The administration of Exendin-4 and CCK affects food intake differentially in female and male rats tested on an alternate day fasting paradigm.

Alternate day fasting (ADF) which involves the repetition of a 2-day cycle of a day of free access to food followed by a day of limited or no access to food, is an effective dietary intervention for weight loss in both humans and rats. We have previously reported that when presented with a high energy (HE) and standard chow diet, rats maintained on an ADF schedule displayed decreased HE diet preference compared to controls. Both male and female ADF rats increased overall intake of chow. However, this increase was driven by both meal size and meal number for males and only number of meals for females. Administration of cholecystokinin (CCK) or the glucagon-like peptide 1 (GLP-1) receptor agonist Exendin-4 (Ex-4) reduces food intake. It appears that CCK decreases food intake primarily through satiety signals whereas GLP-1 signaling may reduce intake by satiety and reward cues. Here, female and male rats were administered (i.p.) saline, 3.0 µg/kg Ex-4 (3 h before test), 3.0 µg/kg CCK (15 min before test) or a combination of both. Next, all rats were presented 23-h access to both HE diet and chow following food-restriction (ADF) or free access to chow (CON). Compared to saline-control sessions, administration of the combination of Ex-4 and CCK, but not Ex-4 or CCK alone, resulted in a decrease in both HE and chow intake early in the session for male ADF rats but the combination primarily decreased chow diet intake early in the session for female ADF rats. Thus, it appears that under these energy homeostatic conditions, administration of Ex-4 or CCK alone does not affect intake in ADF rats, but the combination produces decreases in feeding that are more than the sum of their individual effects. These findings support a role for the combination of GLP-1 and CCK signaling in the changes in diet preference induced by an alternate day fasting paradigm differentially in female and male rats.

Acute and long-lasting effects of adolescent fluoxetine exposure on feeding behavior in Sprague-Dawley rats.

The antidepressant medication fluoxetine (FLX) is frequently prescribed for the management of mood-related illnesses in the adolescent population-yet its long-term neurobehavioral consequences are not understood. To investigate how juvenile FLX exposure influences feeding behavior in adulthood, we conducted two experiments. In Experiment 1, adolescent male and female Sprague-Dawley rats were administered with 20 mg/kg/day FLX (postnatal day [PND] 35-49) and exposed to a binge access paradigm in adulthood (PND72+) to evaluate potential alterations for sweetened-fat preference. No long-term FLX-induced differences in preference for sweetened fat versus chow, nor total caloric intake, were noted; however, females displayed higher preference for sweetened fat compared to males. In Experiment 2, PND35 male rats received FLX (PND35-49) and were exposed to chronic variable stress (CVS) in adulthood (PND74-88). During treatment, FLX decreased body weight and intake (meal size), but not total meal number. Also, no differences in meal pattern parameters were observed after FLX completion. Likewise, no differences in meal pattern parameters to a palatable diet (45% fat, 17% sucrose) presented from PND74 to PND88, even after CVS, were observed. Our findings indicate that juvenile FLX reduces body weight gain acutely via reduced meal size intake; however, no long-term changes in ad libitum feeding behavior or binge access to a palatable stimulus are evident.

Effect of early-life stress or fluoxetine exposure on later-life conditioned taste aversion learning in Sprague-Dawley rats.

In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.

Administration of Exendin-4 but not CCK alters lick responses and trial initiation to sucrose and intralipid during brief-access tests.

Administration of cholecystokinin (CCK) or the glucagon-like peptide 1 (GLP-1) receptor agonist Exendin-4 (Ex-4) reduces food intake. Findings in the literature suggest CCK reduces intake primarily as a satiety signal whereas GLP-1 may play a role in both satiety and reward-related feeding signals. Compounds that humans describe as âsweetâ and âfattyâ are palatable yet are signaled via separate transduction pathways. Here, unconditioned lick responses to sucrose and intralipid were measured in a brief-access lick procedure in food-restricted male rats in response to i.p. administration of Ex-4 (3 h before test), CCK (30 min before test), or a combination of both. The current experimental design measures lick responses to water and varying concentrations of both sucrose (0.03, 0.1, and 0.5 M) and intralipid (0.2%, 2%, and 20%) during 10-s trials across a 30-min single test session. This design minimized postingestive influences. Compared with saline-injected controls, CCK (1.0, 3.0, or 6.0 µg/kg) did not change lick responses to sucrose or intralipid. Number of trials initiated and lick responses to both sucrose and intralipid were reduced in rats injected with 3.0 µg/kg, but not 1.0 µg/kg Ex-4. The supplement of CCK did not alter lick responses or trials initiated compared with Ex-4 administration alone. These findings support a role for GLP-1 but not CCK in the oral responsiveness to palatable stimuli. Furthermore, Ex-4-induced reductions were observed for both sucrose and intralipid, compounds representing âsweetâ and âfat,â respectively.

Alternate day fasting decreases preference for a calorically dense diet by increasing chow intake and altering meal pattern parameters.

Alternate day fasting (ADF) is an effective dietary strategy for weight loss in both humans and rats. However, fasting can elicit hyperphagia in rats, particularly upon access to a calorically dense, high-energy (HE) diet. To examine the effects of ADF on HE diet preference, male and female Sprague-Dawley rats were randomly assigned to receive either ad-libitum or alternate day access to both chow and HE food. Meal pattern analysis was conducted to provide a more detailed explanation of changes in HE preference. ADF rats had a decreased preference for the HE diet compared to controls. Both male and female ADF rats increased in overall intake of chow. However, for male ADF rats, the decrease in HE preference was driven by an increase in both size and number of chow meals; for females, it was driven only by an increase in number of chow meals. Meal size is controlled by both positive feedback (e.g., from the oral cavity) and negative feedback (e.g., from postoral inhibitory signals). Thus, for males, fasting appeared to increase orosensory stimulation and/or decrease sensitivity to inhibitory cues towards chow. For females, fasting appeared to decrease sensitivity to inhibitory cues towards chow. The decrease in HE preference observed in the current study may contribute to the effectiveness of ADF as a dietary strategy for weight loss.

Short-Term Exposure to a Calorically Dense Diet Alters Taste-Evoked Responses in the Chorda Tympani Nerve, But Not Unconditioned Lick Responses to Sucrose.

Upon presentation of a calorically dense diet, rats display hyperphagia driven by increased meal size. The increased meal size and hyperphagia are most robust across the first several days of diet exposure before changes in body weight are evident, thus it is plausible that one of the factors that drives the hyperphagia may be enhanced orosensory responsivity. Here, electrophysiological responses to an array of taste stimuli were recorded from the chorda tympani nerve, a branch of the facial nerve that innervates taste receptors in the anterior tongue, of rats presented a high-energy (45% fat and 17% sucrose) diet for 3 days. Responses in the high-energy diet group were significantly higher for 0.01, 0.03, 0.06 and 0.3 M sucrose; 0.05 M Na-saccharin; and 0.01 M quinine compared with those of chow-fed controls. Another cohort of animals was tested in 30-min brief-access taste sessions (10-s trials) to a sucrose concentration series across the first 6 days of high-energy diet presentation. Both groups responded in a concentration-dependent manner. No significant group differences in unconditioned licking or trials initiated were revealed. Results from a third cohort of rats showed that responses to sucrose in a brief-access taste test also remained largely unchanged as a function of 3-day access to a sucrose solution. Taken together, these findings suggest that 3 days of high-energy diet exposure results in alterations to peripheral gustatory signaling yet these changes do not necessarily generalize to changes in responsiveness to sucrose, as least as measured in this procedure.

Cross-Generalization Profile to Orosensory Stimuli of Rats Conditioned to Avoid a High Fat/High Sugar Diet.

The orosensory characteristics of a diet play a role in its acceptance and rejection. The current study was designed to investigate the gustatory components that contribute to the intake of a palatable, high-energy diet (HE; 45% calories from fat, 17% calories from sucrose). Here, rats were conditioned to avoid HE diet by pairings with i.p. injections of LiCl to induce visceral malaise. Subsequently, the degree of generalization was tested to an array of taste compounds using a brief-access lick procedure (10-s trials, 30-min sessions). Compared to NaCl-injected controls, LiCl-injected rats suppressed licking response to 100% linoleic acid and 20% intralipid, and to a lesser extent 17% sucrose. There was more variability in the lick responses to sucrose among the LiCl-injected rats. Rats that tended to suppress licking responses to sucrose generalized this response to glucose, fructose and Na-saccharin but not to Polycose. In contrast, LiCl-injected rats did not significantly suppress lick responses to water, NaCl, citric acid, or quinine compared to controls rats. The brief access feature of this procedure, allows for behavioral measures when postingestive factors are minimized. These findings support a role for gustatory cues in the detection of high fat/high sugar diets. Furthermore, it appears that the fat component is a more salient orosensory feature of the HE diet.

A predictive model of rat calorie intake as a function of diet energy density.

Easy access to high-energy food has been linked to high rates of obesity in the world. Understanding the way that access to palatable (high fat or high calorie) food can lead to overconsumption is essential for both preventing and treating obesity. Although the body of studies focused on the effects of high-energy diets is growing, our understanding of how different factors contribute to food choices is not complete. In this study, we present a mathematical model that can predict rat calorie intake to a high-energy diet based on their ingestive behavior to a standard chow diet. Specifically, we propose an equation that describes the relation between the body weight ( W), energy density ( E), time elapsed from the start of diet ( T), and daily calorie intake ( C). We tested our model on two independent data sets. Our results show that the suggested model can predict the calorie intake patterns with high accuracy. Additionally, the only free parameter of our proposed equation (ρ), which is unique to each animal, has a strong correlation with their calorie intake.

Exposure to activity-based anorexia impairs contextual learning in weight-restored rats without affecting spatial learning, taste, anxiety, or dietary-fat preference.

UNLABELLED: Relapse rates are high amongst cases of anorexia nervosa (AN) suggesting that some alterations induced by AN may remain after weight restoration. OBJECTIVE: To study the consequences of AN without confounds of environmental variability, a rodent model of activity-based anorexia (ABA) can be employed. We hypothesized that exposure to ABA during adolescence may have long-term consequences in taste function, cognition, and anxiety-like behavior after weight restoration. METHODS: To test this hypothesis, we exposed adolescent female rats to ABA (1.5 h food access, combined with voluntary running wheel access) and compared their behavior to that of control rats after weight restoration was achieved. The rats were tested for learning/memory, anxiety, food preference, and taste in a set of behavioral tests performed during the light period. RESULTS: Our data show that ABA exposure leads to reduced performance during the novel object recognition task, a test for contextual learning, without altering performance in the novel place recognition task or the Barnes maze, both tasks that test spatial learning. Furthermore, we do not observe alterations in unconditioned lick responses to sucrose nor quinine (described by humans as "sweet" and "bitter," respectively). Nor Do we find alterations in anxiety-like behavior during an elevated plus maze or an open field test. Finally, preference for a diet high in fat is not altered. DISCUSSION: Overall, our data suggest that ABA exposure during adolescence impairs contextual learning in adulthood without altering spatial leaning, taste, anxiety, or fat preference.

Alterations in sucrose sham-feeding intake as a function of diet-exposure in rats maintained on calorically dense diets.

We previously reported that rats increase meal size upon initial presentation of a calorically dense diet. The increase may be attributed to increased orosensory stimulation and/or reduced sensitivity to post-ingestive inhibitory signals. During feeding both types of signals are simultaneously in play; thus here, we compare responses in rats presented a high-energy diet (HE) or 45% high-fat diet (HF) with those of chow-fed controls (CHOW) in a sham-feeding procedure in which post-ingestive feedback is minimized. Measures of sham-feeding to sucrose were taken before diet manipulation (baseline), ~5 days (dynamic phase) and ~6 weeks (static phase) following introduction of the palatable diet, as well as after animals were switched back to standard chow (recovery phase). Some but not all the hypotheses based on our previous findings were confirmed by the outcomes here. Consistent with our hypothesis that enhanced orosensory stimulation during the dynamic phase compared with the static phase would generalize to increased intake of other palatable stimuli, HE rats showed higher sucrose intake during the dynamic phase compared with the static phase. Contrary to what we hypothesized, HE and HF rats did not increase responses to sucrose compared to CHOW rats. In fact, HE rats showed decreased responses compared to CHOW controls. Thus changes in orosensory stimulation do not necessarily generalize to increased intake of other palatable stimuli.

A new gustometer for taste testing in rodents.

In recent years, to circumvent the interpretive limitations associated with intake tests commonly used to assess taste function in rodents, investigators have developed devices called gustometers to deliver small volumes of taste samples and measure immediate responses, thereby increasing confidence that the behavior of the animal is under orosensory control. Most of these gustometers can be used to measure unconditioned licking behavior to stimuli presented for short durations and/or can be used to train the animal to respond to various fluid stimuli differentially so as to obtain a reward and/or avoid punishment. Psychometric sensitivity and discrimination functions can thus be derived. Here, we describe a new gustometer design, successfully used in behavioral experiments, that was guided by our experience with an older version used for over 2 decades. The new computer-controlled gustometer features no dead space in stimulus delivery lines, effective cleaning of the licking substrate, and the ability to measure licking without passing electrical current through the animal. The parts and dimensions are detailed, and the benefits and limitations of certain design features are discussed. Schematics for key circuits are provided as supplemental information. Accordingly, it should be possible to fabricate this device in a fashion customized for one's needs.

Behavioral characterization of the hyperphagia synphilin-1 overexpressing mice.

Synphilin-1 is a cytoplasmic protein that has been shown to be involved in the control of energy balance. Previously, we reported on the generation of a human synphilin-1 transgenic mouse model (SP1), in which overexpression of human synphilin-1 resulted in hyperphagia and obesity. Here, behavioral measures in SP1 mice were compared with those of their age-matched controls (NTg) at two time points: when there was not yet a group body weight difference ("pre-obese") and when SP1 mice were heavier ("obese"). At both time points, meal pattern analyses revealed that SP1 mice displayed higher daily chow intake than non-transgenic control mice. Furthermore, there was an increase in meal size in SP1 mice compared with NTg control mice at the obese stage. In contrast, there was no meal number change between SP1 and NTg control mice. In a brief-access taste procedure, both "pre-obese" and "obese" SP1 mice displayed concentration-dependent licking across a sucrose concentration range similar to their NTg controls. However, at the pre-obese stage, SP1 mice initiated significantly more trials to sucrose across the testing sessions and licked more vigorously at the highest concentration presented, than the NTg counterparts. These group differences in responsiveness to sucrose were no longer apparent in obese SP1 mice. These results suggest that at the pre-obese stage, the increased trials to sucrose in the SP1 mice reflects increased appetitive behavior to sucrose that may be indicative of the behavioral changes that may contribute to hyperphagia and development of obesity in SP1 mice. These studies provide new insight into synphilin-1 contributions to energy homeostasis.

Maternal high-fat diet during pregnancy and lactation reduces the appetitive behavioral component in female offspring tested in a brief-access taste procedure.

Maternal high-fat diet appears to disrupt several energy balance mechanisms in offspring. Here, female offspring from dams fed a high-fat diet (HF) did not significantly differ in body weight compared with those fed chow (CHOW), when weaned onto chow diet. Yet when presented with both a chow and a high-fat diet, high-fat intake was significantly higher in HF compared with CHOW offspring. To assess taste-based responsiveness, offspring (12 wk old) were tested in 30-min sessions (10-s trials) to a sucrose concentration series in a brief-access taste test. Compared with CHOW, the HF offspring initiated significantly fewer trials but did not significantly differ in the amount of concentration-dependent licking. Thus, rather than affect lick response (consummatory), maternal diet affects spout approach (appetitive), which may be attributed to motivation-related mechanisms. Consistent with this possibility, naltrexone, an opioid receptor antagonist, further reduced trial initiation, but not licking in both groups. With naltrexone administration, the group difference in trial initiation was no longer evident, suggesting differences in endogenous opioid activity between the two groups. Relative expression of µ-opioid receptor in the ventral tegmental area was significantly lower in HF rats. When trial initiation was not required in one-bottle intake tests, no main effect of maternal diet on the intake of sucrose and corn oil emulsions was observed. Thus, the maternal high-fat diet-induced difference in diet preference is not likely due to changes in the sensory orosensory component of the taste stimulus but may depend on alterations in satiety signals or absorptive mechanisms.

Similarities and differences between "proactive" and "passive" stress-coping rats in responses to sucrose, NaCl, citric acid, and quinine.

A stress-coping style describes a set of behavioral and physiological measures that characterize an individual's response to stressful stimuli. It would follow that different stress-coping styles are associated with differential sensitivity for taste stimuli. Animals with stress-coping characteristics better suited to an environment in which new foods are more frequently encountered may show enhanced orosensitivity to cues that signal toxins and/or nutritional value. Here, rats were categorized as "proactive" or "passive" based on results from a defensive burying test. Next, the brief-access taste procedure was used to compare unconditioned licking responses to a concentration array of compounds that humans describe as "sweet" (sucrose), "salty" (NaCl), "sour" (citric acid), and "bitter" (quinine) across the 2 groups. Both groups displayed concentration-dependent lick responses to sucrose, NaCl, citric acid, and quinine. The passive group initiated significantly fewer trials to sucrose than the proactive rats, but the groups did not significantly differ in trial initiation for the other 3 test compounds. Thus, differences in food intake, body weight, and glucose homeostasis between the stress-coping styles are not likely driven by alterations in orosensory responsivity. However, the current findings lend support to the hypothesis that the 2 groups differ in reward-related signaling mechanisms.

Analyses of meal patterns across dietary shifts.

The direct controls of meal size can be categorized into positive signals such as those from the oral cavity and negative signals such as postoral inhibitory cues. It follows that the relative contribution of these signals, and in turn meal pattern parameters, change across periods of high-energy diet exposure. Here, we compared daily intake and meal pattern analysis in male Sprague-Dawley rats presented a high-energy diet for 6weeks then standard chow for ∼1week (HE), with those of standard chow fed controls (CHOW). These measures allow for evaluation of (1) whether there are distinct dynamic and static phases of DIO and if so, how they are characterized, (2) how meal patterns change across short and long term HE experience, and (3) ingestive behavioral changes when HE-fed animals are returned to standard chow. The HE animals showed significantly higher intake primarily driven by an increase in meal size compared to CHOW controls. This was most pronounced during the first several days of high-energy diet exposure thus characterizing the dynamic phase. Intake and meal size decreased with longer exposure to the diet but remained significantly higher than those of CHOW. Increased meal size could be driven by enhanced orosensory stimulation and/or reduced sensitivity to postoral inhibitory feedback. Distribution curves derived from histogram plots of meal size revealed both larger average meal size (right shift) and spread (standard deviation) thus it is tempting to speculate that more than one type of mechanism influences increased meal size. Meal number decreased suggesting post meal inhibitory signaling is relatively intact. However, this increase was insufficient to compensate for the increased meal size. When HE animals were switched to standard chow, daily intake and meal size decreased and eventually returned to values comparable to those of the CHOW rats. Meal number remained lower suggesting altered physiological mechanism(s) that underlie the control of ingestive behavior as a function of previous high-energy diet exposure.

Overexpression of neuropeptide Y in the dorsomedial hypothalamus increases trial initiation but does not significantly alter concentration-dependent licking to sucrose in a brief-access taste test.

Evidence in the literature raises the possibility that alterations in neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) may contribute to hyperphagia leading to body weight gain. Previously, we have shown that compared to AAVGFP controls, adeno-associated virus (AAV)-mediated overexpression of NPY in the DMH of lean rats resulted in significantly higher body weight gain that was attributed to increased food intake, and this was further exacerbated by a high-fat diet. Here, we tested AAVNPY and AAVGFP control rats in a brief-access taste procedure (10-s trials, 30-min sessions) to an array of sucrose concentrations under ad libitum and partial food and water access conditions. The test allows for some segregation of the behavioral components by providing a measure of trial initiation (appetitive) and unconditioned licks at each concentration (consummatory). Consistent with previous findings suggesting that NPY has a primary effect on appetitive function, overexpression of DMH NPY did not significantly alter concentration-dependent licking response to sucrose but when tested in a non-restricted food and water schedule, AAVNPY rats initiated significantly more sucrose trials compared to AAVGFP controls in a brief-access taste test.

Contribution of the TRPV1 channel to salt taste quality in mice as assessed by conditioned taste aversion generalization and chorda tympani nerve responses.

In rodents, at least two transduction mechanisms are involved in salt taste: 1) the sodium-selective epithelial sodium channel, blocked by topical amiloride administration, and 2) one or more amiloride-insensitive cation-nonselective pathways. Whereas electrophysiological evidence from the chorda tympani nerve (CT) has implicated the transient receptor potential vanilloid-1 (TRPV1) channel as a major component of amiloride-insensitive salt taste transduction, behavioral results have provided only equivocal support. Using a brief-access taste test, we examined generalization profiles of water-deprived C57BL/6J (WT) and TRPV1 knockout (KO) mice conditioned (via LiCl injection) to avoid 100 µM amiloride-prepared 0.25 M NaCl and tested with 0.25 M NaCl, sodium gluconate, KCl, NH(4)Cl, 6.625 mM citric acid, 0.15 mM quinine, and 0.5 M sucrose. Both LiCl-injected WT and TRPV1 KO groups learned to avoid NaCl+amiloride relative to controls, but their generalization profiles did not differ; LiCl-injected mice avoided the nonsodium salts and quinine suggesting that a TRPV1-independent pathway contributes to the taste quality of the amiloride-insensitive portion of the NaCl signal. Repeating the experiment but doubling all stimulus concentrations revealed a difference in generalization profiles between genotypes. While both LiCl-injected groups avoided the nonsodium salts and quinine, only WT mice avoided the sodium salts and citric acid. CT responses to these stimuli and a concentration series of NaCl and KCl with and without amiloride did not differ between genotypes. Thus, in our study, TRPV1 did not appear to contribute to sodium salt perception based on gustatory signals, at least in the CT, but may have contributed to the oral somatosensory features of sodium.

Orosensory detection of sucrose, maltose, and glucose is severely impaired in mice lacking T1R2 or T1R3, but Polycose sensitivity remains relatively normal.

Evidence in the literature supports the hypothesis that the T1R2+3 heterodimer binds to compounds that humans describe as sweet. Here, we assessed the necessity of the T1R2 and T1R3 subunits in the maintenance of normal taste sensitivity to carbohydrate stimuli. We trained and tested water-restricted T1R2 knockout (KO), T1R3 KO and their wild-type (WT) same-sex littermate controls in a two-response operant procedure to sample a fluid and differentially respond on the basis of whether the stimulus was water or a tastant. Correct responses were reinforced with water and incorrect responses were punished with a time-out. Testing was conducted with a modified descending method of limits procedure across daily 25-min sessions. Both KO groups displayed severely impaired performance and markedly decreased sensitivity when required to discriminate water from sucrose, glucose, or maltose. In contrast, when Polycose was tested, KO mice had normal EC(50) values for their psychometric functions, with some slight, but significant, impairment in performance. Sensitivity to NaCl did not differ between these mice and their WT controls. Our findings support the view that the T1R2+3 heterodimer is the principal receptor that mediates taste detection of natural sweeteners, but not of all carbohydrate stimuli. The combined presence of T1R2 and T1R3 appears unnecessary for the maintenance of relatively normal sensitivity to Polycose, at least in this task. Some detectability of sugars at high concentrations might be mediated by the putative polysaccharide taste receptor, the remaining T1R subunit forming either a homodimer or heteromer with another protein(s), or nontaste orosensory cues.

Behavioral evidence for a glucose polymer taste receptor that is independent of the T1R2+3 heterodimer in a mouse model.

Although it is clear that the heterodimer formed by the T1R2 and T1R3 proteins serves as the primary taste receptor for sweeteners, there is growing evidence that responses to glucose polymers may be mediated by a different taste receptor. Here we report that although T1R2 knock-out (KO) and T1R3 KO mice displayed severely impaired responding to glucose, maltose, and maltotriose in an initial session of a brief-access taste test (5 s trials, 25 min sessions) relative to wild-type (WT) mice, they subsequently increased their licking as a function of concentration for maltose and maltotriose with continued testing, presumably due to associating weak oral cues with positive post-ingestive consequences. Interestingly, these KO mice displayed relatively normal concentration-dependent licking to Polycose, a mixture of glucose polymers, even in the first session. Importantly, the experience-dependent increase in responsiveness to the sugars observed with the T1R2 and T1R3 single KO mice was not statistically significant in the T1R2/3 double KO mice. The double KO mice, however, still displayed significant concentration-dependent responding to Polycose in the first test session, albeit lick rates were slightly lower than those seen for WT mice, perhaps because small amounts of glucose, maltose, and maltotriose found in Polycose were enhancing the signal in WT mice or because T1R2 or T1R3 can possibly heteromerize with another protein to form a fully functional glucose polymer receptor. These findings provide behavioral evidence that glucose polymers, with an optimal chain length greater than three glucose moieties, stimulate a taste receptor independent of the T1R2+3 heterodimer.

The functional role of the T1R family of receptors in sweet taste and feeding.

The discovery of the T1R family of Class C G protein-coupled receptors in the peripheral gustatory system a decade ago has been a tremendous advance for taste research, and its conceptual reach has extended to other organ systems. There are three proteins in the family, T1R1, T1R2, and T1R3, encoded by their respective genes, Tas1r1, Tas1r2, and Tas1r3. T1R2 combines with T1R3 to form a heterodimer that binds with sugars and other sweeteners. T1R3 also combines with T1R1 to form a heterodimer that binds with l-amino acids. These proteins are expressed not only in taste bud cells, but one or more of these T1Rs have also been identified in the nasal epithelium, gut, pancreas, liver, kidney, testes and brain in various mammalian species. Here we review current perspectives regarding the functional role of these receptors, concentrating on sweet taste and feeding. We also discuss behavioral findings suggesting that a glucose polymer mixture, Polycose, which rodents avidly prefer, appears to activate a receptor that does not depend on the combined expression of T1R2 and T1R3. In addition, although the T1Rs have been implicated as playing a role in glucose sensing, T1R2 knock-out (KO) and T1R3 KO mice display normal chow and fluid intake as well as normal body weight compared with same-sex littermate wild type (WT) controls. Moreover, regardless of whether they are fasted or not, these KO mice do not differ from their WT counterparts in their Polycose intake across a broad range of concentrations in 30-minute intake tests. The functional implications of these results and those in the literature are considered.