated that they can also be found in GI tract [33] and are involved in satiety and homeostatic control functions [24,34]. Some authors have reported TAS downregulation in metabolic diseases such obesity and T2DM [24]. ...
Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.
... Carbohydrate sensing (TAS1R2-TAS1R3, Na + -glucose cotransporter type 1 (SGLT1)) occurs mainly in L-cells which secrete GLP-1 [108,109]. In addition, bitter taste receptors on EECs may represent an important target to reduce appetite [110]. ...
The global burden of obesity and the challenges of prevention prompted researchers to investigate the mechanisms that control food intake. Food ingestion triggers several physiological responses in the digestive system, including the release of gastrointestinal hormones from enteroendocrine cells that are involved in appetite signalling. Disturbed regulation of gut hormone release may affect energy homeostasis and contribute to obesity. In this review, we summarize the changes that occur in the gut hormone balance during the pre- and postprandial state in obesity and the alterations in the diurnal dynamics of their plasma levels. We further discuss how obesity may affect nutrient sensors on enteroendocrine cells that sense the luminal content and provoke alterations in their secretory profile. Gastric bypass surgery elicits one of the most favorable metabolic outcomes in obese patients. We summarize the effect of different strategies to induce weight loss on gut enteroendocrine function. Although the mechanisms underlying obesity are not fully understood, restoring the gut hormone balance in obesity by targeting nutrient sensors or by combination therapy with gut peptide mimetics represents a novel strategy to ameliorate obesity.
... Already several years, bitter tastants are speculated to be involved in gut peptide release and to influence hunger sensations via the gut-brain axis (28). EECs express TAS2Rs and based on extensive in vitro research, bitter tastants are able to affect gut peptide release (5,11,(29)(30)(31)(32). ...
Bitter tastants are recently introduced as potential hunger-suppressive compounds, the so-called "Bitter pill". However, the literature about bitter administration lacks consistency in methods and findings. We want to test whether hunger ratings and hormone plasma levels are affected by: 1) the site of administration: intragastrically (IG) or intraduodenally (ID), 2) the bitter tastant itself, quinine hydrochloride (QHCl) or denatonium benzoate (DB), and 3) the timing of infusion. Therefore, 14 healthy, female volunteers participated in a randomized, placebo-controlled six-visit crossover study. After an overnight fast, DB (1µmol/kg), QHCl (10µmol/kg) or placebo were given IG or ID via a nasogastric feeding tube. Blood samples were taken 10 min prior to administration and every 10 min after administration for a period of 2 hours. Hunger was rated at the same timepoints on a visual analogue scale (VAS). ID bitter administration did not affect hunger sensations, motilin or acyl-ghrelin release compared with its PLC infusion. IG QHCl infusion tended to suppress hunger increase, especially between 50-70 minutes after infusion, simultaneously with reduced motilin values. Here, acyl-ghrelin was not affected. IG DB did not affect hunger or motilin, however acyl-ghrelin levels were reduced 50-70 minutes after infusion. Plasma values of glucagon-like peptide 1 and cholecystokinin were too low to be properly detected or to have any physiological relevance. In conclusion, bitter tastants should be infused into the stomach to reduce hunger sensations and orexigenic gut peptides. QHCl has the best potential to reduce hunger sensations, and it should be infused 60 minutes before food intake.
... Odorant and taste receptors are extensively expressed in ectopic organs and their role in wound healing, cancer cells division inhibition, and obesity have been identified (19,10,26,29). Targeting of TAS2R family and OLFR544 from ORs and TRs, respectively, shows promising future in controlling obesity and asthma [188,189,222]. However, mysteries regarding testicular and sperm odorant and taste receptors interaction and functionality still need to be revealed. ...
Sperm chemotaxis, which guide sperm toward oocyte, is tightly associated with sperm capacitation, motility, and fertility. However, the molecular mechanism of sperm chemotaxis is not known. Re-productive odorant and taste receptors, belong to G-protein-coupled receptors (GPCR) super-family, cause an increase in intracellular Ca2+ concentration which is pre-requisite for sperm capacitation and acrosomal reaction, and result in sperm hyperpolarization and increase motility through ac-tivation of Ca2+-dependent Cl¯ channels. Recently, odorant receptors (ORs) in olfactory transduction pathway were thought to be associated with post-thaw sperm motility, freeze tolerance or freeza-bility and cryo-capacitation-like change during cryopreservation. Investigation of the roles of odorant and taste receptors (TRs) is important for our understanding of the freeze tolerance or freezability mechanism and improve the motility and fertility of post-thaw sperm. Here, we re-viewed the roles, mode of action, impact of odorant and taste receptors on sperm chemotaxis and post-thaw sperm quality.
... The bitter receptors hTAS2R7 and hTAS2R14 have been reported to selectively increase the levels of cholecystokinin (CCK), a hormone that increases satiety. All of these receptors are likely to be activated by the sequences obtained in this study, thereby indicating a potential for further investigation into chickpea protein hydrolysates and T2DM [38]. ...
The chickpea (Cicer arietinum L.) is one of the most important pulses worldwide. The objective was to identify, compare and evaluate peptides from chickpea hydrolysates produced by two enzymatic treatments. The antidiabetic potential and bitterness of the peptides and induction of bitter receptors were identified in silico. Proteins were isolated from the Kabuli variety. Peptides were produced from the proteins using a simulated digestive system (pepsin/pancreatin, 1:50 Enzyme/Protein, E/P), and these peptides were compared with those produced via bromelain hydrolysis (1:50 E/P). The protein profiles, sequences and characteristics of the peptides were evaluated. The biochemical inhibition and molecular docking of dipeptidyl peptidase-IV (DPP-IV), α-amylase and α-glucosidase were also studied. The molecular docking identified peptides from enzymatic hydrolysis as inhibitors of DPP-IV. The high hydrophobicity of the peptides indicated the potential for bitterness. There was no correlation between peptide length and DPP-IV binding. Peptides sequenced from the pepsin/pancreatin hydrolysates, PHPATSGGGL and YVDGSGTPLT, had greater affinity for the DPP-IV catalytic site than the peptides from the bromelain hydrolysates. These results are in agreement with their biochemical inhibition, when considering the inhibition of sitagliptin (54.3 µg/mL) as a standard. The bitter receptors hTAS2R38, hTAS2R5, hTAS2R7 and hTAS2R14 were stimulated by most sequences, which could be beneficial in the treatment of type 2 diabetes. Chickpea hydrolysates could be utilized as functional ingredients to be included in the diet for the prevention of diabetes.
There is increasing evidence linking bitter taste receptor (BTR) signalling to gut hormone secretion and glucose homeostasis. However, its effect on islet hormone secretion has been poorly characterised. This study investigated the effect of the bitter substance, denatonium benzoate (DB), on hormone secretion from mouse pancreatic islets and INS-1 832/13 cells. DB (0.5-1mM) augmented insulin secretion at both 2.8mM and 16.7mM glucose. This effect was no longer present at 5mM DB likely due to greater levels of cellular apoptosis. DB-stimulated insulin secretion involved closure of the K ATP channel, activation of T2R signalling in beta-cells and intra-islet GLP-1 release. DB also enhanced glucagon and somatostatin secretion, but the underlying mechanism was less clear. Together, this study demonstrates that the bitter substance, DB, is a strong potentiator of islet hormone secretion independent of glucose. This observation highlights the potential for widespread off-target effects associated with the clinical use of bitter-tasting substances.
For decades bitter taste receptors (TAS2R) were thought to be located only in the mouth and to serve as sensors for nutrients and harmful substances. However, in recent years Tas2r have also been reported in extraoral tissues such as the skin, the lungs, and the intestine, where their function is still uncertain. To better understand the physiological role of these receptors, in this paper we focused on the intestine, an organ in which their activation may be similar to the receptors found in the mouth. We compare the relative presence of these receptors along the gastrointestinal tract in three main species of biomedical research (mice, rats and humans) using sequence homology. Current data from studies of rodents are scarce and while more data are available in humans, they are still deficient. Our results indicate, unexpectedly, that the reported expression profiles do not always coincide between species even if the receptors are orthologs. This may be due not only to evolutionary divergence of the species but also to their adaptation to different dietary patterns. Further studies are needed in order to develop an integrated vision of these receptors and their physiological functionality along the gastrointestinal tract.
Citrus is an important source of flavonoids in our daily diet. Citrus flavonoids have antioxidant, anticancer, anti‐inflammatory, and cardiovascular disease prevention functions. Studies have shown that some pharmaceutical values of flavonoids may be related to their binding to bitter taste receptors, thus activating downstream signal transduction pathways; however, the underlying mechanism has not been systematically elucidated. In this paper, the biosynthesis pathway and the absorption and metabolism of citrus flavonoids were briefly reviewed, and the relationship between flavonoid structure and bitter taste intensity was investigated. In addition, the pharmacological effects of bitter flavonoids and the activation of bitter taste receptors in combating various diseases were discussed. This review provides an important basis for the targeted design of citrus flavonoid structures to make them more biologically active and more attractive as powerful drugs for the effective treatment of chronic diseases such as obesity, asthma, and neurological diseases.
Obesity is characterized by chronic low-grade inflammation that could lead to the other health complications, such as cardiovascular disease, diabetes, and various cancers. Nutrient intake and dietary preferences are often modulated by taste receptors in the taste buds. Emerging evidence has shown that taste perception is altered during the development of obesity. It is demonstrated that suppression of taste receptor or taste signaling molecules can potentiate inflammatory response, whereas progressive inflammation has shown to attenuate the expression of taste receptors in vivo, which could be suggestive of an interplay between taste signaling and inflammation. This review summarizes the interactions between types 1 and 2 taste receptors and inflammation, as well as the impact of obesity on taste signaling. Taken together, taste receptors might play a crucial role in regulating the inflammatory response during obesity and hence may serve as a potential therapeutic target to prevent the progression of obesity.
Taste receptors are located on the epithelial surface throughout the alimentary canal to identify nutrients and potential toxins. In the oral cavity, the role of taste is to encourage or discourage ingestion, while in the gastrointestinal (GI) tract, the taste receptors help the body prepare for an appropriate response to the ingested foods. The GI sensing of bitter compounds may alter the secretion of appetite-related hormones thereby reducing food intake, which may have potential use for managing health outcomes. This systematic literature review investigated the acute effects of administering different bitter tasting compounds on circulating levels of selected GI hormones, subjective appetite, and energy intake in humans. A literature search was conducted using Medline, CINAHL and Web of Science databases. Of 290 articles identified, 16 met the inclusion criteria. Twelve studies assessed food intake; four of these found bitter administration decreased food intake and eight did not. Fourteen studies assessed subjective appetite; seven found bitter administration affected at least one measure of appetite and seven detected no significant changes. Nine studies included measures of GI hormones; no significant effects were found for changes in GLP-1, CCK or PYY. Four studies measured motilin and ghrelin and found mostly consistent changes in either food intake or subjective appetite. Overall, the data on food intake and subjective appetite were inconsistent, with only motilin and ghrelin responsive to post-oral bitter administration. There is limited consistent conclusive evidence that bitter compounds influence food intake, appetite or hormones with the reasons for this discussed within.
Systematic review registration
CRD42021226102.
The property theory of Chinese materia medica is one of the foundations of traditional Chinese medicine. The property of Chinese materia medica (PCMM) is a multi-dimensional expression of the effect of Chinese materia medica (CMM), and it is related to the clinical prescription that fully reflects the clinical effect evaluation of CMM in a holistic, systematic, and scientific way. This paper discusses the source, development, and application of the PCMM by considering not only the five dimensions that constitute the PCMM but also the recognition of the human body and disease as given in traditional Chinese medicine. This paper aims to provide theoretical guidance for the rational use and development of CMMs.
Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.
Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader‐Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge‐eating disorder are also discussed.
Taste receptors, first identified on the tongue, are best known for their role in guiding our dietary preferences. The expression of taste receptors for umami, sweet, and bitter have been demonstrated in tissues outside of the oral cavity, including in the airway, brain, gastrointestinal tract, and reproductive organs. The extra-oral taste receptor chemosensory pathways and the endogenous taste receptor ligands are generally unknown, but there is increasing data suggesting that taste receptors are involved in regulating some aspects of innate immunity, and may potentially control the composition of the nasal microbiome in healthy individuals or patients with upper respiratory diseases like chronic rhinosinusitis (CRS). For this reason, taste receptors may serve as potential therapeutic targets, providing alternatives to conventional antibiotics. This review focuses on the physiology of sweet (T1R) and bitter (T2R) taste receptors in the airway and their activation by secreted bacterial products. There is particular focus on T2R38 in sinonasal ciliated cells, as well as the sweet and bitter receptors found on specialized sinonasal solitary chemosensory cells. Additionally, this review explores the impact of genetic variations in these receptors on the differential susceptibility of patients to upper airway infections, such as CRS.
Background/aims:
Nutrient-induced gut hormone release (eg, cholecystokinin [CCK]) and the modulation of gut motility (particularly pyloric stimulation) contribute to the regulation of acute energy intake. Non-caloric bitter compounds, including quinine, have recently been shown in cell-line and animal studies to stimulate the release of gastrointestinal hormones by activating bitter taste receptors expressed throughout the gastrointestinal tract, and thus, may potentially suppress energy intake without providing additional calories. This study aims to evaluate the effects of intraduodenally administered quinine on antropyloroduodenal pressures, plasma CCK and energy intake.
Methods:
Fourteen healthy, lean men (25 ± 5 years; BMI: 22.5 ± 2.0 kg/m2) received on 4 separate occasions, in randomized, double-blind fashion, 60-minute intraduodenal infusions of quinine hydrochloride at doses totaling 37.5 mg ("Q37.5"), 75 mg ("Q75") or 225 mg ("Q225"), or control (all 300 mOsmol). Antropyloroduodenal pressures (high-resolution manometry), plasma CCK (radioimmunoassay), and appetite perceptions/gastrointestinal symptoms (visual analog questionnaires) were measured. Ad libitum energy intake (buffet-meal) was quantified immediately post-infusion. Oral quinine taste-thresholds were assessed on a separate occasion using 3-alternative forced-choice procedure.
Results:
All participants detected quinine orally (detection-threshold: 0.19 ± 0.07 mmol/L). Intraduodenal quinine did not affect antral, pyloric or duodenal pressures, plasma CCK (pmol/L [peak]; control: 3.6 ± 0.4, Q37.5: 3.6 ± 0.4, Q75: 3.7 ± 0.3, Q225: 3.9 ± 0.4), appetite perceptions, gastrointestinal symptoms or energy intake (kcal; control: 1088 ± 90, Q37.5: 1057 ± 69, Q75: 1029 ±7 0, Q225: 1077 ± 88).
Conclusion:
Quinine, administered intraduodenally over 60 minutes, even at moderately high doses, but low infusion rates, does not modulate appetite-related gastrointestinal functions or energy intake.
Background and objectives:
The present study was conducted to evaluate the relationship between taste identification ability and body mass index (BMI) by studying the response to the administration of different taste stimuli to both sides of the tongue in three different groups of subjects.
Subjects and methods:
Thirty healthy normal-weight volunteers, 19 healthy overweight subjects, and 22 obese subjects were enrolled. For each subject, the lateralization Oldfield score, body weight, height, and blood pressure were determined. The taste test is based on filter paper strips soaked with 4 taste stimuli presented at different concentrations to evoke 4 basic taste qualities (salty, sour, sweet, and bitter); pure rapeseed oil and water were also administered to evoke fat and neutral taste qualities. The stimuli were applied to each side of the protruded tongue. Subjects were asked to identify the taste from a list of eight descriptions according to a multiple choice paradigm.
Results:
The results showed a general lowering of taste sensitivity with the increase of BMI, except for the taste of fat with rapeseed oil as the stimulus. Other variables affecting taste sensitivity are age (negative association), gender (women generally show higher sensitivity), and taste stimuli concentration (positive association).
Conclusions:
Our findings could provide important insights into how new therapies could be designed for weight loss and long-term weight maintenance and how diets could be planned combining the correct caloric and nutritional supply with individual taste preferences.
G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules.
Significance
Intestinal tuft cells are sentinels monitoring the luminal contents and play a critical role in type 2 immunity. In this work, Trichinella spiralis excretion–secretion and extract were shown to directly induce interleukin 25 (IL-25) release from the intestinal villi, evoke calcium responses in tuft cells, and activate Tas2r bitter-taste receptors, whereas the bitter compound salicin was shown to activate and induce tuft cells to release IL-25. Gα-gustducin/Gβ1γ13 and/or Gαo/Gβ1γ13, Plcβ2, Ip 3 r2, and Trpm5 comprise the signal transduction pathways that tuft cells utilize to initiate type 2 immune responses. Potentiation of Trpm5 by a natural sweet compound, stevioside, can enhance the tuft cell–ILC2 circuit’s activity, indicating that modulating these signaling components can help devise new means of combating parasites.
Background:
The role of taste perception in the development and persistence of obesity is currently unclear due to conflicting results from psychophysical and other studies. No study to date has assessed whether there is an underlying fundamental difference in the physiology of taste tissue between lean and obese individuals.
Method/subjects:
We analysed the transcriptomic profile (RNA-seq) of human fungiform taste papillae biopsied from lean (n = 23) and obese (n = 13) Caucasian females (age range 18-55) to identify differences in gene expression.
Results:
Obesity status was the major contributor to variance in global gene expression between individuals. A total of 62 genes had significantly different gene expression levels between lean and obese (P < 0.0002), with the specific taste associated genes phospholipase C beta 2 (PLCβ2) and sonic hedge-hog (SHH) having significantly reduced expression in obese group. Genes associated with inflammation and immune response were the top enriched biological pathways differing between the lean and the obese groups. Analysis of a broader gene set having a twofold change in expression (2619 genes) identified three enriched theme groups (sensory perception, cell and synaptic signalling, and immune response). Further, analysis of taste associated genes identified a consistent reduction in the expression of taste-related genes (in particular reduced type II taste cell genes) in the obese compared to the lean group.
Conclusion:
The findings show obesity is associated with altered gene expression in tastebuds. Furthermore, the results suggest the tastebud microenvironment is distinctly different between lean and obese persons and, that changes in sensory gene expression contribute to this altered microenvironment. This research provides new evidence of a link between obesity and altered taste and in the future may help design strategies to combat obesity.
After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution — with the use of knockout models — sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.
Chemosensory signaling in organs such as the mouth and gut contributes to the mechanisms that control metabolism. We investigated the chemosensory pathways that regulate secretion of the hunger hormone ghrelin in response to neurotransmitters, bitter and sweet tastants at the cellular level in the human gut mucosa, and the disturbances in this regulatory pathway induced by obesity. Obesity impaired ghrelin protein production and adrenalin‐induced ghrelin secretion in fundic cells, which was counterbalanced by somatostatin. Bitter agonists selective for taste receptor type 2 (TAS2Rs), TAS2R5 and TAS2R10 stimulated ghrelin secretion in fundic cells. The stimulatory effect of the broadly tuned bitter agonist, denatonium benzoate, was selectively blunted by obesity in the small intestine but not in the fundus. Luminal glucose concentrations inhibited ghrelin secretion via sodium‐dependent glucose cotransporter and taste receptor type 1 member 3. Obesity altered the sensitivity of the ghrelin cell to glucose in the small intestine but not in the fundus. Sweet taste receptor activation inhibited bitter taste signaling of the ghrelin cell. In conclusion, obesity impairs the sympathetic drive that controls ghrelin release in the fundus and affects the sensitivity of the ghrelin cell to bitter and sweet stimuli in the small intestine but not in the fundus. Region‐selective targeting of gut taste receptors in obesity is indicated.—Wang, Q., Liszt, K. I., Deloose, E., Canovai, E., Thijs, T., Farré, R., Ceulemans, L. J., Lannoo, M., Tack, J., Depoortere, I. Obesity alters adrenergic and chemosensory signaling pathways that regulate ghrelin secretion in the human gut. FASEB J. 33, 4907–4920 (2019). www.fasebj.org
The human G-protein-coupled bitter taste receptor T2R38 has recently been demonstrated to be expressed on peripheral blood neutrophils, monocytes and lymphocytes. To further define a potential contribution of the T2R38 receptor in adaptive immune response, the objective of this study was to analyze its expression in resting and activated lymphocytes and T cell subpopulations. Freshly isolated PBMC from healthy donors were used for expression analysis by flow cytometry. Quantum™ MESF beads were applied for quantification in absolute fluorescence units. Activation methods of T cells were anti-CD3/CD28, phytohaemagglutinin (PHA) or phorbol 12-myristate 13-acetate (PMA) together with ionomycin. Lymphocytes from young donors expressed higher levels of T2R38 compared to the elderly. CD3+ T cells expressed higher levels that CD19+ B cells. Receptor expression followed T cell activation with an upregulation within 24 h and a peak at 72 h. Higher levels of T2R38 were produced in lymphocytes by stimulation with anti-CD3/CD28 compared to PHA or PMA/ionomycin. Both subpopulations of CD4+ as well as CD8+ T cells were found to express the T2R38 receptor; this was higher in CD4+ than CD8+ cells; the amount of T2R38 in central and effector memory cells was higher as compared to naïve cells, although this was not statistically significant for CD8+ cells without prior activation by anti-CD3/CD28. Upon treatment of PBMC with the natural T2R38 agonist goitrin Calcium flux was activated in the lymphocyte population with functional T2R38 receptor at >20 μM which was completely blocked by phospholipase Cβ-2 inhibitor U73211. Further, goitrin selectively inhibited TNF-alpha secretion in PBMC with functional T2R38. This quantitative analysis of T2R38 expression in distinct PBMC subsets may provide a basis for understanding the significance of bitter compounds in immune modulation. Whether these findings can have implications for the treatment of inflammatory and immunologic disorders by bitter tasting pharmaceuticals or foods needs further investigation.
BitterDB (http://bitterdb.agri.huji.ac.il) was introduced in 2012 as a central resource for information on bitter-tasting molecules and their receptors. The information in BitterDB is frequently used for choosing suitable ligands for experimental studies, for developing bitterness predictors, for analysis of receptors promiscuity and more. Here, we describe a major upgrade of the database, including significant increase in content as well as new features. BitterDB now holds over 1000 bitter molecules, up from the initial 550. When available, quantitative sensory data on bitterness intensity as well as toxicity information were added. For 270 molecules, at least one associated bitter taste receptor (T2R) is reported. The overall number of ligand-T2R associations is now close to 800. BitterDB was extended to several species: in addition to human, it now holds information on mouse, cat and chicken T2Rs, and the compounds that activate them. BitterDB now provides a unique platform for structure-based studies with high-quality homology models, known ligands, and for the human receptors also data from mutagenesis experiments, information on frequently occurring single nucleotide polymorphisms and links to expression levels in different tissues.
The integumentary (i.e., skin) and gustatory systems both function to protect the human body and are a first point of contact with poisons and pathogens. These systems may share a similar protective mechanism because, as we show here, both human taste and skin cells express mRNA for bitter ‘taste’ receptors (TAS2Rs). We used gene-specific methods to measure mRNA from all known bitter receptor genes in adult human skin from freshly biopsied samples and from samples collected at autopsy from the Genotype-Tissue Expression project. Human skin expressed some but not all TAS2Rs, and for those that were expressed, the relative amounts differed markedly among individuals. For some TAS2Rs, mRNA abundance was related to presumed sun exposure based on the location from which the skin sample was collected (TAS2R14, TAS2R30, TAS2R42, and TAS2R60), sex (TAS2R3, TAS2R4, TAS2R8, TAS2R9, TAS2R14, and TAS2R60), and age (TAS2R5), although these effects were not large. These findings contribute to our understanding of extraoral expression of chemosensory receptors.
Taste receptors exist in several organs from tongue to colon and have diverse functions dependent on specific cell type. In enteroendocrine L-cells, stimulation of taste receptor signaling induces incretin hormones. Among incretin hormones, glucagon-like peptide-1 (GLP-1) induces insulinotropic action by activating GLP-1 receptor of pancreatic β-cells. However, GLP-1 mimetic medicines have reported clinical side effects, such as autoimmune hepatitis, acute kidney injury, pancreatitis, and pancreatic cancer. Here, we hypothesized that if natural components in ethnomedicines can activate agonistic action of taste receptor; they may stimulate GLP-1 and therefore, could be developed as safe and applicable medicines to type 2 diabetes mellitus (T2DM) with minimal side effects. Cucurbitacin B (CuB) is composed of triterpenoid structure and its structural character, that represents bitterness, can stimulate AMP-activated protein kinase (AMPK) pathway. CuB ameliorated hyperglycemia by activating intestinal AMPK levels and by inducing plasma GLP-1 and insulin release in diabetic mice. This hypoglycemic action was decreased in dorsomorphin-injected mice and α-gustducin null mice. Moreover, systemic inhibition study in differentiated NCI-H716 cell line showed that CuB-mediated GLP-1 secretion was involved in activation of AMPK through α-gustducin and Gβγ-signaling of taste receptors. In summary, we conclude that, CuB represents novel hypoglycemic agents by activation of AMPK and stimulation of GLP-1 in differentiated enteroendocrine L-cells. These results suggest that taste receptor signaling-based therapeutic agents within tremendously diverse ethnomedicines, could be applied to developing therapeutics for T2DM patients.
Objectives:
Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes.
Methods:
KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling.
Results:
We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone.
Conclusions:
Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.
Bitter taste receptors (T2Rs), discovered in many tissues outside the tongue, have recently become potential therapeutic targets. We showed previously that airway epithelial cells express several T2Rs that activate innate immune responses that may be important for treatment of airway diseases such as chronic rhinosinusitis. It is imperative to more clearly understand what compounds activate airway T2Rs as well as their full range of functions. T2R isoforms in airway motile cilia (T2Rs 4, 14, 16, and 38) produce bactericidal levels of nitric oxide (NO) that also increase ciliary beating, promoting clearance of mucus and trapped pathogens. Bacterial quorum-sensing acyl-homoserine lactones (AHLs) activate T2Rs and stimulate these responses in primary airway cells. Quinolones are another type of quorum sensing molecule used by Pseudomonas aeruginosa. To elucidate if bacterial quinolones activate airway T2Rs, we analyzed calcium, cAMP, and NO dynamics using a combination of fluorescent indicator dyes and FRET-based protein biosensors. T2R-transfected HEK293T cells, several lung epithelial cell lines, and primary sinonasal cells grown and differentiated at air-liquid interface were tested with 2-heptyl-3-hydroxy-4-quinolone (known as Pseudomonas quinolone signal; PQS), 2,4-dihydroxyquinolone (DHQ), and 4-hydroxy-2-heptylquinolone (HHQ). In HEK293T cells, PQS activated T2R4, 16, and 38 while HHQ activated T2R14. DHQ had no effect. PQS and HHQ increased calcium and decreased both baseline and stimulated cAMP levels in cultured and primary airway cells. In primary cells, PQS and HHQ activated levels of NO synthesis previously shown to be bactericidal. This study suggests airway T2R-mediated immune responses are activated by bacterial quinolones as well as AHLs.
Background
Bitter (T2R) and sweet (T1R) taste receptors in the airway are important in innate immune defense, and variations in taste receptor functionality in one T2R (T2R38) correlate with disease status and disease severity in chronic rhinosinusitis (CRS). Quinine is a bitter compound that is an agonist for several T2Rs also expressed on sinonasal cells, but not for T2R38. Because of this property, quinine may stimulate innate immune defense mechanisms in the airway, and functional differences in quinine perception may be reflective of disease status in CRS.
Methods
Demographic and taste intensity data were collected prospectively from CRS patients and non-CRS control subjects. Sinonasal tissue from patients undergoing rhinologic surgery was also collected and grown at an air–liquid interface (ALI). Nitric oxide (NO) production and dynamic regulation of ciliary beat frequency in response to quinine stimulation were assessed in vitro.
Results
Quinine reliably increased ciliary beat frequency and NO production in ALI cultures in a manner consistent with T2R activation (p < 0.01). Quinine taste intensity rating was performed in 328 CRS patients and 287 control subjects demonstrating that CRS with nasal polyps (CRSwNP) patients rated quinine as significantly less intense than did control subjects.
Conclusion
Quinine stimulates airway innate immune defenses by increasing ciliary beat frequency and stimulating NO production in a manner fitting with T2R activation. Patient variability in quinine sensitivity is observed in taste intensity ratings, and gustatory quinine “insensitivity” is associated with CRSwNP status. Thus, taste tests for quinine may be a biomarker for CRSwNP, and topical quinine has therapeutic potential as a stimulant of innate defenses.
Glucagon-like peptide-1 (GLP-1) is involved in the regulation of insulin secretion and glucose homeostasis. GLP-1 release is stimulated when berberine interacts with a novel G protein family (TAS2Rs) in enteroendocrine cells. In this study, we used STC-1 cells and examined a marked increase in Ca²⁺ in response to various bitter compounds. Ca²⁺ responses to traditional Chinese medicine extracts, including berberine, phellodendrine and coptisine, in STC-1 cells were suppressed by the phospholipase C (PLC) inhibitor U-73122, suggesting the involvement of bitter taste receptors in changing the physiological status of enteroendocrine cells in a PLC-dependent manner. STC-1 cells showed berberine-up-regulated preproglucagon (GLP-1 precursor) mRNA and GLP-1 secretion. A QPCR analysis demonstrated that TAS2R38, a subtype of the bitter taste receptor, was associated with GLP-1 secretion. Berberine-mediated GLP-1 secretion was attenuated in response to small interfering RNA silencing of TAS2R38. The current studies demonstrated that Gα-gustducin co-localized with GLP-1 and Tas2r106 in the STC-1 cells. We further utilized inhibitors of PLC and TRPM5, which are known to participate in taste signal transduction, to investigate the underlying pathways mediated in berberine-induced GLP-1 secretion. Berberine-induced GLP-1 release from enteroendocrine cells is modulated in a PLC-dependent manner through a process involving the activation of bitter taste receptors. Together, our data demonstrated a berberine-mediated GLP-1 secretion pathway in mouse enteroendocrine cells that could be of therapeutic relevance to hyperglycemia and the role of bitter taste receptors in the function of the small intestine.
In the upper respiratory epithelium, bitter and sweet taste receptors present in solitary chemosensory cells influence antimicrobial innate immune defense responses. Whereas activation of bitter taste receptors (T2Rs) stimulates surrounding epithelial cells to release antimicrobial peptides, activation of the sweet taste receptor (T1R) in the same cells inhibits this response. This mechanism is thought to control the magnitude of antimicrobial peptide release based on the sugar content of airway surface liquid. We hypothesized that d-amino acids, which are produced by various bacteria and activate T1R in taste receptor cells in the mouth, may also activate T1R in the airway. We showed that both the T1R2 and T1R3 subunits of the sweet taste receptor (T1R2/3) were present in the same chemosensory cells of primary human sinonasal epithelial cultures. Respiratory isolates of Staphylococcus species, but not Pseudomonas aeruginosa, produced at least two d-amino acids that activate the sweet taste receptor. In addition to inhibiting P. aeruginosa biofilm formation, d-amino acids derived from Staphylococcus inhibited T2R-mediated signaling and defensin secretion in sinonasal cells by activating T1R2/3. d-Amino acid–mediated activation of T1R2/3 also enhanced epithelial cell death during challenge with Staphylococcus aureus in the presence of the bitter receptor–activating compound denatonium benzoate. These data establish a potential mechanism for interkingdom signaling in the airway mediated by bacterial d-amino acids and the mammalian sweet taste receptor in airway chemosensory cells.
The chemical variability of the intestinal lumen requires the presence of molecular receptors detecting the various substances naturally occurring in the diet and as a result of the activity of the microbiota. Despite their early discovery, intestinal bitter taste receptors (Tas2r) have not yet been assigned an unambiguous physiological function. Recently, using a CRE-recombinant approach we showed that the Tas2r131 gene is expressed in a subset of mucin-producing goblet cells in the colon of mice. Moreover, we also demonstrated that the expression of the Tas2r131 locus is not restricted to this region. In the present study we aimed at characterizing the presence of positive cells also in other gastrointestinal regions. Our results show that Tas2r131⁺ cells appear in the jejunum and the ileum, and are absent from the stomach and the duodenum. We identified the positive cells as a subpopulation of deep-crypt Paneth cells in the ileum, strengthening the notion of a defensive role for Tas2rs in the gut. To get a broader perspective on the expression of bitter taste receptors in the alimentary canal, we quantified the expression of all 35 Tas2r genes along the gastrointestinal tract by qRT-PCR. We discovered that the number and expression level of Tas2r genes profoundly vary along the alimentary canal, with the stomach and the colon expressing the largest subsets.
Significance
This study shows that caffeine's effect on gastric acid secretion (GAS) is more complex than has been previously thought. Oral and gastric bitter taste receptors are involved in the regulation of GAS in humans. This regulatory process can be modified by the bitter-masking compound homoeriodictyol. Practical applications of the results may include treatment of gastroesophageal reflux disease or peptic ulcer by manipulating gastric pH by means of bitter tastants and inhibitors.
The past decade has witnessed a consolidation and refinement of the extraordinary progress made in taste research. This Review describes recent advances in our understanding of taste receptors, taste buds, and the connections between taste buds and sensory afferent fibres. The article discusses new findings regarding the cellular mechanisms for detecting tastes, new data on the transmitters involved in taste processing and new studies that address longstanding arguments about taste coding.
Context
KDT501 is a novel isohumulone drug which has demonstrated beneficial effects on metabolic parameters in mice.
Objective
This study was intended to examine potential improvements in metabolism in humans.
Design and Setting
Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center setting.
Participants
Nine obese participants were part of the study. All had either prediabetes, or had normal glucose tolerance plus three features of metabolic syndrome.
Intervention
All participants were treated with escalating doses of KDT501 to a maximum dose of 1000mg q12h for a total of 28 days.
Outcome measures
Changes in carbohydrate metabolism measured with oral glucose tolerance, HOMA-IR and euglycemic clamp; changes in plasma lipids and response to a lipid tolerance test; changes in plasma inflammatory markers.
Results
The drug was well tolerated. After KDT501 treatment, plasma triglycerides were reduced at 4 hours during a lipid tolerance test. Furthermore, there were significant increases in plasma adiponectin, HMW adiponectin, and significant decreases in plasma TNFα. There were no significant changes in oral glucose tolerance test results or insulin sensitivity measures.
Conclusions
Despite the small sample size and the short duration of therapy, KDT501 administration reduced measures of systemic inflammation and improved post meal plasma triglyceride levels, which may be beneficial in participants with insulin resistance or metabolic syndrome.
Asthma is characterized by airway inflammation, mucus secretion, remodeling and hyperresponsiveness (AHR). Recent research has established the bronchodilatory effect of bitter taste receptor (TAS2R) agonists in various models. Comprehensive pre-clinical studies aimed at establishing effectiveness of TAS2R agonists in disease models are lacking. Here we aimed to determine the effect of TAS2R agonists on features of asthma. Further, we elucidated a mechanism by which TAS2R agonists mitigate features of asthma. Asthma was induced in mice using intranasal house dust mite or aerosol ova-albumin challenge, and chloroquine or quinine were tested in both prophylactic and treatment models. Allergen challenge resulted in airway inflammation as evidenced by increased immune cells infiltration and release of cytokines and chemokines in the lungs, which were significantly attenuated in TAS2R agonists treated mice. TAS2R agonists attenuated features of airway remodeling including smooth muscle mass, extracellular matrix deposition and pro-fibrotic signaling, and also prevented mucus accumulation and development of AHR in mice. Mechanistic studies using human neutrophils demonstrated that inhibition of immune cell chemotaxis is a key mechanism by which TAS2R agonists blocked allergic airway inflammation and exerted anti-asthma effects. Our comprehensive studies establish the effectiveness of TAS2R agonists in mitigating multiple features of allergic asthma.
Chronic rhinosinusitis has a significant impact on patient quality of life, creates billions of dollars of annual healthcare costs, and accounts for ~20% of adult antibiotic prescriptions in the US. Due to the rise of resistant microorganisms, there is a critical need to better understand how to stimulate and/or enhance innate immune responses as a therapeutic modality to treat respiratory infections. We recently identified bitter taste receptors (taste family type 2 receptors, or T2Rs) as important regulators of sinonasal immune responses and potential important therapeutic targets. Here, we examined the immunomodulatory potential of flavones, a class of flavonoids previously demonstrated to have antibacterial and anti-inflammatory effects. Some flavones are also T2R agonists. We found that several flavones inhibit Muc5AC and iNOS upregulation as well as cytokine release in primary and cultured airway cells in response several inflammatory stimuli. This occurs at least partly through inhibition of protein kinase C and receptor tyrosine kinase activity. We also demonstrate that sinonasal ciliated epithelial cells express T2R14, which closely co-localizes (<7 nm) with the T2R38 isoform. Heterologously-expressed T2R14 responds to multiple flavones. These flavones also activate T2R14-driven calcium signals in primary cells that activate nitric oxide production to increase ciliary beating and mucociliary clearance. T2R14 responses were not affected by TAS2R38 polymorphisms encoding functional (PAV) or non-functional (AVI) T2R38. Our data demonstrate that T2R14 in sinonasal cilia is a potential therapeutic target for upper respiratory infections, and that flavones may have clinical potential as topical therapeutics, particularly in T2R38 AVI/AVI individuals.
Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem.
One key to animal survival is the detection and avoidance of potentially harmful compounds by their bitter taste. Variable
numbers of taste 2 receptor genes expressed in the gustatory end organs enable bony vertebrates (Euteleostomi) to recognize
numerous bitter chemicals. It is believed that the receptive ranges of bitter taste receptor repertoires match the profiles
of bitter chemicals that the species encounter in their diets. Human and mouse genomes contain pairs of orthologous bitter
receptor genes that have been conserved throughout evolution. Moreover, expansions in both lineages generated species-specific
sets of bitter taste receptor genes. It is assumed that the orthologous bitter taste receptor genes mediate the recognition
of bitter toxins relevant for both species, whereas the lineage-specific receptors enable the detection of substances differently
encountered by mice and humans. By challenging 34 mouse bitter taste receptors with 128 prototypical bitter substances in
a heterologous expression system we identified cognate compounds for 21 receptors, 19 of which were previously orphan receptors.
We demonstrate that mouse taste 2 receptors, like their human counterparts, vary greatly in their breadth of tuning, ranging
from very broadly to extremely narrowly tuned receptors. However, when compared to humans, mice possess fewer broadly tuned
receptors and an elevated number of narrowly tuned receptors, supporting the idea that a large receptor repertoire is the
basis for the evolution of specialized receptors. Moreover, we demonstrate that sequence-orthologous bitter taste receptors
have distinct agonist profiles. Species-specific gene expansions have enabled further diversification of bitter substance
recognition spectra.
Quinine is a bitter tasting compound that is involved in the regulation of body weight as demonstrated in in vivo animal models and in vitro models of the adipogenic system. Arguments exist over the positive or negative roles of quinine in both in vivo animal models and in vitro cell models, which motivates us to further investigate the functions of quinine in the in vitro adipogenic system. To clarify the regulatory functions of quinine in adipogenesis, mouse primary preadipocytes were induced for differentiation with quinine supplementation. The results showed that quinine enhanced adipogenesis in a dose dependent manner without affecting lipolysis. The pro-adipogenic effect of quinine was specific, as other bitter tasting agonists had no effect on adipogenesis. Moreover, the pro-adipogenic effect of quinine was mediated by activation of ERK/S6 (extracellular-signal-regulated kinase/Ribosomal protein S6) signaling. Knockdown of bitter taste receptor T2R106 (taste receptor, type 2, member 106) impaired the pro-adipogenic effect of quinine and suppressed the activation of ERK/S6 signaling. Taken together, quinine stimulates adipogenesis through ERK/S6 signaling, which at least partly functions via T2R106.
Bitter taste receptors (TAS2Rs) are traditionally thought to be expressed exclusively on the taste buds of the tongue. However, accumulating evidence has indicated that this receptor family performs non-gustatory functions outside the mouth in addition to taste. Here, we examined the role of TAS2Rs in human and mouse detrusor smooth muscle (DSM). We showed that mRNA for various TAS2R subtypes was expressed in both human and mouse detrusor smooth muscle (DSM) at distinct levels. Chloroquine (CLQ), an agonist for TAS2Rs, concentration-dependently relaxed carbachol- and KCl-induced contractions of human DSM strips. Moreover, 100 µM of CLQ significantly inhibited spontaneous and electrical field stimulation (EFS)-induced contractions of human DSM strips. After a slight contraction, CLQ (1 mM) entirely relaxed carbachol-induced contraction of mouse DSM strips. Furthermore, denatonium and quinine concentration-dependently decreased carbachol-induced contractions of mouse DSM strips. Finally, we demonstrated that CLQ treatment significantly suppressed the overactive bladder (OAB) symptoms of mice with partial bladder outlet obstruction (PBOO). In conclusion, we for the first time provide evidence of the existence of TAS2Rs in the urinary DSM and demonstrate that TAS2Rs may represent a potential target for OAB. These findings open a new approach to develop drugs for OAB in the future.
Bitter taste receptors (T2Rs) are expressed in the mammalian gastrointestinal mucosa. In the mouse colon, T2R138 is localized to enteroendocrine cells and is upregulated by long-term high fat diet that induces obesity. The aims of this study were to test whether T2R38 expression is altered in overweight/obese (OW/OB) compared to normal weight (NW) subjects and characterize the cell types expressing T2R38, the human counterpart of mouse T2R138, in human colon. Colonic mucosal biopsies were obtained during colonoscopy from 35 healthy subjects (20 OW/OB and 15 NW) and processed for quantitative RT-PCR and immunohistochemistry using antibodies to T2R38, chromogranin A (CgA), glucagon like peptide-1 (GLP-1), cholecystokinin (CCK), or peptide YY (PYY). T2R38 mRNA levels in the colonic mucosa of OW/OB were increased (> 2 fold) compared to NW subjects but did not reach statistical significance (P = 0.06). However, the number of T2R38 immunoreactive (IR) cells was significantly increased in OW/OB vs. NW subjects (P = 0.01) and was significantly correlated with BMI values (r = 0.7557; P = 0.001). In both OW/OB and NW individuals, all T2R38-IR cells contained CgA-IR supporting they are enteroendocrine. In both groups, T2R38-IR colocalized with CCK-, GLP1- or PYY-IR. The overall CgA-IR cell population was comparable in OW/OB and NW individuals. This study shows that T2R38 is expressed in distinct populations of enteroendocrine cells in the human colonic mucosa and supports T2R38 upregulation in OW/OB subjects. T2R38 might mediate host functional responses to increased energy balance and intraluminal changes occurring in obesity, which could involve peptide release from enteroendocrine cells.
Quorum-sensing molecules, also known as autoinducer, are essential for bacterial biofilm formation. Our focus is on N-(3-oxododecanoyl)-L-homoserine lactone (AHL-12), because it is also known as an "interkingdom signalling molecule", which means that it also interacts with mammalian cells. AHL-12 activates defense-relevant functions of phagocytic cells, including enhancement of phagocytosis, increased expression of adhesion receptors, and induction of chemotaxis. This leads to the hypothesis that early recognition of developing biofilms might be the key to a successful host defense against biofilm infection. In that context we studied activation of phagocytic cells by AHL-12, and found that phagocytes are activated via a rather specialised receptor that was not previously described on myeloid cells, the bitter taste receptor T2R38. Taste receptors are commonly associated with cells of the gustatory system. The extragustatory expression, however, suggests an additional role, namely the sensing of the onset of bacterial biofilm infection.
Intestinal chemosensory signaling pathways involving the gustatory G-protein, gustducin, and bitter taste receptors (TAS2R) have been implicated in gut hormone release. Alterations in gut hormone profiles may contribute to the success of bariatric surgery. This study investigated the involvement of the gustatory signaling pathway in the development of diet-induced obesity and the therapeutic potential of targeting TAS2Rs to induce body weight loss. α-gustducin-deficient (α-gust-/-) mice became less obese than wild type (WT) mice when fed a high-fat diet (HFD). White adipose tissue (WAT) mass was lower in α-gust-/- mice due to increased heat production as a result of increases in brown adipose tissue (BAT) thermogenic activity, involving increased protein expression of uncoupling protein 1. Intra-gastric treatment of obese WT and α-gust-/- mice with the bitter agonists denatonium benzoate (DB) or quinine (Q) during 4 weeks resulted in an α-gustducin-dependent decrease in body weight gain associated with a decrease in food intake (DB), but not involving major changes in gut peptide release. Both WAT and 3T3-F442A pre-adipocytes express TAS2Rs. Treatment of pre-adipocytes with DB or Q decreased differentiation into mature adipocytes. In conclusion, interfering with the gustatory signaling pathway protects against the development of HFD-induced obesity presumably through promoting BAT activity. Intra-gastric bitter treatment inhibits weight gain, possibly by directly affecting adipocyte metabolism.
Bitter taste receptors (TAS2Rs) are present in extra-oral tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut smooth muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in smooth muscle tissue along the mouse gut and in human gastric smooth muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca2+ release and extracellular Ca2+-influx, partially masked by a hyperpolarizing K+-efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca2+-rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.
Background/aims:
Bitter taste receptors are expressed throughout the digestive tract. Data on animals have suggested these receptors are involved in the gut hormone release, but no data are available in humans. Our aim is to assess whether bitter agonists influence food intake and gut hormone release in healthy subjects.
Methods:
Twenty healthy volunteers were enrolled in a double-blind cross-over study. On two different days, each subject randomly received an acid-resistant capsule containing either placebo or 18 mg of hydrochloride (HCl) quinine. After 60 minutes, all subjects were allowed to eat an ad libitum meal until satiated. Plasma samples were obtained during the experiment in order to evaluate cholecystokinin (CCK) and ghrelin levels. Each subject was screened to determine phenylthiocarbamide (PTC) tasting status.
Results:
Calorie intake was significantly lower when subjects received HCl quinine than placebo (514±248 kcal vs 596±286 kcal; p=0.007). Significantly higher CCK ΔT90vsT0 and ΔT90vsT60 were found when subjects received HCl quinine than placebo (0.70±0.69 ng/ml vs 0.10±0.86 ng/ml, p=0.026; 0.92±0.75 ng/ml vs. 0.50±0.55 ng/ml, p=0.033, respectively). PTC tasters ingested a significantly lower amount of calories when they received HCl quinine compared to placebo (526±275 kcal vs 659±320 kcal;p=0.005), whereas no significant differences were found for PTC non-tasters (499±227 kcal vs 519±231 kcal;p=0.525).
Conclusions:
This study showed that intra-duodenal release of a bitter compound is able to significantly affect calorie intake and CCK release after a standardized meal. Our results suggest that bitter taste receptor signaling may have a crucial role in the control of food intake.
Gastric emptying and the release of gastrointestinal (GI) hormones are major determinants of postprandial blood glucose concentrations and energy intake. Preclinical studies suggest that activation of GI bitter taste receptors potently stimulates GI hormones, including glucagon-like peptide-1 (GLP-1), thus, may reduce postprandial glucose and energy intake. We evaluated the effects of intragastric quinine on the glycemic response to, and gastric emptying of, a mixed-nutrient drink, and on subsequent energy intake, in healthy men. The study consisted of two parts; part A included 15, and part B 12, lean men (aged 26±2 years). In each part, participants received, on 3 separate occasions, in double-blind, randomized fashion, intragastric quinine (275 mg or 600 mg), or control, 30 min before a mixed-nutrient drink (part A), or before a buffet-meal (part B). In part A, plasma glucose, insulin, glucagon and GLP-1 concentrations were measured at baseline, after quinine alone, and for 2 h following the drink. Gastric emptying of the drink was also measured. In part B, energy intake at the buffet-meal was quantified. Q600 and Q275 alone stimulated insulin modestly (P<0.05). After the drink, Q600 and Q275 reduced plasma glucose and stimulated insulin (P<0.05), Q275 stimulated GLP-1 (P<0.05), and Q600 tended to stimulate GLP-1 (P=0.066) and glucagon (P=0.073), compared with control. Quinine did not affect gastric emptying of the drink or energy intake. In conclusion, in healthy men, intragastric quinine reduces postprandial blood glucose and stimulates insulin and GLP-1, but does not slow gastric emptying, or reduce energy intake, under our experimental conditions.
Olfactory and taste receptors are expressed primarily in the nasal olfactory epithelium and gustatory taste bud cells, where they transmit real-time sensory signals to the brain. However, they are also expressed in multiple extra-nasal and extra-oral tissues, being implicated in diverse biological processes including sperm chemotaxis, muscle regeneration, bronchoconstriction and bronchodilatation, inflammation, appetite regulation and energy metabolism. Elucidation of the physiological roles of these ectopic receptors is revealing potential therapeutic and diagnostic applications in conditions including wounds, hair loss, asthma, obesity and cancers. This Review outlines current understanding of the diverse functions of ectopic olfactory and taste receptors and assesses their potential to be therapeutically exploited.
New findings:
What is the central question of this study? This study aims to evaluate artesunate for its usage as a bronchodilator drug agent in asthma treatment. What is the main finding and its importance? We find that artesunate reduces airway resistance in both normal and ovalbumin-treated Balb/c mice in vivo, and reduces traction force while inducing Ca2+ influx of the cultured airway smooth muscle cells in vitro most likely via bitter taste receptor. This finding provides important evidence at both animal and cellular level that artesunate may be a potential alternative bronchodilator for treating obstructive airway diseases such as asthma.
Abstract:
Following the surprising discovery that bitter taste receptors (TAS2Rs) express in the lung and can be stimulated to relax airway smooth muscle cells (ASMCs), there is a great interest to search for bitter taste receptor agonist as novel bronchodilator for asthma therapy. Among the great many other natural bitter substances, artesunate is of special interest to be evaluated for this purpose because of its pharmacological value as a derivative from the well-known anti-malarial artemisinin. Therefore, in this study we treated either normal or ovalbumin (OVA)-induced asthmatic Balb/c mice in vivo with artesunate (30, 60, 120 μg, respectively) via aerosol inhalation. Subsequently, we measured the airway resistance of the mice in the presence or absence of artesunate. In addition, we treated either mouse or human ASMCs cultured in vitro with artesunate (0.25∼2.0 mM) and then measured the traction force and intracellular calcium flux ([Ca2+ ]i ) of the cells in the presence or absence of artesunate. The results demonstrate that artesunate dose-dependently attenuated airway resistance in both the normal and OVA-treated mice but more potently in the latter. And the in vivo efficacy of artesunate at 120 μg was comparable to that of conventional bronchodilator, salbutamol at 3 μg in terms of airway resistance reduction. Artesunate also reduced traction force and induced [Ca2+ ]i in the cultured ASMCs, which was mediated, at least partially, by TAS2R signaling in the human ASMCs. These results together suggest that artesunate may be a potential cheap and safe bronchodilator to complement the current therapy of asthma. This article is protected by copyright. All rights reserved.
Secretion of gastric acid, aimed at preventing bacterial growth and aiding the digestion of foods in the stomach, is chiefly stimulated by dietary intake of protein and amino acids (AAs). However, AAs' key structural determinants responsible for their effects on mechanisms regulating gastric acid secretion (GAS) have not been identified yet. In this study, AAs have been tested in the parietal cell model HGT-1 on GAS and on mRNA expression of genes regulating GAS. AAs' taste intensities from 0 (not bitter at all) to 10 (very bitter) were assessed in a sensory study, in which ARG (L: 6.42 ± 0.41; D: 4.62 ± 0.59) and ILE (L:4.21 ± 0.43; D: 2.28 ± 0.33) were identified as bitter tasting candidates in both isomeric forms. Pearson correlation showed that GAS in HGT-1 cells is directly associated with the bitter taste quality (r: -0.654) in combination with the molecular weight of L-AA (r:-0.685).
Objectives:
Intragastric bitter tastants may decrease appetite and food intake. We aimed to investigate the gut-brain signaling and brain mechanisms underlying these effects.
Methods:
Brain responses to intragastric quinine-hydrochloride (QHCl, 10 µmol/kg) or placebo infusion were recorded using functional magnetic resonance imaging in 15 healthy women. Appetite-related sensations, plasma levels of gastrointestinal hormones and hedonic food intake (ad libitum drink test) were assessed.
Results:
Lower octanoylated ghrelin (P<0.04), total ghrelin (P<0.01), and motilin (P<0.01) plasma levels were found after QHCl administration, along with lower prospective food consumption ratings (P<0.02) and hedonic food intake (P<0.05). QHCl increased neural activity in the hypothalamus and hedonic (anterior insula, putamen, caudate, pallidum, amygdala, anterior cingulate cortex, orbitofrontal cortex, midbrain) regions, but decreased activity in the homeostatic medulla (all pFWE-corrected<0.05). Differential brain responses to QHCl versus placebo covaried with subjective and hormonal responses and predicted differences in hedonic food intake.
Discussion:
Intragastric QHCl decreases prospective and actual food intake in healthy women by interfering with homeostatic and hedonic brain circuits in a ghrelin- and motilin-mediated fashion. These findings suggest a potential of bitter tastants to reduce appetite and food intake, through the gut-brain axis.
We have recently identified a cholinergic chemosensory cell in the urethral epithelium, urethral brush cell (UBC), that, upon stimulation with bitter or bacterial substances, initiates a reflex detrusor activation. Here, we elucidated cholinergic mechanisms that modulate UBC responsiveness. We analyzed muscarinic acetylcholine receptor (M1-5 mAChR) expression by using RT-PCR in UBCs, recorded [Ca2+]i responses to a bitter stimulus in isolated UBCs of wild-type and mAChR-deficient mice, and performed cystometry in all involved strains. The bitter response of UBCs was enhanced by global cholinergic and selective M2 inhibition, diminished by positive allosteric modulation of M5, and unaffected by M1, M3, and M4 mAChR inhibitors. This effect was not observed in M2 and M5 mAChR-deficient mice. In cystometry, M5 mAChR-deficient mice demonstrated signs of detrusor overactivity. In conclusion, M2 and M5 mAChRs attenuate the bitter response of UBC via a cholinergic negative autocrine feedback mechanism. Cystometry suggests that dysfunction, particularly of the M5 receptor, may lead to such symptoms as bladder overactivity.-Deckmann, K., Rafiq, A., Erdmann, C., Illig, C., Durschnabel, M., Wess, J., Weidner, W., Bschleipfer, T., Kummer, W. Muscarinic receptors 2 and 5 regulate bitter response of urethral brush cells via negative feedback.
Therapies to prevent diabetes in particular the progressive loss of β-cell mass and function and/or to improve the dysregulated metabolism associated with diabetes are highly sought. The incretin-based therapy comprising GLP-1R agonists and DPP-4 inhibitors have represented a major focus of pharmaceutical R&D over the last decade. The incretin hormone GLP-1 has powerful antihyperglycemic effect through direct stimulation of insulin biosynthesis and secretion within the β-cells; it normalizes β-cell sensitivity to glucose, has an antiapoptotic role, stimulates β-cell proliferation and differentiation, and inhibits glucagon secretion. However, native GLP-1 therapy is inappropriate due to the rapid post-secretory inactivation by DPP-4. Therefore, incretin mimetics developed on the backbone of the GLP-1 or exendin-4 molecule have been developed to behave as GLP-1R agonists but to display improved stability and clinical efficacy. New formulations of incretins and their analogs based on micro- and nanomaterials (i.e., PEG, PLGA, chitosan, liposomes and silica) and innovative encapsulation strategies have emerged to achieve a better stability of the incretin, to improve its pharmacokinetic profile, to lower the administration frequency or to allow another administration route and to display fewer adverse effects. An important advantage of these formulations is that they can also be used at the targeted non-invasive imaging of the beta-cell mass. This review therefore focuses on the current state of these efforts as the next step in the therapeutic evolution of this class of antidiabetic drugs.
The number and variety of bitter compounds originating from plants is vast. Whereas some bitter chemicals are toxic and should not be ingested, other compounds exhibit health beneficial effects, which is manifest in the cross-cultural believe that the bitterness of medicine is correlated with the desired medicinal activity. The bitter taste receptors in the oral cavity serve as sensors for bitter compounds and, since they are expressed in numerous extraoral tissues throughout the body, may also be responsible for some physiological effects exerted by bitter compounds. Chinese herbal medicine uses bitter herbs since ancient times for the treatment of various diseases, however, the routes by which these herbs modify physiology are frequently not well understood. We therefore screened 26 bitter substances extracted from medical herbs for the activation of the 25 human bitter taste receptors. We identified 6 receptors activated by in total 17 different bitter compounds. Interestingly, we observed a bias in bitter taste receptor activation with 10 newly identified agonists for the broadly tuned receptor TAS2R46, 7 agonists activating the TAS2R14 and 2 compounds activating narrowly tuned receptors, suggesting that these receptors play dominant roles in the evaluation and perhaps physiological activities of Chinese herbal medicines. This article is protected by copyright. All rights reserved.
Background:
Intragastric administration of the bitter tastant denatonium benzoate inhibits the increase of motilin plasma levels and antral contractility. While these findings suggest that gastrointestinal bitter taste receptors could be new targets to modulate gastrointestinal motility and hormone release, they need confirmation with other bitter receptor agonists. The primary aim was to evaluate the effect of intragastric administration of the bitter tastant quinine-hydrochloride (QHCl) on motilin and ghrelin plasma levels. Secondly, we studied the effect on interdigestive motility.
Methods:
Ten healthy female volunteers were recruited (33±4 y; 22±0.5 kg/m²). Placebo or QHCl (10 μmol/kg) was administered intragastrically through a nasogastric feeding tube after an overnight fast in a single-blind randomized fashion. Administration started 20 min after the first phase III of the migrating motor complex. The measurement continued for another 2 h after the administration. Blood samples were collected every 10 min with the baseline sample taken 10 min prior to administration.
Key results:
The increase in plasma levels of motilin (administration; P=.04) and total ghrelin (administration; P=.02) was significantly lower after QHCl. The fluctuation of octanoylated ghrelin was reduced after QHCl (time by administration; P=.03). Duodenal motility did not differ. The fluctuation of antral activity differed over time between placebo and QHCl (time by administration; P=.03).
Conclusions and inferences:
QHCl suppresses the increase of both motilin and ghrelin plasma levels. Moreover, QHCl reduced the fluctuation of antral motility. These findings confirm the potential of bitter taste receptors as targets for modifying interdigestive motility in man.
The sensory components of alcohol affect the onset of individual's drinking. Therefore, variations in taste receptor genes may lead to differential sensitivity for alcohol taste, which may modify an individual's drinking behavior. This study examined the influence of genetic variants in the taste-sensing mechanism on alcohol drinking behavior and the choice of alcoholic beverages. A total of 1829 Koreans were analyzed for their alcohol drinking status (drinker/non-drinker), total alcohol consumption (g/day), heavy drinking (≥30 g/day) and type of regularly consumed alcoholic beverages. Twenty-one genetic variations in bitterness, sweetness, umami and fatty acid sensing were also genotyped. Our findings suggested that multiple genetic variants modified individuals' alcohol drinking behavior. Genetic variations in the T2R bitterness receptor family were associated with overall drinking behavior. Subjects with the TAS2R38 AVI haplotype were less likely to be a drinker [odds ratio (OR): 0.75, 95% confidence interval (CI): 0.59-0.95], and TAS2R5 rs2227264 predicted the level of total alcohol consumption (p = 0.01). In contrast, the T1R sweet and umami receptor family was associated with heavy drinking. TAS1R3 rs307355 CT carriers were more likely to be heavy drinkers (OR: 1.53, 95% CI: 1.06-2.19). The genetic variants were also associated with the choice of alcoholic beverages. The homo-recessive type of TAS2R4 rs2233998 (OR: 1.62, 95% CI: 1.11-2.37) and TAS2R5 rs2227264 (OR: 1.72, 95% CI: 1.14-2.58) were associated with consumption of rice wine. However, TAS1R2 rs35874116 was associated with wine drinking (OR: 0.65, 95% CI: 0.43-0.98) and the consumption level (p = 0.04). These findings suggest that multiple genetic variations in taste receptors influence drinking behavior in Koreans. Genetic variations are also responsible for the preference of particular alcoholic beverages, which may contribute to an individual's alcohol drinking behavior.
Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.
Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.
Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 μmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.
Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.
Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intake. This trial was registered at clinicaltrials.gov as NCT02759926.
