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Indian Institute of Technology Jodhpur
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Washoku
Collaboration with J. Alfredo Martinez from University of Navarra, Spain
Nutrition sensing in the brain
The goal of this project is to clarify the brain network related to the processing of information of ingested nutrients.
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Hypertensive patients who adopt a sodium-restricted diet have difficulty maintaining this change, and this could increase stress. On the other hand, soup rich in umami substances (dashi) was reported to reduce indexes of anxiety and stress. The objective of this study was to measure mood and physiological stress indexes during administration of a sodium-restricted diet with and without an umami substance (free L-glutamate) by a cross-over randomized, single-blind, placebo-controlled trial in Japanese female university students. The baseline was measured for 5 days followed by a sodium-restricted diet intervention phase that lasted for 10 days. The Profile of Mood States questionnaire was administered, a stress marker in saliva (chromogranin-A) was measured, and the amount of sodium intake was confirmed from 24 h urine collection samples. Results showed that the sodium reduction was verified by 24 h urine excretion. The percentage of change in the stress marker from the baseline showed that the stress level in group without the umami substance was significantly higher than that in the group with the umami substance (p = 0.013) after receiving a sodium-reduced diet for 6 or more days, indicating that stress was alleviated. This study suggested that umami substances might help to ameliorate stress during a sodium-reduced diet, especially in the initial phase.
Background Evidence has demonstrated that excess salt intake is associated with the development of several non-communicable diseases. Therefore, reformulating the sodium content of foods is an important global public health effort to achieve salt reduction and improve health. This study aimed to model sodium replacement with 'umami' substances and estimate the possible reduction effects of the umami substances on the daily salt intake among Japanese adults. The umami substances considered in this study include glutamate or monosodium glutamates (MSG), calcium diglutamate (CDG), inosinate, and guanilate.MethodsA sample of 21,805 participants aged 57.8 years on average from the National Health and Nutrition Survey (NHNS) were used in the analysis. First, we employed a multivariable linear regression approach, with overall salt intake (g/day) as a dependent variable, adjusting for intake (g/day) from food items and other covariates, to estimate the contributions of each food item to daily salt intake. We then considered three hypothetical scenarios with varying market share percentages of umami substitute foods (30%, 60%, and 100%). We estimated the population-level salt reduction for each scenario, by age and gender, based on the contribution of each food to salt intake estimated by the regression model and the estimated salt reduction rates by food item based on an extensive literature review. Under the 100% scenario, the achievement rates for national and global dietary goals of salt intake in the Japanese population were also calculated.ResultsWithout compromising the taste, the universal incorporation of umami substances can reduce the salt intake of adult Japanese persons by 12.0-21.1% in the population level, which is equivalent to 1.27-2.22g of salt reduction. A mean daily salt intake before and after scenario in universal umami substance’s incorporation changes from 9.95g to 7.73g for the total population, from 10.83g to 8.40g for men and from 9.21g to 7.17g for women, respectively. Approximately 60% of Japanese adults could achieve the national dietary goal of 8g/day, while only 7.6% could meet the global target of 5.0g/day. Conclusions Our study provides essential information on the potential salt reduction from sodium replacement with alternatives. The universal incorporation of umami substances into some foods could achieve the national dietary goals for the Japanese. However, the reduced salt intake level still falls short of the global dietary recommendation of 5g of salt daily.
Background Low vegetable intake is one of the key dietary risk factors known to be associated with a range of health problems, including cardiovascular diseases (CVDs), cancer, and diabetes and kidney diseases (DKDs). Using data from Japan’s National Health and Nutrition Surveys and the Global Burden of Diseases study in 2017, this study aimed to forecast the impact of change in vegetable intake on disability-adjusted life years (DALYs) between 2017 and 2040 for three diseases. Methods We generated a three-component model of cause-specific DALYs, including changes in major behavioural and metabolic risk predictors, the socio-demographic index and an autoregressive integrated moving average model to project future DALY rates for 2017–2040 using the data between 1990 and 2016. Data on Vegetable consumption and risk predictors, and DALY rate were obtained from Japan’s National Health and Nutrition Surveys and the Global Burden of Diseases Study in 2017. We also modelled three scenarios of better, moderate and worse cases to evaluate the impact of change in vegetable consumption on the DALY rates for three diseases (CVDs, cancer, and DKDs). Results Projected mean vegetable intake in the total population showed a decreasing trend through 2040 to 237.7 g/day. A significant difference between the reference scenario and the better case scenario was observed with un-overlapped 95% prediction intervals of DALY rates in females aged 20–49 years (− 8.0%) for CVDs, the total population for cancer (− 5.6%), and in males (− 8.2%) and females (− 13.7%) for DKDs. Conclusions Our analysis indicates that increased vegetable consumption would have a significant reduction in the burdens of CVDs, cancer and DKDs in Japan. By estimating the disease burden attributable to low vegetable intake under different scenarios of future vegetable consumption, our study can inform the design of targeted interventions for public health challenges.
Background: Low vegetable intake is one of the key dietary risk factors known to be associated with a range of health problems, including cardiovascular diseases (CVDs), cancer, and diabetes and kidney diseases (DKDs). Using data from Japan's National Health and Nutrition Surveys and the Global Burden of Diseases study in 2017, this study aimed to forecast the impact of change in vegetable intake on disability-adjusted life years (DALYs) between 2017 and 2040 for three diseases. Methods: We generated a three-component model of cause-specific DALYs, including changes in major behavioural and metabolic risk predictors, the socio-demographic index and an autoregressive integrated moving average model to project future DALY rates for 2017-2040 using the data between 1990 and 2016. Data on Vegetable consumption and risk predictors, and DALY rate were obtained from Japan’s National Health and Nutrition Surveys and the Global Burden of Diseases Study in 2017. We also modelled three scenarios of better, moderate and worse cases to evaluate the impact of change in vegetable consumption on the DALY rates for three diseases (CVDs, cancer, and DKDs). Results: Projected mean vegetable intake in the total population showed a decreasing trend through 2040 to 237.7g/day. A significant difference between the reference scenario and the better case scenario was observed with un-overlapped 95% prediction intervals of DALY rates in females aged 20-49 years (-8.0%) for CVDs, the total population for cancer (-5.6%), and in males (-8.2%) and females (-13.7%) for DKDs. Conclusions: Our analysis indicates that increased vegetable consumption would have a significant reduction in the burdens of CVDs, cancer and DKDs in Japan. By estimating the disease burden attributable to low vegetable intake under different scenarios of future vegetable consumption, our study can inform the design of targeted interventions for public health challenges.
Objective This study aimed to predict disability-adjusted life years (DALYs) rate in Japan through 2040 with plausible future scenarios of fruit intake for neoplasms, cardiovascular diseases (CVDs), and diabetes and kidney diseases (DKDs). Design Data from National Health and Nutrition Surveys and the Global Burden of Diseases study in 2017 were used. We developed an autoregressive integrated moving average model with four future scenarios. Reference scenario maintains the current trend. Best scenario assumes that the goal defined in Health Japan 21 is achieved in 2023 and is kept constant afterwards. Moderate scenario assumes the goal is achieved in 2040. Constant scenario applies the same proportion of 2016 for the period between 2017-2040. Setting DALYs rates in Japan were predicted for the period between 2017-2040. Participants Human subjects were not utilized. Results In our reference forecast, the DALYs rates in all-ages group were projected to be stable for CVDs and continue increasing for neoplasms and DKDs. Age-group-specific DALYs rates for these three disease groups were forecasted to decrease, with some exceptions. Among men aged 20–49, DALYs attributable to CVDs differed substantially between the scenarios, implying that there is a significant potential for reducing the burden of CVDs by increasing fruit intake at the population level. Conclusions Our scenario analysis shows that higher fruit intake is associated with lower disease burden in Japan. Further research is required to assess which policies and interventions can be used to achieve an increase in fruit intake as modelled in the scenarios of this study.
Background In Japan, a high-sodium diet is the most important dietary risk factor and is known to cause a range of health problems. This study aimed to forecast Japan’s disability-adjusted life year (DALYs) for chronic diseases that would be associated with high-sodium diet in different future scenarios of salt intake. We modelled DALY forecast and alternative future scenarios of salt intake for cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and stomach cancer (SC) from 2017 to 2040. Methods We developed a three-component model of disease-specific DALYs: a component on the changes in major behavioural and metabolic risk predictors including salt intake; a component on the income per person, educational attainment, and total fertility rate under 25 years; and an autoregressive integrated moving average model to capture the unexplained component correlated over time. Data on risk predictors were obtained from Japan’s National Health and Nutrition Surveys and from the Global Burden of Disease Study 2017. To generate a reference forecast of disease-specific DALY rates for 2017–2040, we modelled the three diseases using the data for 1990–2016. Additionally, we generated better, moderate, and worse scenarios to evaluate the impact of change in salt intake on the DALY rate for the diseases. Results In our reference forecast, the DALY rates across all ages were predicted to be stable for CVDs, continuously increasing for CKDs, and continuously decreasing for SC. Meanwhile, the age group-specific DALY rates for these three diseases were forecasted to decrease, with some exceptions. Except for the ≥70 age group, there were remarkable differences in DALY rates between scenarios, with the best scenario having the lowest DALY rates in 2040 for SC. This represents a wide scope of future trajectories by 2040 with a potential for tremendous decrease in SC burden. Conclusions The gap between scenarios provides some quantification of the range of policy impacts on future trajectories of salt intake. Even though we do not yet know the policy mix used to achieve these scenarios, the result that there can be differences between scenarios means that policies today can have a significant impact on the future DALYs.
Objective The Japanese government has developed and promoted a national nutrient-based dietary guideline for preventing lifestyle-related chronic disease. However, its impact in a real-life setting has never been evaluated. We performed a critical appraisal of the guideline by examining the association between adherence to the guideline and lifestyle-related outcome indicators. Methods This is a retrospective observational cross-sectional study using nationally representative data on health and nutrition characteristics from the 2016 National Health and Nutrition Survey of Japan. We considered 3,861 participants aged ≥20 years, with evidence of low health risks of diabetes, hypertension, hyperlipidemia, and obesity. Five health outcome indicators (hemoglobin A1c (HbA1c), systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, and body mass index), were employed. A summary score was developed to reflect adherence to the recommended intake of seven nutrients defined by the guideline, including proteins, fat, saturated fatty acid, carbohydrate, dietary fiber, sodium, and potassium. Multivariate quartile regression approaches were employed to examine the association between the adherence score and the health outcome indicators, adjusting for the covariates. Results Overall, the proportion of those who adhered to the guideline (adherence rate) for all seven nutrients was only 0.3%. There was considerable variation in the adherence rate between the different nutrients, from 24.2% to 61.8%. After adjustment for covariates, in most health outcome indicators, regardless of age category and quartile, there was no clear association between the guideline adherence score and indicators. Conclusions There is plenty of scope for improving the guideline. Nutrient impact on health may not necessarily depend on the amount of each nutrient in the diet. The significance and contribution of synergies between nutrients and complex interactions within foods to health outcomes need to be explored in future guideline updates.
As incomes steadily increase globally, traditional diets have been displaced by diets that are usually animal-based with a high content of "empty calories" or refined sugars, refined fats, and alcohol. Dietary transition coupled with the expansion of urbanization and lower physical activity have been linked to the global growth in the prevalence of obesity, overweight and life style-related non-communicable diseases. The challenge is in how to reverse the trend of high consumption of less healthy food by more healthful and more environmentally sustainable diets. The increasing recognition that each individual has specific needs depending on age, metabolic condition, and genetic profile adds complexity to general nutritional considerations. If we were to promote the consumption of low-energy and low salt but nutritious diets, taste becomes a relevant food quality. The Japanese traditional diet (Washoku), which is characterized by high consumption of fish and soybean products and low consumption of animal fat and meat, relies on the effective use of umami taste to enhance palatability. There may be a link between Washoku and the longevity of the people in Japan. Thus Washoku and umami may be valuable tools to support healthy eating.
Eating behavior is an important factor that can affect human nutrition status both under- and overnutrition. Human eating behavior is influenced by physiological and psychological inputs. Maslow’s Motivation Theory that consists of five stages can be used to explain human eating behavior due to the physiological and psychological effects. Physiologically, basic senses in the gustatory system and visceral sense in the gastrointestinal system signal to different parts of brain to function on hunger, satiety, food memory, and palatability, which mainly involves human survival and safety. In more developed societies, psychological inputs from social norm, status, and recognition can be equally or even more influential to human eating behavior than the physiological ones. In order to solve the nutrition problems, several researches were performed in humans and animals on foods and food ingredients as well as their physiological and psychological mechanisms. Foods containing natural or added umami tastant were found to have effect on food palatability and satiety via the sensations from mouth and viscera. Therefore, umami tastant should be beneficial in solving both ends of nutrition problems. The decayed gustatory system of elderly people can be aroused by umami tastant, which consequently increases their appetite. Umami tastant can physiologically signal for satiety, which is useful for controlling caloric intake. Sodium content can be reduced by 35% at the same salty taste by mixing low-concentrated sodium chloride solution with umami tastant, MSG. Washoku is an ideal menu due to its low calorie and rich in umami tastant.
Currently, several types of amino acids are being produced and used worldwide. Nevertheless, several new functions of amino acids have been recently discovered that could result in other applications. For example, oral stimulation by glutamate triggers the cephalic phase response to prepare for food digestion. Further, the stomach and intestines have specific glutamate-recognizing systems in their epithelial mucosa. Regarding clinical applications, addition of monosodium glutamate to the medicinal diet has been shown to markedly enhance gastric secretion in a vagus-dependent manner. Branched-chain amino acids (BCAAs) are the major components of muscles, and ingestion of BCAAs has been found to be effective for decreasing muscle pain. BCAAs are expected to be a solution for the serious issue of aging. Further, ingestion of specific amino acids could be beneficial. Glycine can be ingested for good night's sleep: glycine ingestion before bedtime significantly improved subjective sleep quality. Ingestion of alanine and glutamine effectively accelerates alcohol metabolism, and ingestion of cystine and theanine effectively prevents colds. Finally, amino acids could be used in a novel clinical diagnostic method: the balance of amino acids in the blood could be an indicator of the risk of diseases such as cancer. These newly discovered functions of amino acids are expected to contribute to the resolution of various issues.
Activation of purinergic receptors in the spinal cord by extracellular ATP is essential for neuropathic hypersensitivity after peripheral nerve injury (PNI). However, the cell type responsible for releasing ATP within the spinal cord after PNI is unknown. Here we show that PNI increases expression of vesicular nucleotide transporter (VNUT) in the spinal cord. Extracellular ATP content ([ATP]e) within the spinal cord was increased after PNI, and this increase was suppressed by exocytotic inhibitors. Mice lacking VNUT did not show PNI-induced increase in [ATP]e and had attenuated hypersensitivity. These phenotypes were recapitulated in mice with specific deletion of VNUT in spinal dorsal horn (SDH) neurons, but not in mice lacking VNUT in primary sensory neurons, microglia or astrocytes. Conversely, ectopic VNUT expression in SDH neurons of VNUT-deficient mice restored PNI-induced increase in [ATP]e and pain. Thus, VNUT is necessary for exocytotic ATP release from SDH neurons which contributes to neuropathic pain.
The bladder urothelium is more than just a barrier. When the bladder is distended, the urothelium functions as a sensor to initiate the voiding reflex, during which it releases ATP via multiple mechanisms. However, the mechanisms underlying this ATP release in response to the various stretch stimuli caused by bladder filling remain largely unknown. Therefore, the aim of this study was to elucidate these mechanisms. By comparing vesicular nucleotide transporter (VNUT)-deficient and wild-type male mice, we showed that ATP has a crucial role in urine storage through exocytosis via a VNUT-dependent mechanism. VNUT was abundantly expressed in the bladder urothelium, and when the urothelium was weakly stimulated (i.e. in the early filling stages), it released ATP by exocytosis. VNUT-deficient mice showed reduced bladder compliance from the early storage phase and displayed frequent urination in inappropriate places without a change in voiding function. We conclude that urothelial, VNUT-dependent ATP exocytosis is involved in urine storage mechanisms that promote the relaxation of the bladder during the early stages of filling.
Conditioned taste aversion (CTA) is a well-established learning paradigm, whereby animals associate tastes with subsequent visceral illness. The prelimbic cortex (PL) has been shown to be involved in the association of events separated by time. However, the nature of PL activity and its functional network in the whole brain during CTA learning remain unknown. Here, using awake functional magnetic resonance imaging and fiber tracking, we analyzed functional brain connectivity during the association of tastes and visceral illness. The blood oxygen level-dependent (BOLD) signal significantly increased in the PL after tastant and lithium chloride (LiCl) infusions. The BOLD signal in the PL significantly correlated with those in the amygdala and agranular insular cortex (IC), which we found were also structurally connected to the PL by fiber tracking. To precisely examine these data, we then performed double immunofluorescence with a neuronal activity marker (c-Fos) and an inhibitory neuron marker (GAD67) combined with a fluorescent retrograde tracer in the PL. During CTA learning, we found an increase in the activity of excitatory neurons in the basolateral amygdala (BLA) or agranular IC that project to the PL. Taken together, these findings clearly identify a role of synchronized PL, agranular IC, and BLA activity in CTA learning.
Objective Expression of taste-related genes in the tongue was analysed to develop a technique for genetic diagnosis of umami taste disorders.Materials And Methods Tissue samples were collected from healthy volunteers by scraping the foliate papillae of the tongue. Immunocytochemistry staining of gustducin, a taste-cell-specific G protein, and gene expression analysis by real-time polymerase chain reaction of β-actin, gustducin (GNAT3), and umami receptors (T1R1, T1R3 and mGluR1) were performed. Changes in umami receptor expression following application of umami substances onto the tongue were analysed.ResultsGustducin-positive cells were observed in the samples, indicating the presence of taste cells. Gene expression of β-actin, GNAT3, T1R1 and T1R3 was detected in all seven samples tested, while that of mGluR1 was detected in four samples. Sequence analysis by NCBI Blast showed that each polymerase chain reaction product had a 99% rate of identification of its target sequence. Stimulation of the tongue with monosodium glutamate significantly upregulated the gene expression levels of T1R1 and T1R3, indicating that this method can detect alterations in umami-related gene expression.Conclusion Evaluation of the expression of the umami receptor genes, T1R1 and T1R3, in the tongue may be clinically useful for objective genetic diagnosis of umami taste disorders.This article is protected by copyright. All rights reserved.
Umami taste is elicited by L-glutamate and some other amino acids and is thought to be initiated by G-protein-coupled receptors. Proposed umami receptors include heterodimers of taste receptor type 1, members 1 and 3 (T1R1+T1R3), and metabotropic glutamate receptors 1 and 4 (mGluR1 and mGluR4). Accumulated evidences support the involvement of T1R1 + T1R3 in umami responses in mice. However, little is known about in vivo function of mGluRs in umami taste. Here, we examined taste responses of the chorda tympani (CT) and the glossopharyngeal (GL) nerves in wild-type mice and mice genetically lacking mGluR4 (mGluR4-KO). Our results indicated that compared to wild-type mice, mGluR4-KO mice showed significantly smaller gustatory nerve responses to glutamate and L(+)-2-amino-4-phosphonobutyrate (L-AP4, an agonist for group III mGluR) in both the CT and GL nerves without affecting responses to other taste stimuli. Residual glutamate responses in mGluR4-KO mice were not affected by (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG, an antagonist for group III mGluR), but were suppressed by gurmarin (a T1R3 blocker) in the CT and (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA, an antagonist for group I mGluR) in the CT and GL nerve. In wild-type mice, both quisqualic acid (an agonist for group I mGluR) and L-AP4 elicited gustatory nerve responses and these responses were suppressed by addition of AIDA and CPPG, respectively. Collectively, the present study provided functional evidences for the involvement of mGluR4 in umami taste responses in mice. The results also suggest that T1R1+T1R3 and mGluR1 are involved in umami taste responses in mice. Thus umami taste would be mediated by multiple receptors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis.
The postingestive effect is different between caloric and noncaloric sweeteners. The gut administration of glucose induces a preference for flavored water which is paired with the intragastric infusion of glucose. However, a comparison of the brain response to the gut glucose and saccharin stimuli still remains to be demonstrated. Here, using functional magnetic resonance imaging, we investigated the blood oxygenation level-dependent signal response to gut glucose and saccharin in the brain of conscious rats. Glucose induced a positive signal increase in the amygdala and nucleus accumben, both of which receive dopaminergic input from the ventral tegmental area. In contrast, saccharin administration did not activate these areas. Both glucose and saccharin increased the blood oxygenation level-dependent signal intensity in the insular cortex and the nucleus of the solitary tract. These results show that there were significant differences between postingestive glucose and saccharin-induced increases in the blood oxygenation level-dependent signal in rats. Together with previous findings, these results suggest distinct activation patterns in the brain for both glucose and saccharin, which is partially due to different changes of internal signals, including the blood glucose and insulin levels.
The 20 different amino acids, in blood as well as in the brain, are strictly maintained at the same levels throughout the day, regardless of food intake. Gastric vagal afferents only respond to free glutamate and sugars, providing recognition of food intake and initiating digestion. Metabolic control of amino acid homeostasis and diet-induced thermogenesis is triggered by this glutamate signalling in the stomach through the gut-brain axis. Rats chronically fed high-sugar and high-fat diets do not develop obesity when a 1% (w/v) monosodium glutamate (MSG) solution is available in a choice paradigm. Deficiency of the essential amino acid lysine (Lys) induced a plasticity in rats in response to Lys. This result shows how the body is able to identify deficient nutrients to maintain homeostasis. This plastic effect is induced by activin A activity in the brain, particularly in certain neurons in the lateral hypothalamic area (LHA) which is the centre for amino acid homeostasis and appetite. These neurons respond to glutamate signalling in the oral cavity by which umami taste is perceived. They play a quantitative role in regulating ingestion of deficient nutrients, thereby leading to a healthier life. After recovery from malnutrition, rats prefer MSG solutions, which serve as biomarkers for protein nutrition.
Digestion and the absorption of food and nutrients have been considered the only functions of the gastrointestinal (GI) tract. However, recent studies suggest that taste cells in the oral cavity and taste-like cells in the GI tract share many common characteristics (taste receptors and transduction signaling). Over the last two decades, it has been revealed that the GI tract is a chemosensory organ that transfers nutrient information via GI hormone secretion (glucagon-like peptide-1, Peptide YY, oxyntomodulin, glucose-dependent insulinotropic polypeptide and others) and the activation of abdominal vagus afferents. In addition, the information relayed via the abdominal vagus nerve plays an important role in autonomic reflexes. This information, both humoral and neural, contributes to the maintenance of homeostasis (digestion, absorption, metabolism and food intake) in the body. In this review, we provide a brief overview of the following: GI chemosensory molecules, their distribution, the effect of nutrients on GI hormone secretion and the activation of vagus afferent nerves. We also focus on the possibility of clinical applications that control abdominal vagus activity.
There is a close relationship between perception of umami, which has become recognized as the fifth taste, and the human physical condition. We have developed a clinical test for umami taste sensitivity using a filter paper disc with a range of six monosodium glutamate (MSG) concentrations. We recruited 28 patients with taste disorders (45-78 years) and 184 controls with no taste disorders (102 young [18-25 years] and 82 older [65-89 years] participants). Filter paper discs (5 mm dia.) were soaked in aqueous MSG solutions (1, 5, 10, 50, 100 and 200 mM), then placed on three oral sites innervated by different taste nerves. The lowest concentration participants correctly identified was defined as the recognition threshold (RT) for MSG. This test showed good reproducibility for inter- and intra-observer variability. We concluded that: (1) The RT of healthy controls differed at measurement sites innervated by different taste nerves; that is, the RT of the anterior tongue was higher than that of either the posterior tongue or the soft palate in both young and older individuals. (2) No significant difference in RT was found between young adults and older individuals at any measurement site. (3) The RT of patients with taste disorders was higher before treatment than that of the healthy controls at any measurement site. (4) The RT after treatment in these patients improved to the same level as that of the healthy controls. (5) The cutoff values of RT, showing the highest diagnostic accuracy (true positives + true negatives), were 200 mM MSG for AT and 50 mM MSG for PT and SP. The diagnostic accuracy at these cutoff values was 0.92, 0.87 and 0.86 for AT, PT and SP, respectively. Consequently, this umami taste sensitivity test is useful for discriminating between normal and abnormal umami taste sensations.
Capsaicin and capsiate, which is an analogue of capsaicin, are agonists of capsaicin-binding transient potential vanilloid 1 (TRPV1) receptors. However, their physiological effects are different. Capsaicin induces thermogenesis and nociception, while the different kinetics of capsiate result in thermogenesis without nociception in the oral cavity. In the present study, using functional magnetic resonance imaging, we compared the brain activation after intragastric infusion of non-nociceptive levels of capsaicin and capsiate in wild-type and TRPV1-knockout (KO) mice. Capsaicin activated several brain regions, such as the periaqueductal grey (PAG), thalamic nuclei and hypothalamus, including the medial preoptic area (mPOA) and ventromedial hypothalamus (VMH). Most of these areas were not activated in TRPV1-KO mice. Capsiate activated several regions, including the thalamic nuclei, mPOA and VMH but not PAG in wild-type mice. Most of the activated areas were not activated by intragastric capsiate infusion in TRPV1-KO mice. These results demonstrate that TRPV1 is critical for the induction of activation in the hypothalamus by capsaicin and capsiate, and these distinct brain activations could help to explain the individual physiological reactions of capsaicin and capsiate.
Our newly developed umami taste sensitivity test revealed the loss of only the umami taste sensation in some elderly patients, whereas the other four basic taste sensations (sweet, salty, sour, bitter) were normal. Such patients all complained of appetite loss and weight loss, resulting in poor overall health. As a treatment for taste disorder patients, improvement of salivary flow has been adopted in our clinic. Umami taste stimulation increases salivary flow rate of not only major but also minor salivary glands. After treatment with umami taste stimulation, patients remarkably regained their appetite, weight and overall health. Sensitivity to umami taste seems to contribute to good overall health in elderly people.
The concentration of free Glutamate (Glu) in rat's milk is approximately 10 times higher than that in plasma. Previous work has shown that mammary tissue actively transports circulatory leucine (Leu), which is transaminated to synthesize other amino acids such as Glu and aspartate (Asp). To investigate the molecular basis of Leu transport and its conversion into Glu in the mammary gland, we characterized the expression of Leu transporters and [3H] Leu uptake in rat mammary cells. Gene expression analysis indicated that mammary cells express two Leu transporters, LAT1 and LAT2, with LAT1 being more abundant than LAT2. This transport system is sodium-independent and transports large neutral amino acids. The Leu transport system in isolated rat mammary cells could be specifically blocked by LAT1 inhibitors BCH and triiodothyronine (T3). In organ cultures, Glu secretion was markedly inhibited by these LAT1 inhibitors. Furthermore, the profiles of Leu uptake inhibition by amino acids in mammary cells were similar to those reported for LAT1. In vivo, concentrations of free Glu and Asp increased in milk by oral gavage with Leu at 6, 12 and 18 days of lactation. These results indicate that the main Leu transporter in mammary tissue is LAT1, and the Leu transporter is a limiting factor for the synthesis and release of Glu and Asp into milk. Our studies provide the bases for the molecular mechanism of Leu transport in mammary tissue by LAT1 and its active role on free Glu secretion in milk, which confer umami taste in suckling pups.
Dietary glutamate (Glu) stimulates to evoke the umami taste, one of the five basic tastes, enhancing food palatability. But it is also the main gut energy source for the absorption and metabolism for each nutrient, thus, only a trace amount of Glu reaches the general circulation. Recently, we demonstrated a unique gut sensing system for free Glu (glutamate signaling). Glu is the only nutrient among amino acids, sugars and electrolytes that activates rat gastric vagal afferents from the luminal side specifically via metabotropic Glu receptors type 1 on mucosal cells releasing mucin and nitrite mono-oxide (NO), then NO stimulates serotonin (5HT) release at the enterochromaffin cell. Finally released 5HT stimulates 5HT3 receptor at the nerve end of the vagal afferent fiber. Functional magnetic resonance imaging (f-MRI, 4.7 T) analysis revealed that luminal sensing with 1 % (w/v) monosodium L-glutamate (MSG) in rat stomach activates both the medial preoptic area (body temperature controller) and the dorsomedial hypothalamus (basic metabolic regulator), resulting in diet-induced thermogenesis during mealing without changes of appetite for food. Interestingly, rats were forced to eat a high fat and high sugar diet with free access to 1 % (w/w) MSG and water in a choice paradigm and showed the strong preference for the MSG solution and subsequently, they displayed lower fat deposition, weight gain and blood leptin. On the other hand, these brain functional changes by the f-MRI signal after 60 mM MSG intubation into the stomach was abolished in the case of total vagotomized rats, suggesting that luminal glutamate signaling contributes to control digestion and thermogenesis without obesity.
Rapid progress in gastroenterology during the first part of the last century has shown that gastrointestinal (GI) function is regulated by neuroendocrine, paracrine and endocrine signals. However, recent advances in chemical sensing, especially in the last decade, have revealed that free L: -amino acids (AA), among other nutrients, play a critical role in modifying exocrine and endocrine secretion, modulating protein digestion, metabolism and nutrient utilization, and supporting the integrity and defense of the GI mucosa. Many of the mechanisms by which AAs elicit these functions in the GI has been linked to the traditional concept of hormone release and nervous system activation. But most these effects are not direct. AAs appear to function by binding to a chemical communication system such as G protein-coupled receptors (GPCRs) that activate signaling pathways. These intracellular signals, although their molecular bases are not completely elucidated yet, are the ones responsible for the neuronal activity and release of hormones that in turn regulate GI functions. This review aims to describe the distribution of the known GPCRs from the class 3 superfamily that bind to different kinds of AA, especially from the oropharyngeal cavity to the stomach, what kind of taste qualities they elicit, such as umami, bitter or sweet, and their activity in the GI tract.
l-Lysine (Lys) is an essential amino acid and plays an important role in anxiogenic behaviour in both human subjects and rodents. Previous studies have shown the existence of neural plasticity between the Lys-deficient state and the normal state. Lys deficiency causes an increase in noradrenaline release from the hypothalamus and serotonin release from the amygdala in rats. However, no studies have used functional MRI (fMRI) to compare the brain response to ingested Lys in normal, Lys-deficient and Lys-recovered states. Therefore, in the present study, using acclimation training, we performed fMRI on conscious rats to investigate the brain response to an intragastric load of Lys. The brain responses to intragastric administration of Lys (3 mmol/kg body weight) were investigated in six rats intermittently in three states: normal, Lys-deficient and recovered state. First, in the normal state, an intragastric load of Lys activated several brain regions, including the raphe pallidus nucleus, prelimbic cortex and the ventral/lateral orbital cortex. Then, after 6 d of Lys deprivation from the normal state, an intragastric load of Lys activated the ventral tegmental area, raphe pallidus nucleus and hippocampus, as well as several hypothalamic areas. After recovering from the Lys-deficient state, brain activation was similar to that in the normal state. These results indicate that neural plasticity in the prefrontal cortex, hypothalamic area and limbic system is related to the internal Lys state and that this plasticity could have important roles in the control of Lys intake.
Optimal growth and health of suckling neonates critically depend on milk production by their mothers. In both humans and animals, branched-chain amino acids (BCAA) are not only the major components of milk proteins but are also nitrogenous precursors for the synthesis of glutamate, glutamine, alanine, and aspartate in the mammary gland. These synthetic pathways, which are initiated by BCAA transaminase, contribute to the high abundance of free and peptide-bound glutamate, glutamine, aspartate and asparagine in milk. In mammary epithelial cells, the carbon skeletons of BCAA can be partially oxidized via branched-chain alpha-ketoacid dehydrogenase to provide energy for highly active metabolic processes, including nutrient transport, protein turnover, as well as lipid and lactose syntheses. In addition, results of recent studies indicate that BCAA play regulatory roles in mammary metabolism. For example, leucine can activate the mammalian target of rapamycin cell signaling pathway to enhance protein synthesis in mammary epithelial cells. Dietary supplementation with BCAA may have great potential to enhance milk synthesis by the lactating mammary gland, thereby improving neonatal survival, growth and development.
Recent evidence indicates that free amino acids are nutrients as well as acting as chemical transmitters within the gastrointestinal tract. Gut glutamate research is the most advanced among 20 amino acids. Free glutamate carries the umami taste sensation on the tongue and a visceral sensation in the gut, especially the stomach. In the field of taste physiology, the physiological meaning of the glutamate-derived chemical sense, the umami taste, has been proposed to be a marker of protein intake. Experimental evidence in gut glutamate physiology strongly supports this hypothesis. Free glutamate is sensed by the abdominal vagus and regulates gastrointestinal functions such as secretion and emptying to accelerate protein digestion. Clinical application of glutamate has also just begun to treat gastrointestinal disorders such as dyspepsia, ulcer, dry mouth and functional dyspepsia. In this review, we introduce recent advances in gut glutamate research and consider the possible contribution of glutamate to health.
Functional magnetic resonance imaging (fMRI) in humans and non-primates has been useful to clarify the brain regions involved in the psychological process such as the reward anticipation. However, there is still no report of the fMRI study on the reward prediction in rodents. This is mainly because of the problem of anesthesia in rodent fMRI. In this study, we first developed awake fMRI method to investigate the brain region involved in reward anticipation in rats. After fMRI adaptation training, rats received light stimulation 1min before intraperitoneal infusion of ethanol solution (4g/kg body weight) in the MRI bore. Five or six days after the start of the experiment, the caudate-putamen, anterior insular cortex, hippocampus, ventral pallidum, nucleus accumbens and medial preoptic area were activated during light presentation. In contrast, no activation was observed in the control group. These results indicate the availability of awake fMRI method to investigate neural plasticity in the psychological process, learning, and memory such as the reward anticipation.
The gustatory and visceral stimulation from food regulates digestion and nutrient utilization, and free glutamate (Glu) release from food is responsible for the umami taste perception that increases food palatability. The results of recent studies reveal a variety of physiological roles for Glu. For example, luminal applications of Glu into the mouth, stomach, and intestine increase the afferent nerve activities of the glossopharyngeal nerve, the gastric branch of the vagus nerve, and the celiac branch of the vagus nerve, respectively. Additionally, luminal Glu evokes efferent nerve activation of each branch of the abdominal vagus nerve. The intragastric administration of Glu activates several brain areas (e.g., insular cortex, limbic system, and hypothalamus) and has been shown to induce flavor-preference learning in rats. Functional magnetic resonance imaging of rats has shown that the intragastric administration of Glu activates the nucleus tractus solitarius, amygdala, and lateral hypothalamus. In addition, Glu may increase flavor preference as a result of its postingestive effect. Considering these results, we propose that dietary Glu functions as a signal for the regulation of the gastrointestinal tract via the gut-brain axis and contributes to the maintenance of a healthy life.
Recent advances in molecular biology have led to the investigation of the molecular mechanism by which chemicals such as odors and tastants are perceived by specific chemosensory organs. For example, G protein-coupled receptors expressed within the nasal epithelium and taste receptors in the oral cavity have been identified as odorant and taste receptors, respectively. However, there is much evidence to indicate that these chemosensory receptors are not restricted to primary chemosensory cells; they are also expressed and have function in other cells such as those in the airways and gastrointestinal (GI) tract. This short review describes the possible mechanisms by which taste signal transduction occurs in the oral cavity and tastants/nutrients are sensed in the GI tract by taste-like cells, mainly enteroendocrine and brush cells. Furthermore, it discusses the future perspectives of chemosensory studies.
One of the unsolved issues in the taste and gastrointestinal chemosensory system is how chemosensory cells transduce chemical information to gustatory or vagus nerves, despite that the majority of chemosensory cells do not form conventional synapses between cells and neurons. For the past decades, studies have suggested that ATP, besides energy currency, could be one of the neurotransmitters. Indeed, recent reports have shown the involvement of ATP in taste signal transmission in certain subsets of taste cells which express G-protein coupled taste receptors to sense sweet, umami or bitter compounds. Furthermore, receptors for nucleotides are highly expressed in vagus nerves, indicating that purinergic signaling also exists in the gastrointestinal tract. We have recently found expression of a novel vesicular nucleotide transporter (VNUT) within particular types of taste cells, however, there has been a debate upon how ATP is stored and released by either hemichannel or lytic release. In this article, we summarize recent advances in the field of taste signal transmission and discuss possible mechanisms of ATP accumulation and secretion in the taste as well as in the digestive system.
Information about nutrients is a critical part of food selection in living creatures. Each animal species has developed its own way to safely seek and obtain the foods necessary for them to survive and propagate. Necessarily, humans and other vertebrates have developed special chemosensory organs such as taste and olfactory organs. Much attention, recently, has been given to the gastrointestinal (GI) tract as another chemosensory organ. Although the GI tract had been considered to be solely for digestion and absorption of foods and nutrients, researchers have recently found taste-signalling elements, including receptors, in this tissue. Further studies have revealed that taste cells in the oral cavity and taste-like cells in the GI tract appear to share common characteristics. Major receptors to detect umami, sweet and bitter are found in the GI tract, and it is now proposed that taste-like cells reside in the GI tract to sense nutrients and help maintain homeostasis. In this review, we summarize recent findings of chemoreception especially through sweet and umami sensors in the GI tract. In addition, the possibility of purinergic transmission from taste-like cells in the GI tract to vagus nerves is discussed.
Recent studies indicate that l-glutamate (l-Glu), abundant in many foods, is a stimulator of gastric vagal afferent nerves. The aim of the present study was to examine the possibility that l-Glu supplementation of a protein-rich liquid diet may prevent the incidence of diarrhoea during repetitive intra-gastric tube feeding. The gastric vagal afferent nerve recording of rats indicated that intra-gastric administration of a protein-rich liquid diet supplemented with 0·5 % monosodium glutamate enhanced the basal afferent activities seen with the protein-rich diet alone. The examination of the faeces showed that the addition of monosodium glutamate to the liquid diet significantly prevented the incidence of diarrhoea induced by repetitive gastric feeding. In conclusion, supplementation of an enteral liquid diet with free l-Glu may ameliorate diarrhoea during intra-gastric tube feeding by sending visceral glutamate information from the stomach to the brain.
Food reward is neurologically and psychologically divided into at least two properties; 'liking' and 'wanting'. Although umami taste enhances food palatability, the liking and wanting properties of umami taste, and the underlying neural mechanisms for these properties are not clear. Here, we compared sucrose (0, 10, 30, 120 and 480 mM) and monosodium l-glutamate (MSG; 0, 10, 30, 60 and 120 mM) solutions using a taste reactivity test to evaluate liking, and fixed/progressive-ratio operant licking tasks to evaluate wanting. To determine the underlying neural mechanisms, we also conducted systemic blockade of opioid receptors in both tests. In the taste reactivity test, the hedonic reactions to 30, 60 and 120 mM MSG were greater than those to water (0mM) but lower than those to 480 mM sucrose. In the operant task, the intake, number of licks, and breakpoint to MSG reached peaks at around 60mM but they were lower than those to 30-480 mM sucrose. The systemic naloxone treatment decreased the hedonic responses to MSG and sucrose, and reduced the incentive salience of MSG but not sucrose. These findings indicate that the hedonic response and incentive salience of MSG is lower than those of sucrose when compared at the maximum response and that the incentive salience of MSG is lower than sucrose even where the hedonic response is similar. The present study also suggest that the hedonic response and incentive salience of umami compound is modulated by brain opioid signaling.
Dietary-free L-glutamate (Glu) in the stomach interacts with specific Glu receptors (T1R1/T1R3 and mGluR1-8) expressed on surface epithelial and gastric gland cells. Furthermore, luminal Glu activates the vagal afferents in the stomach through the paracrine cascade including nitric oxide and serotonin (5-HT). To elucidate the role of dietary Glu in neuroendocrine control of the gastrointestinal phase of gastric secretion. In Pavlov or Heidenhain gastric pouch dogs, secretion was measured in the pouch while monosodium glutamate (MSG) was intubated into the main stomach alone or in combination with liquid diets. In both experimental models, supplementation of the amino acid-rich diet with MSG (100 mmol/l) enhanced secretions of acid, pepsinogen and fluid, and elevated plasma gastrin-17. However, MSG did not affect secretion stimulated by the carbohydrate-rich diet and had no effect on basal secretion when applied in aqueous solution. Effects of MSG were abolished by denervation of the stomach and proximal small intestine with intragastrically applied lidocaine and partially suppressed with the 5-HT(3) receptor blocker granisetron. Supplementation of amino acid-rich liquid diets with MSG enhances gastrointestinal phase secretion through neuroendocrine pathways which are partially mediated by 5-HT. Possible mechanisms are discussed.
Chemosensing of nutrients in the gastrointestinal tract plays physiologically important roles in the regulation of food intake behaviors, including digestion, absorption, metabolism and other subsequently occurring body functions via brain activation. Free amino acids, liberated from ingested foods, are of course essential nutrients which compose the body proteins and sometimes determine the taste of the food. Glutamate, one of the most abundant amino acids in the foods and the liberated free form, critically contributes to the 'umami' taste perception. Recently, it has been revealed that dietary glutamate has many beneficial functions in the gastrointestinal tract. However, the precise mechanism of glutamate sensing still remains unclear. Using primary rat gastric mucosal cell cultures, we demonstrated that somatostatin-secreting D cells are candidate cells for glutamate sensing in the stomach through inhibition of somatostatin release. Considering that somatostatin is one of the major negative regulators of gastric functions, it is suggested that some parts of glutamate's beneficial effects could be explained by suppression of the inhibitory somatostatin effects, i.e. stimulation, by glutamate.
In this study we investigated the effects of intragastric infusion of palatable basic taste substances (umami, sweet, and salty) on the activity of the vagal gastric afferent nerve (VGA), the vagal celiac efferent nerve (VCE), and the splanchnic adrenal efferent nerve (SAE) in anesthetized rats. To test the three selected taste groups, rats were infused with inosine monophosphate (IMP) and L: -glutamate (GLU) for umami, with glucose and sucrose for sweet, and with sodium chloride (NaCl) for salty. Infusions of IMP and GLU solutions significantly increased VGA activity and induced the autonomic reflex, which activated VCE and SAE; these reflexes were abolished after sectioning of the VGA. Infusions of glucose, sucrose and NaCl solutions, conversely, had no significant effects on VGA activity. These results suggest that umami substances in the stomach send information through the VGA to the brain and play a role in the reflex regulation of visceral functions.
The brain's response to ethanol intake has been extensively investigated using electrophysiological recordings, brain lesion techniques, and c-Fos immunoreactivity. However, few studies have investigated this phenomenon using functional magnetic resonance imaging (fMRI). In the present study, we used fMRI to investigate the blood oxygenation level-dependent (BOLD) signal response to an intragastric (IG) load of ethanol in conscious, ethanol-naive rats. An intragastrically infused 10% ethanol solution induced a significant decrease in the intensity of the BOLD signal in several regions of the brain, including the bilateral amygdala (AMG), nucleus accumbens (NAc), hippocampus, ventral pallidum, insular cortex, and cingulate cortex, and an increase in the BOLD signal in the ventral tegmental area (VTA) and hypothalamic regions. Treatment with bicuculline, which is an antagonist of the gamma-aminobutyric acid A (GABA(A)) receptor, increased the BOLD signal intensity in the regions that had shown decreases in the BOLD signal after the IG infusion of 10% ethanol solution, but it did not affect the BOLD signal increase in the hypothalamus. Treatment with SCH39166, which is an antagonist of D1-like receptors, eliminated the increase in the BOLD signal intensity in the hypothalamic areas but did not affect the BOLD signal decrease following the 10% ethanol infusion. These results indicate that an IG load of ethanol caused both a GABA(A) receptor-mediated BOLD decrease in the limbic system and the cortex and a D1-like receptor-mediated BOLD increase in the hypothalamic regions in ethanol-naive rats.
Afferent signals from the olfactory system, gustatory system and gastrointestinal (GI) tract control visceral functions such as oral and gut secretions and several digestive, endocrine, thermogenic, cardiovascular and renal responses via autonomic reflexes. It is well known that odors and tastes, such as umami, can stimulate oral and GI secretions to improve food intake and digestion in a process termed the cephalic phase response. The perception of GI nutrients, such as carbohydrates and amino acids, can control food digestion, absorption and utilization via the vago-vagal reflex during a meal. Recent advances in understanding the molecular physiology of taste indicate that taste receptors able to sense such nutrients are widely distributed in the GI tract, including the oral cavity. These receptors act as nutrient sensors to trigger food digestion, the release of GI peptides and the formation of food preferences. In this paper, we review recent evidence on the regulation of GI functions by the autonomic nervous system via peripheral odor and nutrient sensors.
Enjoying taste should be one of the greatest pleasures in human life. However, aging is sometimes associated with decreased taste sensitivity, also known as hypogeusia. The loss of taste not only affects quality of life, but can also cause weight loss and health problems in the elderly. Our recent study has shown that 37% of test subjects over 65 years of age exhibited hypogeusia. Further, whole saliva secretion, including minor salivary secretion, was significantly decreased in elderly patients with gustatory impairment, but was normal in all elderly subjects with normal taste thresholds. These data indicate that hyposalivation is closely related to hypogeusia. Moreover, clinical studies have shown that treatment of hyposalivation diminishes hypogeusia, indicating that salivation is essential to maintain normal taste function. However, many medications for relief of dry mouth, such as parasympathomimetic (cholinomimetic) drugs, have serious adverse effects. Palpitation, sweating, nausea, diarrhea and dizziness have all been observed in elderly patients taking parasympathomimetic drugs. To circumvent this problem, glutamate, which produces umami taste, was demonstrated to increase salivary secretion and thereby improve hypogeusia by enhancing the gustatory-salivary reflex. Our data suggests that umami is an effective tool for the relief of hypogeusia without the side effects of parasympathomimetic drugs.
Fasting has been used to control epilepsy since antiquity, but the mechanism of coupling between metabolic state and excitatory neurotransmission remains unknown. Previous work has shown that the vesicular glutamate transporters (VGLUTs) required for exocytotic release of glutamate undergo an unusual form of regulation by Cl(-). Using functional reconstitution of the purified VGLUTs into proteoliposomes, we now show that Cl(-) acts as an allosteric activator, and the ketone bodies that increase with fasting inhibit glutamate release by competing with Cl(-) at the site of allosteric regulation. Consistent with these observations, acetoacetate reduced quantal size at hippocampal synapses and suppresses glutamate release and seizures evoked with 4-aminopyridine in the brain. The results indicate an unsuspected link between metabolic state and excitatory neurotransmission through anion-dependent regulation of VGLUT activity.
In this study, we compared the blood oxygen level-dependent (BOLD) signal changes between intragastric load of monosodium L-glutamate (MSG) and inosine monophosphate (IMP), which elicit the umami taste. An intragastric load of 30 mM IMP or 60 mM MSG induced a BOLD signal increase in several brain regions, including the nucleus of the solitary tract (NTS), lateral hypothalamus (LH), and insular cortex. Only MSG increased the BOLD signal in the amygdala (AMG). The time course of the BOLD signal changes in the NTS and the LH in the IMP group was different from that of the MSG group. We further compared the brain regions correlated with the BOLD signal change in the NTS between MSG and IMP groups. The BOLD responses in the hippocampus and the orbital cortex were associated with activation of the NTS in both MSG and IMP groups, but the association in the AMG and the pyriform was only in MSG group. These results indicate that gut stimulation with MSG and IMP evoked BOLD responses in distinct regions with different temporal patterns and that the mechanism of perception of L-glutamate and IMP in the gastrointestinal tract differed from that in the taste-sensing system.
Taste cells are chemosensory epithelial cells that sense distinct taste quality such as umami, sweet, bitter, sour and salty. Taste cells utilize G protein-coupled receptors to detect umami, sweet and bitter taste whereas ion channels are responsible for detecting salty and sour taste. Among these taste receptors, taste receptor type 2, T1R2 (or Tas1r2), has been identified as a sole sweet taste receptor in mammals that mediates sweet signals upon dimerization with T1R3. However, because of limited availability of reliable antibodies and low expression level of G protein-coupled receptors, it is uneasy to identify the cell-types that express these receptors in non-taste tissues. In this study, we have generated a T1R2-LacZ reporter knock-in mouse to investigate tissue distribution of T1R2 at a single-cell level. We found that the LacZ gene expression in these mice was faithful to the expression of T1R2 in the taste tissue and in the gastrointestinal tract where T1R3 expression has been reported. Surprisingly, T1R2 expression was also found in the testis. Mice homozygous for T1R2 deletion lacked T1R2 protein analyzed by the antibody raised against T1R2 peptide sequences. In summary, the T1R2 knock-in mouse is a powerful tool to analyze the putative targets for sweeteners as well as to study the physiological roles of T1R2 in detecting sugars.
Objectives:The minor salivary glands are important in maintaining and promoting oral health, because they are widely distributed throughout the oral mucosa and contribute up to half of the secretory IgA as well as a part of the mucins present in the mouth. The greatest amount of salivary secretion is produced during eating, that is, reflex salivation caused by the autonomic nervous system. Reflex salivation in the parotid gland is well known to have been induced by umami taste as well as by the four basic tastes, however, such reflex salivary response has yet to be reported for the minor salivary glands. Against this background, our study was undertaken to answer the questions of how minor salivary glands contribute to reflex salivation following gustatory stimulation. Methods:Labial minor salivary flow was measured in eleven healthy human subjects using the iodine-starch filter-paper method (2003 Shoji et al.). The gustatory stimuli were sucrose (sweet), sodium chloride (salty), tartaric acid (sour), quinine hydrochloride (bitter), and monosodium glutamate (MSG) (umami). Gustatory stimuli were applied for 30 seconds on the tongue surface by cotton wool dipped into each taste solution. Before and after each stimulus, labial minor salivary flow was repeatedly measured. Results:Our results show that, first, all gustatory stimuli elicited labial minor gland saliva secretion with a correlation to the concentration. Second, the overall order of relative salivary flow response was tartaric acid >= MSG > sodium chloride >quinine hydrochloride >= sucrose. Third, the peak flow provided a greater response to MSG, equal to that for tartaric acid, compared to the other taste solutions. Finally, reflex labial minor gland salivation in response to MSG was longer-lasting in comparison to other stimuli. Conclusions:These results indicate that gustatory stimuli elicit minor salivary secretion, and umami taste seems to be particularly effective to moisten oral mucosa.
It is well known that the postingestive effect modulates subsequent food preference. We previously showed that monosodium L-glutamate (MSG) can increase flavor preference by its postingestive effect. The neural pathway involved in mediating this effect, however, remains unknown. We show here the role of the vagus nerve in acquiring this learned flavor preference and in the brain's response to intragastric glutamate infusion. Adult rats with an intragastric cannula underwent total abdominal branch vagotomies (TVX), common hepatic branch vagotomies (HVX), total abdominal branch vagotomies with the common hepatic branch intact (TVXh), or sham operations (Sham). Following recovery, rats were subjected to a conditioned flavor preference paradigm, in which they drank a flavored solution (CS+) paired with intragastric MSG or another flavored solution (CS-) paired with intragastric distilled water. After conditioning, the Sham and HVX groups demonstrated significantly higher intake of CS+ than CS-, whereas the TVXh and TVX groups showed no significant differences. We then conducted an fMRI study to identify the brain areas that responded to the intragastric glutamate in each group. In the Sham, HVX and TVXh groups, intragastric MSG significantly increased the BOLD intensity in the nucleus of the solitary tract. The amygdala, hippocampus and lateral hypothalamus were also activated in the Sham and HVX groups but not in the TVXh and TVX groups. These results indicate that the abdominal vagus nerve is necessary for acquiring preference and that the lateral hypothalamus and limbic system could be key areas for integrating the information on gut glutamate and oronasal stimuli.
Dietary free glutamate is known to elicit umami, one of the five basic tastes perceived via the specific taste sensor cells on the tongue. Recent studies suggest the specific glutamate sensors exist in the gastric mucosa and contribute to the regulation of gastrointestinal functions, yet the precise mechanism remains still unknown. We established the method to enrich various cell fractions from the isolated rat gastric mucosa and characterized the expression of putative glutamate sensors using such cell fractions. The gastric mucosal cell fractions such as surface mucous, parietal, chief, and endocrine cells were successfully prepared by mucosal protease digestion, elutriation, and gradient centrifugation. The characteristics of these cells were confirmed by real-time RT-PCR using the respective cell-specific markers. Parietal cell fraction exclusively expressed putative umami receptor molecules such as T1R1 and mGluR1 compared to other fractions, although the degree of expression was low. In contrast, the representative taste cell specific markers such as PLCbeta2 and TRPM5 were specifically expressed in the smaller endocrine cell fraction. Both parietal and smaller endocrine cell fractions also positively expressed some mGluR subtypes. The chief-cell fraction less expressed T1R1 and mGluR1. These results suggest that multiple glutamate sensors, probably different mechanisms from taste buds, contribute to the glutamate sensing in the gastric mucosa.
Ammonia is one of the important toxins produced by Helicobacter pylori (H. pylori), the major cause of peptic ulcer diseases. We examined whether glutamine or marzulene (a gastroprotective drug containing 1% sodium azulene and 99% glutamine) protects the gastric mucosa against H. pylori in vivo and investigated the mechanism underlying glutamine-induced mucosal protection against ammonia in gastric epithelial cells in vitro. Mongolian gerbils were fed for 3 months with a diet containing glutamine (2%-20%) or marzulene (20%) starting from 2 weeks or 2 years after H. pylori infection. Then, gastric mucosal changes were evaluated both macro- and microscopically. Cultured gastric epithelial cells were incubated in the presence of ammonia, with or without glutamine; and cell viability, ammonia accumulation, and chemokine production were determined. Gerbils exhibited edema, congestion, and erosion after 3-month infection; and after 2-year infection, they showed cancer-like changes in the gastric mucosa. Glutamine and marzulene significantly suppressed these pathological changes caused in the gastric mucosa by H. pylori infection. Ammonia was accumulated in the cells, resulting in an increase in chemokine production and a decrease in cell viability. These pathological responses were prevented by glutamine. In addition, glutamine decreased chemokine production and cell death through inhibition of cellular accumulation of ammonia, resulting in the prevention of H. pylori-induced gastric diseases in vivo. These results suggest that glutamine/marzulene would be useful for prophylactic treatment of H. pylori-induced gastric diseases in patients.
Recent advancement in molecular biology in the field of taste perception has raised the possibility for ingested nutrients to be tasted in the upper gastrointestinal tract as well as tongue. Many works suggest that the individual 20 amino acid including glutamate can be detected by the vagus afferent within the duodenum. Recently, it was reveled that the rat gastric branch of the vagus nerve could specifically detect a non-essential amino acid, glutamate. The glutamate signaling could be transferred to the vagus nerve via mucosal chemical substances such as NO and serotonin. That leaded us to hypothesize that amino acid-sensing pathway exist in the gastric mucosa, like observed in the chemical sensing systems similar to the one functioning in the tongue and intestine. In this review, we summarized current status of gut amino acid-sensing research and possible significance of the amino acid induced visceral information in the body nutrient homeostasis.
The postingestive actions after intragastric or oronasal stimulation of fat have been well investigated. The blood oxygenation level-dependent (BOLD) signal changes, however, after intragastric load of corn oil emulsion have yet to be elucidated. Here, using functional magnetic resonance imaging, we investigated the BOLD signal response to gut corn oil emulsion in nonanesthetized rats. Intragastrically infused 7% corn oil emulsion induced a BOLD signal increase in several brain regions, including the bilateral amygdala, hippocampus and the ventral tegmental area. These results indicate that the limbic system responds to gut corn oil emulsion and that activation of this system could promote the reinforcing action for food with high fat content.
A century ago, an amino acid, L-glutamate (Glu), was found to be the important substance for umami (savory) taste of a Japanese soup stock cooked with sea tangle. Since that time, umami seasoning has been used to make foods palatable all over the world. Chemical analysis proved that Glu had been used for savory seasonings around the world, though its taste had been hidden behind the flavors of fat or herbs. Recently, research has shown that Glu affects the chemical senses not only in the oral cavity but also in the gastrointestinal tract, and it modulates the ingestion, digestion and metabolism of proteins. Umami taste, one of the five basic tastes along with sweet, salty, sour and bitter tastes, derived from Japanese cuisine, might be applicable for the nutritional care of elderly people, who are at risk for protein malnutrition even in developed countries.
It is important to investigate the effect of anesthesia on blood oxygenation level-dependent (BOLD) signals in an animal model. Many researchers have investigated the BOLD response to visual, sensory, and chemical stimuli in anesthetized rats. There are no reports, however, comparing the differences in the BOLD signal change between anesthetized and conscious rats when a visceral nutrient signal arises. Here, using functional magnetic resonance imaging (fMRI), we investigated the differences in the BOLD signal changes after intragastric administration of l-glutamate (Glu) under three anesthesia conditions: conscious, alpha-chloralose-anesthetized, and isoflurane-anesthetized condition. Under the conscious and alpha-chloralose condition, we observed the significant BOLD signal increase in the medial prefrontal cortex (mPFC), insular cortex (IC), hippocampus, and several hypothalamic regions including the lateral and ventromedial nucleus. In chloralose group, however, gut Glu stimulation induced BOLD signal increase in the prelimbic cortex and orbital cortex, which did not activate in conscious condition. Meanwhile, under isoflurane-anesthetized condition, we did not observe the BOLD signal increase in these areas. BOLD signal intensity in the nucleus of the solitary tract (NTS), to which vagus nerve transmits the visceral information from the gastrointestinal tract, increased in all conditions. Importantly, under conscious condition, we observed increased BOLD signal intensity in several regions related to the metabolic state (i.e. hunger or satiety), such as the mPFC, ventromedial and lateral hypothalamus (LH). Our results suggest that alpha-chloralose and isoflurane anesthesia caused distinct effects on BOLD response to the gut l-Glu stimulation in several brain regions.
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