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From the root barks of a Central African tree Millettia dubia De Wild. (Fabaceae), ten previously undescribed oleanane-type glycosides were isolated by various chromatographic protocols. Their structures were elucidated by spectroscopic methods, mainly 2D NMR experiments and mass spectrometry, as mono- and bidesmosidic glycosides of mesembryanthemoidigenic acid, hederagenin and oleanolic acid. The stimulation of the sweet taste receptor TAS1R2/TAS1R3 by these glycosides was evaluated, and structure/activity relationships were proposed. Two of them showed an agonist effect on TAS1R2/TAS1R3.
Assuntos
Glicosídeos , Ácido Oleanólico , Receptores Acoplados a Proteínas G , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Glicosídeos/química , Glicosídeos/farmacologia , Glicosídeos/isolamento & purificação , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Humanos , Millettia/química , Casca de Planta/química , Raízes de Plantas/químicaRESUMO
The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and TAS1R and TAS2R38 (TAS2Rs member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the TAS1R3 gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26-51.99) and shortness of breath (OR 4.83, 95% CI 1.71-17.32) in comparison with T/C carriers. Finally, no significant associations between the TAS2R38 haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed TAS1R3 gene involvement in determining COVID-19 symptom severity independently of TAS2R38 activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.
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BACKGROUND: Non-nutritive sweeteners (such as sucralose) bind to sweet receptors Tas1r2/Tas1r3 on intestinal endocrine L cells after diets to upregulate blood glucose. However, the mechanism by which sucralose regulates postprandial blood glucose (PBG) has not been clarified to date. We hypothesized that the gut sweet taste receptor was one of the targets for sucralose to regulate PBG. The aim of this study was to examine the effect of sucralose on PBG based on the gut sweet taste receptor signaling pathway and to explore the mechanism. Therefore, we examined PBG, genes, and proteins associated with the gut sweet receptor pathway in sucralose-exposed mice. RESULTS: The results showed that after 12 weeks of sucralose exposure the PBG of mice increased significantly, and the expression of intestinal sweet taste receptors increased correspondingly. Within the concentration range of this experiment, a significant increase of PBG was observed in mice fed on sucralose with a concentration equal to or higher than 0.33 g L-1 . CONCLUSION: Long-term consumption of sucralose may increase body weight and the risk of elevated PBG, resulting in overexpression of sweetness receptors and glucose transporters. The mechanism of these effects might be the result of non-nutritive sweeteners binding to sweetness receptors Tas1r2/Tas1r3 in gut endocrine cells and upregulating Slc5a1 and Slc2a2. But we cannot rule out that the rise in PBG is the result of a combination of sweet receptors and gut microbes. Therefore, the effect of gut microbes on PBG needs to be studied further. © 2023 Society of Chemical Industry.
Assuntos
Adoçantes não Calóricos , Sacarose/análogos & derivados , Paladar , Camundongos , Animais , Glicemia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Increased sugar intake and taste dysfunction have been reported in patients with inflammatory bowel disease (IBD), a chronic disorder characterized by diarrhea, pain, weight loss and fatigue. It was previously unknown whether taste function changes in mouse models of IBD. Mice consumed dextran sodium sulfate (DSS) during three 7-day cycles to induce chronic colitis. DSS-treated mice displayed signs of disease, including significant weight loss, diarrhea, loss of colon architecture, and inflammation of the colon. After the last DSS cycle we assessed taste function by recording electrophysiological responses from the chorda tympani (CT) nerve, which transmits activity from lingual taste buds to the brain. DSS treatment significantly reduced neural taste responses to natural and artificial sweeteners. Responses to carbohydrate, salt, sour or bitter tastants were unaffected in mice with colitis, but umami responses were modestly elevated. DSS treatment modulated the expression of receptor subunits that transduce sweet and umami stimuli in oral taste buds as a substrate for functional changes. Dysregulated systemic cytokine responses, or dysbiosis that occurs during chronic colitis may be upstream from changes in oral taste buds. We demonstrate for the first time that colitis alters taste input to the brain, which could exacerbate malnutrition in IBD patients.
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We have previously shown that l-glucose, the non-caloric enantiomer of d-glucose, activates the human sweet taste receptor T1R2/T1R3 transiently expressed in HEK293T cells. Here, we show that d- and l-glucose can also activate T1R2 and T1R3 expressed without the counterpart monomer. Serine mutation to alanine in residue 147 in the binding site of T1R3 VFT domain, completely abolishes T1R3S147A activation by either l- or d-glucose, while T1R2/T1R3S147A responds in the same way as T1R2 expressed without its counterpart. We further show that the original T1R2 reference sequence (NM_152232.1) is less sensitive by almost an order of magnitude than the reference sequence at the time this study was performed (NM_152232.4). We find that out of the four differing positions, it is the R317G in the VFT domain of T1R2, that is responsible for this effect in vitro. It is significant for both practical assay sensitivity and because glycine is found in this position in ~20% of the world population. While the effects of the mutations and the partial transfections were similar for d and l enantiomers, their dose-response curves remained distinct, with l-glucose reaching an early plateau.
Assuntos
Glucose , Paladar , Humanos , Glucose/farmacologia , Glucose/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células HEK293 , Sítios de LigaçãoRESUMO
This study aims to investigate whether the trajectory of dental caries in the life course is associated with rs307355 (TAS1R3) and rs35874116 (TAS1R2) and if there is an epistatic association between rs307355 (TAS1R3) and rs35874116 (TAS1R2). A representative sample of all 5,914 births from the 1982 Pelotas birth cohort was prospectively investigated, and the decayed, missing, and filled teeth (DMF-T) components were assessed at ages 15 (n = 888), 24 (n = 720), and 31 (n = 539) y. Group-based trajectory modeling was used to identify groups with similar trajectories of DMF-T components in the life course. Genetic material was collected, and rs307355 (TAS1R3) and rs35874116 (TAS1R2) were genotyped. Ethnicity was evaluated using ADMIXTURE. Generalized multifactor dimensionality reduction software was used to investigate epistatic interactions. Considering rs307355 (TAS1R3) in the additive effect, the genotype TT was associated with the high decayed trajectory group (odds ratio [OR] = 4.52; 95% confidence interval [CI], 1.15-17.74) and the high missing trajectory group (OR = 3.35; 95% CI, 1.09-10.26). In the dominant effect, the genotype CT/TT was associated with the high decayed trajectory group (OR = 1.64; 95% CI, 1.14-2.35). Allele T was associated with an increased odds of 64% (OR = 1.64; 95% CI, 1.20-2.25) for the decayed component and 41% (OR = 1.41; 95% CI, 1.04-1.92) for the missing component. No associations were observed between rs307355 (TAS1R3) and the filled component. rs35874116 (TAS1R2) was not associated with DMF-T components. Positive epistatic interactions were observed involving rs307355 (TAS1R3) and rs35874116 (TAS1R2) with the decayed component (OR = 1.72; 95% CI, 1.04-2.84). Thus, rs307355 (TAS1R3) genotypes and alleles seem positively associated with the trajectory of decayed and missing components in the life course. Epistatic interaction between rs307355 and rs35874116 may increase the decayed caries trajectory.
Assuntos
Cárie Dentária , Paladar , Humanos , Adolescente , Paladar/genética , Suscetibilidade à Cárie Dentária/genética , Cárie Dentária/genética , Acontecimentos que Mudam a Vida , GenótipoRESUMO
The phytochemical study of Wisteria sinensis (Sims) DC. (Fabaceae), commonly known as the Chinese Wisteria, led to the isolation of seven oleanane-type glycosides from an aqueous-ethanolic extract of the roots. Among the seven isolated saponins, two have never been reported before: 3-O-α-L-rhamnopyranosyl-(1â2)-ß-D-glucopyranosyl-(1â2)-ß-D-glucuronopyranosyl-22-O-acetylolean-12-ene-3ß,16ß,22ß,30-tetrol, and 3-O-ß-D-xylopyranosyl-(1â2)-ß-D-glucuronopyranosylwistariasapogenol A. Based on the close structures between the saponins from W. sinensis, and the glycyrrhizin from licorice, the stimulation of the sweet taste receptor TAS1R2/TAS1R3 by these glycosides was evaluated.
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Saponinas , Wisteria , Glicosídeos/farmacologia , Glicosídeos/química , Paladar , Saponinas/químicaRESUMO
Individual differences in sweet taste sensitivity can affect dietary preferences as well as nutritional status. Despite the lack of consensus, it is believed that sweet taste is impacted by genetic and environmental variables. Here we determined the effect of well-established factors influencing the general taste variability, such as gender and fungiform papillae density, specific genetic variants (SNPs of TAS1R2 and TAS1R3 receptors genes), and non-specific genetic factors (PROP phenotype and genotype), on the threshold and suprathreshold sweet taste sensitivity. Suprathreshold measurements showed that the sweet taste response increased in a dose-dependent manner, and this was related to PROP phenotype, gender, rs35874116 SNP in the TAS1R2 gene, and rs307355 SNP in the TAS1R3 gene. The threshold values and density of fungiform papillae exhibited a strong correlation, and both varied according to PROP phenotype. Our data confirm the role of PROP taste status in the sweet perception related to fungiform papilla density, show a higher sweet sensitivity in females who had lower BMI than males, and demonstrate for the first time the involvement of the rs35874116 SNP of TAS1R2 in the sweet taste sensitivity of normal weight subjects with body mass index (BMI) ranging from 20.2 to 24.8 kg/m2. These results may have an important impact on nutrition and health mostly in subjects with low taste ability for sweets and thus with high vulnerability to developing obesity or metabolic disease.
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Papilas Gustativas , Paladar , Masculino , Feminino , Animais , Paladar/fisiologia , Polimorfismo de Nucleotídeo Único , Papilas Gustativas/fisiologia , Percepção Gustatória/genética , GenótipoRESUMO
The Ile191Val variant of the TAS1R2 gene of sweet taste receptors causes a partial loss-of-function and is associated with reduced glucose excursions in a healthy lean cohort. However, it is unclear whether this polymorphism contributes to the regulation of glucose homeostasis in metabolically unhealthy individuals. Thus, we used participants with variable glycemic profiles and obesity to assess the effects of the TAS1R2-Ile191Val variant. We found that the Val minor allele carriers had lower HbA1c at all levels of fasting glucose and glucose tolerance. These effects were not due to differences in beta-cell function or insulin sensitivity assessed with a frequently sampled intravenous glucose tolerance test. This study extends our previous findings and provides further evidence that sweet taste receptor function may contribute to glucose regulation in humans.
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The detection of energy-rich sweet food items has been important for our survival during evolution, however, in light of the changing lifestyles in industrialized and developing countries our natural sweet preference is causing considerable problems. Hence, it is even more important to understand how our sense of sweetness works, and perhaps even, how we may deceive it for our own benefit. This chapter summarizes current knowledge about sweet tastants and sweet taste modulators on the compound side as well as insights into the structure and function of the sweet taste receptor and the transduction of sweet signals. Moreover, methods to assess the activity of sweet substances in vivo and in vitro are compared and discussed.
Assuntos
Receptores Acoplados a Proteínas G , Paladar , Humanos , Receptores Acoplados a Proteínas G/químicaRESUMO
Four oleanane-type glycosides were isolated from a horticultural cultivar "Green Elf" of the endemic Pittosporum tenuifolium (Pittosporaceae) from New Zealand: three acylated barringtogenol C glycosides from the leaves, with two previously undescribed 3-O-ß-d-glucopyranosyl-(1â2)-[α-l-arabinopyranosyl-(1â3)]-ß-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, 3-O-ß-d-galactopyranosyl-(1â2)-[α-l-arabinopyranosyl-(1â3)]-ß-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, and the known 3-O-ß-d-glucopyranosyl-(1â2)-[α-l-arabinopyranosyl-(1â3)]-ß-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C (Eryngioside L). From the roots, the known 3-O-ß-d-glucopyranosyl-(1â2)-ß-d-galactopyranosyl-(1â2)-ß-d-glucuronopyranosyloleanolic acid (Sandrosaponin X) was identified. Their structures were elucidated by spectroscopic methods including 1D- and 2D-NMR experiments and mass spectrometry (ESI-MS). According to their structural similarities with gymnemic acids, the inhibitory activities on the sweet taste TAS1R2/TAS1R3 receptor of an aqueous ethanolic extract of the leaves and roots, a crude saponin mixture, 3-O-ß-d-glucopyranosyl-(1â2)-[α-l-arabinopyranosyl-(1â3)]-ß-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, and Eryngioside L were evaluated.
Assuntos
Rosales/química , Saponinas/isolamento & purificação , Triterpenos/isolamento & purificação , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/antagonistas & inibidores , Células HEK293 , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Nova Zelândia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Folhas de Planta/química , Raízes de Plantas/química , Plantas Medicinais/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Saponinas/química , Saponinas/farmacologia , Espectrometria de Massas por Ionização por Electrospray , Triterpenos/química , Triterpenos/farmacologiaRESUMO
It has recently been shown that taste receptors, in addition to being present in the oral cavity, exist in various extra-oral organs and tissues such as the thyroid, lungs, skin, stomach, intestines, and pancreas. Although their physiological function is not yet fully understood, it appears that they can help regulate the body's homeostasis and provide an additional defense function against pathogens. Since the vast majority of drugs are bitter, the greatest pharmacological interest is in the bitter taste receptors. In this review, we describe how bitter taste 2 receptors (TAS2Rs) induce bronchodilation and mucociliary clearance in the airways, muscle relaxation in various tissues, inhibition of thyroid stimulating hormone (TSH) in thyrocytes, and release of glucagon-like peptide-1 (GLP-1) and ghrelin in the digestive system. In fact, substances such as dextromethorphan, chloroquine, methimazole and probably glimepiride, being agonists of TAS2Rs, lead to these effects. TAS2Rs and taste 1 receptors (TAS1R2/3) are G protein-coupled receptors (GPCR). TAS1R2/3 are responsible for sweet taste perception and may induce GLP-1 release and insulin secretion. Umami taste receptors, belonging to the same superfamily of receptors, perform a similar function with regard to insulin. The sour and salty taste receptors work in a similar way, both being channel receptors sensitive to amiloride. Finally, gene-protein coupled receptor 40 (GPR40) and GPR120 for fatty taste perception are also protein-coupled receptors and may induce GLP-1 secretion and insulin release, similar to those of other receptors belonging to the same superfamily.
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Receptores Acoplados a Proteínas G/metabolismo , Animais , Mucosa Gástrica/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Pulmão/metabolismo , Pâncreas/metabolismo , Pele/metabolismo , Papilas Gustativas/metabolismo , Percepção Gustatória/fisiologia , Glândula Tireoide/metabolismoRESUMO
OBJECTIVE: Sweet taste receptors (STR) are expressed in the gut and other extra-oral tissues, suggesting that STR-mediated nutrient sensing may contribute to human physiology beyond taste. A common variant (Ile191Val) in the TAS1R2 gene of STR is associated with nutritional and metabolic outcomes independent of changes in taste perception. It is unclear whether this polymorphism directly alters STR function and how it may contribute to metabolic regulation. METHODS: We implemented a combination of in vitro biochemical approaches to decipher the effects of TAS1R2 polymorphism on STR function. Then, as proof-of-concept, we assessed its effects on glucose homeostasis in apparently healthy lean participants. RESULTS: The Ile191Val variant causes a partial loss of function of TAS1R2 through reduced receptor availability in the plasma membrane. Val minor allele carriers have reduced glucose excursions during an OGTT, mirroring effects previously seen in mice with genetic loss of function of TAS1R2. These effects were not due to differences in beta-cell function or insulin sensitivity. CONCLUSIONS: Our pilot studies on a common TAS1R2 polymorphism suggest that STR sensory function in peripheral tissues, such as the intestine, may contribute to the regulation of metabolic control in humans.
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Glucose/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Paladar/genética , Adulto , Feminino , Células HEK293 , Humanos , MasculinoRESUMO
Asperuloside is an iridoid glycoside found in many medicinal plants that has produced promising anti-obesity results in animal models. In previous studies, three months of asperuloside administration reduced food intake, body weight, and adipose masses in rats consuming a high fat diet (HFD). However, the mechanisms by which asperuloside exerts its anti-obesity properties were not clarified. Here, we investigated homeostatic and nutrient-sensing mechanisms regulating food intake in mice consuming HFD. We confirmed the anti-obesity properties of asperuloside and, importantly, we identified some mechanisms that could be responsible for its therapeutic effect. Asperuloside reduced body weight and food intake in mice consuming HFD by 10.5 and 12.8% respectively, with no effect on mice eating a standard chow diet. Fasting glucose and plasma insulin were also significantly reduced. Mechanistically, asperuloside significantly reduced hypothalamic mRNA ghrelin, leptin, and pro-opiomelanocortin in mice consuming HFD. The expression of fat lingual receptors (CD36, FFAR1-4), CB1R and sweet lingual receptors (TAS1R2-3) was increased almost 2-fold by the administration of asperuloside. Our findings suggest that asperuloside might exert its therapeutic effects by altering nutrient-sensing receptors in the oral cavity as well as hypothalamic receptors involved in food intake when mice are exposed to obesogenic diets. This signaling pathway is known to influence the subtle hypothalamic equilibrium between energy homeostasis and reward-induced overeating responses. The present pre-clinical study demonstrated that targeting the gustatory system through asperuloside administration could represent a promising and effective new anti-obesity strategy.
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Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Monoterpenos Ciclopentânicos/farmacologia , Glucosídeos/farmacologia , Piranos/farmacologia , Percepção Gustatória/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos , Animais , Glicemia , Dieta Hiperlipídica , Ingestão de Energia/efeitos dos fármacos , Grelina/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Insulina/sangue , Leptina/metabolismo , Masculino , Camundongos , Pró-Opiomelanocortina/metabolismoRESUMO
Taste receptor type 1, member 2 (TAS1R2) controls the oral sensing of sweetness. Genetic variations in TAS1R2 have been shown to be associated with differential sweetness intensity and varying carbohydrate intake levels among individuals. This study examined whether rs7534618 A > C in TAS1R2 is associated with dietary behavior and energy nutrient intake in Korean females. A cross-sectional design utilizing data from the Multi-Rural Communities Cohort Study, which was a nationwide epidemiological research project in Korea, was applied in this study. In total, 2198 females were analyzed to evaluate the differences in macronutrient intake levels and intake of carbohydrate-rich and sweet-tasting foods between the rs7534618 genotypes. The findings suggest that individuals with the CC minor genotype tended to have lower carbohydrate but higher fat intake than subjects with the A* genotype (p = 0.035 and p = 0.042, respectively). Subjects with the CC genotype also exhibited less intake of total grains but greater intake of bread than those with the A* genotype (p = 0.017 and p = 0.006, respectively). However, these observed associations were statistically modest (false discovery rate adjusted p > 0.05). In conclusion, TAS1R2 rs7534618 is not a decisive genetic modifier of nutrition and dietary intake in Korean females. However, given the paucity of studies, these putative associations between the TAS1R variation and dietary intake may be referred for further sensory genetic studies in Koreans.
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Receptores Acoplados a Proteínas G , Paladar , Estudos de Coortes , Estudos Transversais , Ingestão de Alimentos , Feminino , Variação Genética , Humanos , Receptores Acoplados a Proteínas G/genética , República da Coreia , Paladar/genéticaRESUMO
The class C G protein-coupled sweet taste receptor (STR) is responsible for the perception of sweet-tasting molecules. Considered an obligate heterodimer, it consists of taste 1 receptor 2 and taste 1 receptor 3 subunits. Interest in the STR has steadily grown, especially since its discovery in extraoral tissues hints at a metabolic role for the receptor. It is now known that many pharmacologically exploitable binding sites exist across the extracellular and transmembrane regions of both subunits of the STR, indicative of its potential amenability to pharmacotherapeutic modulation. In this review, we briefly describe the structural characteristics and functional relevance of the STR. Then, from a molecular pharmacology perspective, we dissect the research surrounding the regulation of STR surface expression and signal transduction, in both oral and extraoral tissues, and discuss the potential for the exploitation of biased agonists for the STR. We find that despite 20 years of research into the STR, the target remains frustratingly enigmatic. Not only are the mechanisms controlling and regulating the surface expression of the STR unclear, but also research into the full repertoire of signaling partners of the STR is at present inconclusive. Critically, the influence of receptor polymorphisms (including those associated with sugar consumption) on the molecular pharmacology of the receptor remains hitherto unexplored. Finally, we provide recommendations on the reporting of reference sequence identification numbers to avoid incorrect attribution of wild-type to these biologically significant polymorphisms, which we argue may have led to some of the inconsistencies in the field.
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Metabolismo dos Carboidratos/genética , Receptores Acoplados a Proteínas G/genética , Paladar/genética , Sítios de Ligação/genética , Dimerização , Regulação da Expressão Gênica/genética , Humanos , Ligação Proteica/genética , Domínios Proteicos/genética , Transdução de Sinais/genética , Paladar/fisiologiaRESUMO
Sweet substances are detected by taste-bud cells upon binding to the sweet-taste receptor, a T1R2/T1R3 heterodimeric G protein-coupled receptor. In addition, experiments with mouse models lacking the sweet-taste receptor or its downstream signaling components led to the proposal of a parallel "alternative pathway" that may serve as metabolic sensor and energy regulator. Indeed, these mice showed residual nerve responses and behavioral attraction to sugars and oligosaccharides but not to artificial sweeteners. In analogy to pancreatic ß cells, such alternative mechanism, to sense glucose in sweet-sensitive taste cells, might involve glucose transporters and KATP channels. Their activation may induce depolarization-dependent Ca2+ signals and release of GLP-1, which binds to its receptors on intragemmal nerve fibers. Via unknown neuronal and/or endocrine mechanisms, this pathway may contribute to both, behavioral attraction and/or induction of cephalic-phase insulin release upon oral sweet stimulation. Here, we critically review the evidence for a parallel sweet-sensitive pathway, involved signaling mechanisms, neural processing, interactions with endocrine hormonal mechanisms, and its sensitivity to different stimuli. Finally, we propose its physiological role in detecting the energy content of food and preparing for digestion.
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Papilas Gustativas/metabolismo , Paladar , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Edulcorantes/metabolismo , Papilas Gustativas/fisiologia , Percepção GustatóriaRESUMO
The taste receptor type I (Tas1R) family consists of three G protein-coupled receptors (T1R1, T1R2, and T1R3) that form heterodimers recognizing sweet compounds (T1R2/T1R3) or amino acids (T1R1/T1R3). These receptors are nutrient sensors that facilitate appropriate physiological responses with nutrient availability. However, their contribution to the development of pathologies associated with overnutrition (e.g., atherosclerosis) is unclear. The aim of the present study was to determine if T1R3 deletion would reduce atherosclerotic plaque development in mice. We generated atherosclerotic mice with whole-body deletion of T1R3 by crossing T1R3-/- mice with ApoE-/- mice. T1R3+/+ ApoE-/- and T1R3-/- ApoE-/- mice were maintained on an atherogenic high-fat diet for 8 weeks. Weight gain and food consumption were measured during the 8-week diet. Atherosclerotic lesion development and size were assessed by en face analysis of intact aortas and microscopic analysis of aortic roots. Our results indicate that T1R3 deletion in male and female ApoE-/- mice reduces aortic atherosclerotic plaque accumulation. Hepatic triglyceride accumulation, which was measured by quantification of oil red O staining, was also reduced in T1R3-/- mice. While the ablation of T1R3 reduced the final body weight of both males and females by approximately 12%, serum lipids, insulin, and glucose were either unchanged or slightly reduced. Immunoblot analysis of the phosphorylation of p70S6K, an effector of mTORC1, suggests T1R3 ablation reduces mTORC1 activity by approximately 50% in the male livers. Collectively, these findings suggest that the whole-body deletion of T1R3 reduces atherosclerosis and hepatic steatosis in a manner largely independent of the measured effects on whole-body glucose and lipid homeostasis.
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Aterosclerose/metabolismo , Fígado Gorduroso/metabolismo , Placa Aterosclerótica , Receptores Acoplados a Proteínas G/fisiologia , Animais , Feminino , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Triglicerídeos/metabolismoRESUMO
Human sweet taste receptor (hSTR) recognizes a wide array of sweeteners, resulting in sweet taste perception. Maltitol and lactitol have been extensively used in place of sucrose due to their capability to prevent dental caries. Herein, several molecular modeling approaches were applied to investigate the structural and energetic properties of these two polyols/hSTR complexes. Triplicate 500 ns molecular dynamics (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA)-based free energy calculations revealed that the TAS1R2 monomer is the preferential binding site for maltitol and lactitol rather than the TAS1R3 region. Several polar residues (D142, S144, Y215, D278, E302, R383, and especially N143) were involved in polyols binding through electrostatic attractions and H-bond formations. The molecular complexation process not only induced the stable form of ligands but also stimulated the conformational adaptation of the TAS1R2 monomer to become a close-packed structure through an induced-fit mechanism. Notably, the binding affinity of the maltitol/TAS1R2 complex (ΔGbind of -17.93 ± 1.49 kcal/mol) was significantly higher than that of the lactitol/TAS1R2 system (-8.53 ± 1.78 kcal/mol), in line with the experimental relative sweetness. These findings provide an in-depth understanding of the differences in the sweetness response between maltitol and lactitol, which could be helpful to design novel polyol derivatives with higher sweet taste perception.
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Maltose/análogos & derivados , Receptores Acoplados a Proteínas G/metabolismo , Álcoois Açúcares/metabolismo , Motivos de Aminoácidos , Sítios de Ligação , Humanos , Cinética , Maltose/química , Maltose/metabolismo , Ligação Proteica , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Álcoois Açúcares/químicaRESUMO
Sweet taste is a cue for calorie-rich food and is innately attractive to animals, including humans. In the context of modern diets, attraction to sweetness presents a significant challenge to human health. Most known sugars and sweeteners bind to the Venus Fly Trap domain of T1R2 subunit of the sweet taste heterodimer. Because the sweet taste receptor structure has not been experimentally solved yet, a possible approach to finding sweet molecules is virtual screening using compatibility of candidate molecules to homology models of sugar-binding site. Here, the constructed structural models, docking and scoring schemes were validated by their ability to rank known sweet-tasting compounds higher than properties-matched random molecules. The best performing models were next used in virtual screening, retrieving recently patented sweeteners and providing novel predictions.