Mice learn to identify and discriminate sugar solutions based on odor cues.

This study examined how olfaction impacts ingestive responses of mice to sugar solutions. Experiment 1 asked whether naïve C57BL/6 (B6) mice could identify 1 M glucose, fructose, or sucrose solutions based on odor cues, during a 30-min 2-bottle acceptability test. We tested mice both before and after they were rendered anosmic with ZnSO4 treatment. We used 2 indirect measures of odor-mediated response: number of trials initiated and latency to initiate licking. Before ZnSO4 treatment, the mice learned how to identify 1 M glucose and fructose (but not sucrose) solutions based on odor cues. ZnSO4 treatment eliminated their ability to identify the glucose and fructose solutions. Experiment 2 asked whether 2 d of exposure to a 1 M glucose, fructose, or sucrose solution improved the identification of the same sugar solution. Following exposure, the B6 mice identified all 3 sugar solutions based on odor cues. Experiment 3 asked whether T1R3 knockout mice (i.e. mice lacking the T1R3 subunit of the T1R2 + R3 sweet taste receptor) could learn to discriminate 0.44 M glucose and fructose solutions based on odor cues. All mice were subjected to a 1-h preference test, both before and after exposure to the 0.44 M glucose and fructose solutions. During exposure, the experimental mice received ZnSO4 treatment, whereas the control mice received saline treatment. Before exposure, neither type of mouse preferred the glucose solution. After exposure, the control mice preferred the glucose solution, whereas the experimental mice did not. Our results reveal that mice can learn to use odor cues to identify and discriminate between sugar solutions.

Individual differences in cephalic-phase insulin response are stable over time and predict glucose tolerance in mice.

Oral stimulation by glucose triggers a rapid insulin response, which enhances glucose tolerance. This so-called cephalic-phase insulin response (CPIR) has been documented in many mammal species, but its functional properties are poorly characterized. Here, we studied CPIR in lean C57BL/6 mice. Experiment 1 asked whether the large individual differences in CPIR magnitude were real or reflected experimental noise. We measured CPIR magnitude four times across a period of 30 days in the same mice. The individual differences in CPIR magnitude were remarkably stable across the repeated trials, indicating that they were real. Experiment 2 examined the functional consequences of individual differences in CPIR magnitude. We found that higher CPIR magnitudes contributed to larger postprandial insulin responses and greater glucose tolerance. Experiment 3 examined the observation that the CPIRs in Experiments 1 and 2 were associated with a rapid rise in blood glucose. To determine whether the rapid rise in blood glucose caused the CPIRs, we asked whether mice would generate a CPIR if we prevented cephalic-phase stimulation of beta cells by either delivering the glucose intragastrically or blocking parasympathetic input to the pancreatic beta cells with atropine. The mice subjected to these treatments experienced a rapid rise in blood glucose, but they did not exhibit a CPIR. This indicates that it was the oral glucose stimulation, and not the rise in blood glucose, that triggered the CPIRs in Experiments 1 and 2. We conclude that (i) individual differences in CPIR magnitude are stable over time; (ii) CPIR magnitudes predicted postprandial insulin responses and glucose tolerance; and (iii) a rapid rise in blood glucose is not sufficient to trigger a CPIR in mice.

Chronic sugar exposure increases daily intake of sugars but decreases avidity for sweeteners in mice.

Little is known about how chronic sugar consumption impacts avidity for and daily intake of sugars. This issue is topical because modern humans exhibit high daily intakes of sugar. Here, we exposed sugar-naïve C57BL/6 mice (across two 28-day exposure periods, EP1 and EP2) to a control (chow and water) or experimental (chow, water and a 11 or 34% sugar solution) diet. The sugar solutions contained sucrose, glucose syrups, or high-fructose syrups. We used brief-access tests to measure appetitive responses to sucralose and sucrose solutions at three time points: baseline (before EP1), after EP1, and after EP2. We used lick rates to infer palatability, and number of trials initiated/test to infer motivation. Exposure to the control diet had no impact on lick rates or number of trials initiated for sucralose and sucrose. In contrast, exposure to the experimental diets reduced licking for the sweeteners to varying degrees. Lick rates were reduced by exposure to sugar solutions containing the 11% glucose syrups, 34% sucrose, 34% glucose syrups and 34% high-fructose syrups. The number of trials initiated was reduced by exposure to all of the sugar solutions. Despite the exposure-induced reductions in avidity for the sweetener solutions, daily intakes of virtually all of the sugar solutions increased across the exposure periods. We conclude that (i) chronic consumption of sugar solutions reduced avidity for the sweetened solutions, (ii) the extent of this effect depended on the concentration and type of sugar, and (iii) avidity for sweet-tasting solutions could not explain the persistently high daily intake of sugar solutions in mice.

Conditioned preference and avoidance induced in mice by the rare sugars isomaltulose and allulose.

Isomaltulose, a slowly digested isocaloric analog of sucrose, and allulose, a noncaloric fructose analog, are promoted as "healthful" sugar alternatives in human food products. Here we investigated the appetite and preference conditioning actions of these sugar analogs in inbred mouse strains. In brief-access lick tests (Experiment 1), C57BL/6 (B6) mice showed similar concentration dependent increases in licking for allulose and fructose, but less pronounced concentration-dependent increases in licking for isomaltulose than sucrose. In Experiment 2, B6 mice were given one-bottle training with a CS+ flavor (e.g., grape) mixed with 8% isomaltulose or allulose and a CS- flavor (e.g., cherry) mixed in water followed by two-bottle CS flavor tests. The isomaltulose mice showed only a weak CS+ flavor preference but a strong preference for the sugar over water. The allulose mice strongly preferred the CS- flavor and water over the sugar. The allulose avoidance may be due to gut discomfort as reported in humans consuming high amounts of the sugar. Experiment 3 found that the preference for 8% sucrose over 8% isomaltulose could be reversed or blocked by adding different concentrations of a noncaloric sweetener mixture (sucralose + saccharin, SS) to the isomaltulose. Experiment 4 revealed that the preference of B6 or FVB/N mice for isomaltulose+0.01%SS or sucrose over 0.1%SS increased after separate experience with the sugars and SS. This indicates that isomaltulose, like sucrose, has postoral appetition effects that enhances the appetite for the sugar. In Experiments 5 and 6, the appetition actions of the two sugars were directly compared by giving mice isomaltulose+0.05%SS vs. sucrose choice tests before and after separate experience with the two sugars. In general, the initial preference the mice displayed for isomaltulose+0.05%SS was reduced or reversed after separate experience with the two sugars although some strain and sex differences were obtained. This indicates that isomaltulose has weaker postoral appetition effects than sucrose.

Consumption of glucose syrup enhances glucose tolerance in mice.

There is debate about the metabolic impact of sugar-sweetened beverages. Here, we tested the hypothesis that ad lib consumption of glucose (Gluc) or high-fructose (HiFruc) syrups improves glucose tolerance in mice. We provided C57BL/6 mice with a control (chow and water) or experimental (chow, water and sugar solution) diet across two consecutive 28-day exposure periods, and monitored changes in body composition, glucose tolerance, cephalic-phase insulin release (CPIR) and insulin sensitivity. The sugar solutions contained 11% concentrations of Gluc or HiFruc syrup; these syrups were derived from either corn starch or cellulose. In Experiment 1, consumption of the Gluc diets reliably enhanced glucose tolerance, while consumption of the HiFruc diets did not. Mice on the Gluc diets exhibited higher CPIR (relative to baseline) by the end of exposure period 1, whereas mice on the control and HiFruc diets did not do so until the end of exposure period 2. Mice on the Gluc diets also exhibited higher insulin sensitivity than control mice at the end of exposure period 2, while mice on the HiFruc diets did not. In Experiment 2, we repeated the previous experiment, but limited testing to the corn-based Gluc and HiFruc syrups. We found, once again, that consumption of the Gluc (but not the HiFruc) diet enhanced glucose tolerance, in part by increasing CPIR and insulin sensitivity. These results show that mice can adapt metabolically to high glucose diets, and that this adaptation process involves upregulating at least two components of the insulin response system.

What Does the Taste System Tell Us About the Nutritional Composition and Toxicity of Foods?

One of the distinctive features of the human taste system is that it categorizes food into a few taste qualities - e.g., sweet, salty, sour, bitter, and umami. Here, I examined the functional significance of these taste qualities by asking what they tell us about the nutritional composition and toxicity of foods. I collected published data on the composition of raw and unprocessed foods - i.e., fruits, endosperm tissues, starchy foods, mushrooms, and meats. Sweet taste is thought to help identify foods with a high caloric or micronutrient density. However, the sweetest foods (fruits) had a relatively modest caloric density and low micronutrient density, whereas the blandest foods (endosperm tissues and meats) had a relatively high caloric and high micronutrient density. Salty taste is thought to be a proxy for foods high in sodium. Sodium levels were higher in meats than in most plant materials, but raw meats lack a salient salty taste. Sour taste (a measure of acidity) is thought to signify dangerous or spoiled foods. While this may be the case, it is notable that most ripe fruits are acidic. Umami taste is thought to reflect the protein content of food. I found that free L-glutamate (the prototypical umami tastant) concentration varies independently of protein content in foods. Bitter taste is thought to help identify poisonous foods, but many nutritious plant materials taste bitter. Fat taste is thought to help identify triglyceride-rich foods, but the role of taste versus mouthfeel in the attraction to fatty foods is unresolved. These findings indicate that the taste system provides incomplete or, in some cases, misleading information about the nutritional content and toxicity of foods. This may explain why inputs from the taste system are merged with inputs from the other cephalic senses and intestinal nutrient-sensing systems. By doing so, we create a more complete sensory representation and nutritional evaluation of foods.

Cephalic phase insulin release: A review of its mechanistic basis and variability in humans.

Cephalic phase insulin release (CPIR) is a transient pulse of insulin that occurs within minutes of stimulation from foods or food-related stimuli. Despite decades of research on CPIR in humans, the body of literature surrounding this phenomenon is controversial due in part to contradictory findings . This has slowed progress towards understanding the sensory and neural basis of CPIR, as well as its overall relevance to health. This review examines up-to-date knowledge in CPIR research and identifies sources of CPIR variability in humans in an effort to guide future research. The review starts by defining CPIR and discussing its presumed functional roles in glucose homeostasis and feeding behavior. Next, the types of stimuli that have been reported to elicit CPIR, as well as the sensory and neural mechanisms underlying the response in rodents and humans are discussed, and areas where knowledge is limited are identified. Finally, factors that may contribute to the observed variability of CPIR in humans are examined, including experimental design, test procedure, and individual characteristics. Overall, oral stimulation appears to be important for eliciting CPIR, especially when combined with other sensory modalities (vision, olfaction, somatosensation). While differences in experimental design and testing procedure likely explain some of the observed inter- and intra-study variability, individual differences also appear to play an important role. Understanding sources of these individual differences in CPIR will be key for establishing its health relevance.

NIH Workshop Report: sensory nutrition and disease.

In November 2019, the NIH held the "Sensory Nutrition and Disease" workshop to challenge multidisciplinary researchers working at the interface of sensory science, food science, psychology, neuroscience, nutrition, and health sciences to explore how chemosensation influences dietary choice and health. This report summarizes deliberations of the workshop, as well as follow-up discussion in the wake of the current pandemic. Three topics were addressed: A) the need to optimize human chemosensory testing and assessment, B) the plasticity of chemosensory systems, and C) the interplay of chemosensory signals, cognitive signals, dietary intake, and metabolism. Several ways to advance sensory nutrition research emerged from the workshop: 1) refining methods to measure chemosensation in large cohort studies and validating measures that reflect perception of complex chemosensations relevant to dietary choice; 2) characterizing interindividual differences in chemosensory function and how they affect ingestive behaviors, health, and disease risk; 3) defining circuit-level organization and function that link and interact with gustatory, olfactory, homeostatic, visceral, and cognitive systems; and 4) discovering new ligands for chemosensory receptors (e.g., those produced by the microbiome) and cataloging cell types expressing these receptors. Several of these priorities were made more urgent by the current pandemic because infection with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing coronavirus disease of 2019 has direct short- and perhaps long-term effects on flavor perception. There is increasing evidence of functional interactions between the chemosensory and nutritional sciences. Better characterization of this interface is expected to yield insights to promote health, mitigate disease risk, and guide nutrition policy.

Mixtures of Sweeteners and Maltodextrin Enhance Flavor and Intake of Alcohol in Adolescent Rats.

Sweet flavorants enhance palatability and intake of alcohol in adolescent humans. We asked whether sweet flavorants have similar effects in adolescent rats. The inherent flavor of ethanol in adolescent rats is thought to consist of an aversive odor, bitter/sweet taste, and burning sensation. In Experiment 1, we compared ingestive responses of adolescent rats to 10% ethanol solutions with or without added flavorants using brief-access lick tests. We used 4 flavorants, which contained mixtures of saccharin and sucrose or saccharin, sucrose, and maltodextrin. The rats approached (and initiated licking from) the flavored ethanol solutions more quickly than they did unflavored ethanol, indicating that the flavorants attenuated the aversive odor of ethanol. The rats also licked at higher rates for the flavored than unflavored ethanol solutions, indicating that the flavorants increased the naso-oral acceptability of ethanol. In Experiment 2, we offered rats chow, water, and a flavored or unflavored ethanol solution every other day for 8 days. The rats consistently consumed substantially more of the flavored ethanol solutions than unflavored ethanol across the 8 days. When we switched the rats from the flavored to unflavored ethanol for 3 days, daily intake of ethanol plummeted. We conclude that sweet and sweet/maltodextrin flavorants promote high daily intake of ethanol in adolescent rats (i.e., 6-10 g/kg) and that they do so in large part by improving the naso-oral sensory attributes of ethanol.

Olfaction contributes to the learned avidity for glucose relative to fructose in mice.

When offered glucose and fructose solutions, rodents consume more glucose solution because it produces stronger postoral reinforcement. Intake of these sugars also conditions a higher avidity for glucose relative to fructose. We asked which chemosensory cue mediates the learned avidity for glucose. We subjected mice to 18 days of sugar training, offering them 0.3, 0.6, and 1 M glucose and fructose solutions. Before and after training, we measured avidity for 0.3 and 0.6 M glucose and fructose in brief-access lick tests. First, we replicated prior work in C57BL/6 mice. Before training, the mice licked at a slightly higher rate for 0.6 M fructose; after training, they licked at a higher rate for 0.6 M glucose. Second, we assessed the necessity of the glucose-specific ATP-sensitive K+ (KATP) taste pathway for the learned avidity for glucose, using mice with a nonfunctional KATP channel [regulatory sulfonylurea receptor (SUR1) knockout (KO) mice]. Before training, SUR1 KO and wild-type mice licked at similar rates for 0.6 M glucose and fructose; after training, both strains licked at a higher rate for 0.6 M glucose, indicating that the KATP pathway is not necessary for the learned discrimination. Third, we investigated the necessity of olfaction by comparing sham-treated and anosmic mice. The mice were made anosmic by olfactory bulbectomy or ZnSO4 treatment. Before training, sham-treated and anosmic mice licked at similar rates for 0.6 M glucose and fructose; after training, sham-treated mice licked at a higher rate for 0.6 M glucose, whereas anosmic mice licked at similar rates for both sugars. This demonstrates that olfaction contributes significantly to the learned avidity for glucose.

Low-calorie sweeteners cause only limited metabolic effects in mice.

There are widespread concerns that low-calorie sweeteners (LCSs) cause metabolic derangement. These concerns stem in part from prior studies linking LCS consumption to impaired glucose tolerance in humans and rodents. Here, we examined this linkage in mice. In experiment 1, we provided mice with chow, water, and an LCS-sweetened solution (saccharin, sucralose, or acesulfame K) for 28 days and measured glucose tolerance and body weight across the exposure period. Exposure to the LCS solutions did not impair glucose tolerance or alter weight gain. In experiment 2, we provided mice with chow, water, and a solution containing saccharin, glucose, or a mixture of both for 28 days, and tested for metabolic changes. Exposure to the saccharin solution increased the insulinemic response of mice to the glucose challenge, and exposure to the saccharin + glucose solution increased the rate of glucose uptake during the glucose challenge. However, neither of these test solutions altered glucose tolerance, insulin sensitivity, plasma triglycerides, or percent body fat. In contrast, exposure to the glucose solution increased glucose tolerance, early insulin response, insulin sensitivity, and percent body fat. We conclude that whereas the LCS-containing solutions induced a few metabolic changes, they were modest compared with those induced by the glucose solution.

Oral Post-Oral Actions of Low-Calorie Sweeteners: A Tale of Contradictions and Controversies.

OBJECTIVE: Many scientists and laypeople alike have concerns about low-calorie sweeteners (LCSs). These concerns stem from both a dissatisfaction with the taste of LCSs and reports that they cause metabolic disruptions (e.g., weight gain, glucose intolerance). METHODS: This article provides a critical review of the literature on LCSs from the standpoint of their taste, gastrointestinal, and metabolic effects; biological fate in the body; and impact on ingestion and glucose homeostasis. RESULTS AND CONCLUSIONS: Mammals can readily discriminate between LCSs and sugars because both types of sweetener activate distinct oral and post-oral sensory pathways. LCSs differ in their ability to access post-oral tissues, but few studies have incorporated this observation into their design. It is difficult to extrapolate results between mice, rats, and humans because of interspecies differences in the taste and post-oral actions of LCSs and the fact that investigators often use different response measures in rodents and humans. There is confounding in the experimental design of some of the most widely cited studies of LCS-induced metabolic disruptions. The uncritical acceptance of these studies has generated considerable controversy. More work is needed to obtain a clearer understanding of the metabolic effects of LCSs.

Postnatal Exposure to Ethanol Increases Its Oral Acceptability to Adolescent Rats.

The aversive flavor of ethanol limits intake by many consumers. We asked whether intermittent consumption of ethanol increases its oral acceptability, using rats as a model system. We focused on adolescent rats because they (like their human counterparts) have a higher risk for alcohol overconsumption than do adult rats following experience with the drug. We measured the impact of ethanol exposure on 1) the oral acceptability of ethanol and surrogates for its bitter (quinine) and sweet (sucrose) flavor components in brief-access lick tests and 2) responses of the glossopharyngeal (GL) taste nerve to oral stimulation with the same chemical stimuli. During the exposure period, the experimental rats had access to chow, water and 10% ethanol every other day for 16 days; the control rats had access to chow and water over the same time period. The experimental rats consumed 7-14 g/day of 10% ethanol across the exposure period. This ethanol consumption significantly increased the oral acceptability of 3%, 6% and 10% ethanol, but had no impact on the oral acceptability of quinine, sucrose or NaCl. The ethanol exposure also diminished responses of the GL nerve to oral stimulation with ethanol, but not quinine, sucrose or NaCl. Taken together, these findings indicate that ethanol consumption increases the oral acceptability of ethanol in adolescent rats and that this increased oral acceptability is mediated, at least in part, by an exposure-induced reduction in responsiveness of the peripheral taste system to ethanol per se, rather than its bitter and sweet flavor components.

Taste of glucose elicits cephalic-phase insulin release in mice.

We reported previously that when C57BL/6 (B6) mice ingest glucose, plasma insulin levels rise above baseline before blood glucose levels do so. This observation led us to speculate that the taste of glucose elicits cephalic-phase insulin release (CPIR) in mice. Here, we examined the specific contributions of taste and glucose to CPIR. In Experiment 1, we bypassed the mouth and delivered glucose directly to the stomach. We found that plasma insulin levels did not rise above baseline until after blood glucose levels did so. This revealed that taste stimulation is necessary for rapid insulin release (i.e., CPIR) in mice. In Experiment 2, we examined the observation that sucrose, maltose and Polycose (a maltodextrin) all elicit CPIR. We proposed in a prior study that these carbohydrates did not directly elicit CPIR; instead, they were digested by oral amylases and alpha-glucosidases, and that it was the enzymatically liberated glucose that elicited CPIR. In support of this possibility, we reported that acarbose (an alpha-glucosidase inhibitor) prevented sucrose, maltose and Polycose from eliciting CPIR. Here, we sought to confirm that glucose alone could elicit CPIR in the presence of acarbose. Indeed, we found that glucose alone and glucose+acarbose each elicited equally robust CPIR. Taken together, these results provide further support for the hypothesis that mice possess a glucose-specific taste transduction pathway that triggers rapid insulin release.

Fetal alcohol exposure reduces responsiveness of taste nerves and trigeminal chemosensory neurons to ethanol and its flavor components.

Fetal alcohol exposure (FAE) leads to increased intake of ethanol in adolescent rats and humans. We asked whether these behavioral changes may be mediated in part by changes in responsiveness of the peripheral taste and oral trigeminal systems. We exposed the experimental rats to ethanol in utero by administering ethanol to dams through a liquid diet; we exposed the control rats to an isocaloric and isonutritive liquid diet. To assess taste responsiveness, we recorded responses of the chorda tympani (CT) and glossopharyngeal (GL) nerves to lingual stimulation with ethanol, quinine, sucrose, and NaCl. To assess trigeminal responsiveness, we measured changes in calcium levels of isolated trigeminal ganglion (TG) neurons during stimulation with ethanol, capsaicin, mustard oil, and KCl. Compared with adolescent control rats, the adolescent experimental rats exhibited diminished CT nerve responses to ethanol, quinine, and sucrose and GL nerve responses to quinine and sucrose. The reductions in taste responsiveness persisted into adulthood for quinine but not for any of the other stimuli. Adolescent experimental rats also exhibited reduced TG neuron responses to ethanol, capsaicin, and mustard oil. The lack of change in responsiveness of the taste nerves to NaCl and the TG neurons to KCl indicates that FAE altered only a subset of the response pathways within each chemosensory system. We propose that FAE reprograms development of the peripheral taste and trigeminal systems in ways that reduce their responsiveness to ethanol and surrogates for its pleasant (i.e., sweet) and unpleasant (i.e., bitterness, oral burning) flavor attributes.NEW & NOTEWORTHY Pregnant mothers are advised to avoid alcohol. This is because even small amounts of alcohol can alter fetal brain development and increase the risk of adolescent alcohol abuse. We asked how fetal alcohol exposure (FAE) produces the latter effect in adolescent rats by measuring responsiveness of taste nerves and trigeminal chemosensory neurons. We found that FAE substantially reduced taste and trigeminal responsiveness to ethanol and its flavor components.

Glucose elicits cephalic-phase insulin release in mice by activating KATP channels in taste cells.

The taste of sugar elicits cephalic-phase insulin release (CPIR), which limits the rise in blood glucose associated with meals. Little is known, however, about the gustatory mechanisms that trigger CPIR. We asked whether oral stimulation with any of the following taste stimuli elicited CPIR in mice: glucose, sucrose, maltose, fructose, Polycose, saccharin, sucralose, AceK, SC45647, or a nonmetabolizable sugar analog. The only taste stimuli that elicited CPIR were glucose and the glucose-containing saccharides (sucrose, maltose, Polycose). When we mixed an α-glucosidase inhibitor (acarbose) with the latter three saccharides, the mice no longer exhibited CPIR. This revealed that the carbohydrates were hydrolyzed in the mouth, and that the liberated glucose triggered CPIR. We also found that increasing the intensity or duration of oral glucose stimulation caused a corresponding increase in CPIR magnitude. To identify the components of the glucose-specific taste-signaling pathway, we examined the necessity of Calhm1, P2X2+P2X3, SGLT1, and Sur1. Among these proteins, only Sur1 was necessary for CPIR. Sur1 was not necessary, however, for taste-mediated attraction to sugars. Given that Sur1 is a subunit of the ATP-sensitive K+ channel (KATP) channel and that this channel functions as a part of a glucose-sensing pathway in pancreatic ß-cells, we asked whether the KATP channel serves an analogous role in taste cells. We discovered that oral stimulation with drugs known to increase (glyburide) or decrease (diazoxide) KATP signaling produced corresponding changes in glucose-stimulated CPIR. We propose that the KATP channel is part of a novel signaling pathway in taste cells that mediates glucose-induced CPIR.

Genetics of Amino Acid Taste and Appetite.

The consumption of amino acids by animals is controlled by both oral and postoral mechanisms. We used a genetic approach to investigate these mechanisms. Our studies have shown that inbred mouse strains differ in voluntary amino acid consumption, and these differences depend on sensory and nutritive properties of amino acids. Like humans, mice perceive some amino acids as having a sweet (sucrose-like) taste and others as having an umami (glutamate-like) taste. Mouse strain differences in the consumption of some sweet-tasting amino acids (d-phenylalanine, d-tryptophan, and l-proline) are associated with polymorphisms of a taste receptor, type 1, member 3 gene (Tas1r3), and involve differential peripheral taste responsiveness. Strain differences in the consumption of some other sweet-tasting amino acids (glycine, l-alanine, l-glutamine, and l-threonine) do not depend on Tas1r3 polymorphisms and so must be due to allelic variation in other, as yet unknown, genes involved in sweet taste. Strain differences in the consumption of l-glutamate may depend on postingestive rather than taste mechanisms. Thus, genes and physiologic mechanisms responsible for strain differences in the consumption of each amino acid depend on the nature of its taste and postingestive properties. Overall, mouse strain differences in amino acid taste and appetite have a complex genetic architecture. In addition to the Tas1r3 gene, these differences depend on other genes likely involved in determining the taste and postingestive effects of amino acids. The identification of these genes may lead to the discovery of novel mechanisms that regulate amino acid taste and appetite.

Do low-calorie sweeteners promote weight gain in rodents?

Low-calorie sweeteners (LCSs) are used globally to increase the palatability of foods and beverages, without the calories of sugar. Recently, however, there have been claims that LCSs promote obesity. Here, I review the literature linking LCS consumption to elevated body weight in rodents. A recent systematic review found when the LCSs were presented in water or chow, only a minority of the studies reported elevated weight gain. In contrast, when the LCSs were presented in yogurt, the majority of the studies reported elevated weight gain. This review focuses on this latter subset of studies, and asks why the combination of LCSs and yogurt promoted weight gain. First, LCSs have been hypothesized to induce metabolic derangement because they uncouple sweet taste and calories. However, the available evidence indicates that the LCS-treated yogurts did not actually taste sweet to rats in the published studies. Without a sweet taste, the concerns about uncoupling sweet taste and calories would not be relevant. Second, in several studies, the LCS-treated yogurt increased weight gain without increasing caloric intake. This indicates that caloric intake alone cannot explain the elevated weight gain. Third, there is evidence that LCSs and yogurt can each alter the gut microbiota of rodents. Given recent work indicating that changes in gut microbiota can modulate body weight, it is possible that the combination of LCS and yogurt alters the gut microbiota in ways that promote weight gain. While this hypothesis remains speculative, it is consistent with the observed rodent data. In human studies, LCSs are usually presented in beverages. Based on the rodent work, it might be worthwhile to evaluate the impact of LCS-treated yogurt in humans.

Sugar-induced cephalic-phase insulin release is mediated by a T1r2+T1r3-independent taste transduction pathway in mice.

Sensory stimulation from foods elicits cephalic phase responses, which facilitate digestion and nutrient assimilation. One such response, cephalic-phase insulin release (CPIR), enhances glucose tolerance. Little is known about the chemosensory mechanisms that activate CPIR. We studied the contribution of the sweet taste receptor (T1r2+T1r3) to sugar-induced CPIR in C57BL/6 (B6) and T1r3 knockout (KO) mice. First, we measured insulin release and glucose tolerance following oral (i.e., normal ingestion) or intragastric (IG) administration of 2.8 M glucose. Both groups of mice exhibited a CPIR following oral but not IG administration, and this CPIR improved glucose tolerance. Second, we examined the specificity of CPIR. Both mouse groups exhibited a CPIR following oral administration of 1 M glucose and 1 M sucrose but not 1 M fructose or water alone. Third, we studied behavioral attraction to the same three sugar solutions in short-term acceptability tests. B6 mice licked more avidly for the sugar solutions than for water, whereas T1r3 KO mice licked no more for the sugar solutions than for water. Finally, we examined chorda tympani (CT) nerve responses to each of the sugars. Both mouse groups exhibited CT nerve responses to the sugars, although those of B6 mice were stronger. We propose that mice possess two taste transduction pathways for sugars. One mediates behavioral attraction to sugars and requires an intact T1r2+T1r3. The other mediates CPIR but does not require an intact T1r2+T1r3. If the latter taste transduction pathway exists in humans, it should provide opportunities for the development of new treatments for controlling blood sugar.