Zukerman S, Glendinning JI, Margolskee RF, Sclafani A. T1R3 taste receptor is critical for sucrose but not Polycose taste. In addition to their well-known preference for sugars, mice and rats avidly consume starch-derived glucose polymers (e.g., Polycose). T1R3 is a component of the mammalian sweet taste receptor that mediates the preference for sugars and artificial sweeteners in mammals. We examined the role of the T1R3 receptor in the ingestive response of mice to Polycose and sucrose. In 60-s two-bottle tests, knockout (KO) mice preferred Polycose solutions (4 -32%) to water, although their overall preference was lower than WT mice (82% vs. 94%). KO mice also preferred Polycose (0.5-32%) in 24-h two-bottle tests, although less so than WT mice at dilute concentrations (0.5-4%). In contrast, KO mice failed to prefer sucrose to water in 60-s tests. In 24-h tests, KO mice were indifferent to 0.5-8% sucrose, but preferred 16 -32% sucrose; this latter result may reflect the post-oral effects of sucrose. Overall sucrose preference and intake were substantially less in KO mice than WT mice. However, when retested with 0.5-32% sucrose solutions, the KO mice preferred all sucrose concentrations, although they drank less sugar than WT mice. The experience-induced sucrose preference is attributed to a post-oral conditioned preference for the T1R3-independent orosensory features of the sugar solutions (odor, texture, T1R2-mediated taste). Chorda tympani nerve recordings revealed virtually no response to sucrose in KO mice, but a near-normal response to Polycose. These results indicate that the T1R3 receptor plays a critical role in the tastemediated response to sucrose but not Polycose.preference; C57BL/6J mice; chorda tympani nerve; saccharin; postoral conditioning THE TASTE OF SUGAR IS HIGHLY attractive to humans and many other animal species. Studies of inbred mouse strains led to the identification of the T1R2 and T1R3 receptor proteins that dimerize to form a sweet taste receptor (1). Selective elimination of these receptor proteins in knockout mice attenuates or completely blocks the behavioral and gustatory nerve responses to sugars and artificial sweeteners (7, 40). Further, allelic variation in the Tas1r3 gene, which codes for the T1R3 protein (3,(17)(18)(19)24), contributes to strain differences in sensitivity (9), lick responsiveness (8, 10), peripheral taste nerve responsiveness (11), and daily intake and preference (11, 22) for sugars and artificial sweeteners.Sugars are not the only carbohydrates that have an attractive taste to some nonhuman species. Twenty years ago, our laboratory published a series of papers demonstrating that rats, mice, hamsters, and gerbils are strongly attracted to the taste of starch-derived glucose polymers such as Polycose and other maltodextrins (26). Behavioral and electrophysiological evidence indicates that Polycose and sucrose have qualitatively distinct taste sensations in rodents. For example, aversions conditioned to Polycose or sucrose do not cross-generalize, and some ta...
Zukerman S, Ackroff K, Sclafani A. Post-oral appetite stimulation by sugars and nonmetabolizable sugar analogs. Am J Physiol Regul Integr Comp Physiol 305: R840 -R853, 2013. First published August 7, 2013 doi:10.1152/ajpregu.00297.2013.-Post-oral sugar actions enhance the intake of and preference for sugar-rich foods, a process referred to as appetition. Here, we investigated the role of intestinal sodium glucose cotransporters (SGLTs) in sugar appetition in C57BL/6J mice using sugars and nonmetabolizable sugar analogs that differ in their affinity for SGLT1 and SGLT3. In experiments 1 and 2, food-restricted mice were trained (1 h/day) to consume a flavored saccharin solution [conditioned stimulus (CSϪ)] paired with intragastric (IG) self-infusions of water and a different flavored solution (CSϩ) paired with infusions of 8 or 12% sugars (glucose, fructose, and galactose) or sugar analogs (␣-methyl-D-glucopyranoside, MDG; 3-O-methyl-D-glucopyranoside, OMG). Subsequent twobottle CSϩ vs. CSϪ choice tests were conducted without coinfusions. Infusions of the SGLT1 ligands glucose, galactose, MDG, and OMG stimulated CSϩ licking above CSϪ levels. However, only glucose, MDG, and galactose conditioned significant CSϩ preferences, with the SGLT3 ligands (glucose, MDG) producing the strongest preferences. Fructose, which is not a ligand for SGLTs, failed to stimulate CSϩ intake or preference. Experiment 3 revealed that IG infusion of MDGϩphloridzin (an SGLT1/3 antagonist) blocked MDG appetition, whereas phloridzin had minimal effects on glucose-induced appetition. However, adding phloretin (a GLUT2 antagonist) to the glucoseϩphloridzin infusion blocked glucose appetition. Taken together, these findings suggest that humoral signals generated by intestinal SGLT1 and SGLT3, and to a lesser degree, GLUT2, mediate post-oral sugar appetition in mice. The MDG results indicate that sugar metabolism is not essential for the post-oral intake-stimulating and preference-conditioning actions of sugars in mice.post-oral sugar conditioning; glucose; fructose; galactose FOOD INTAKE AND PREFERENCE are guided by oral sensations (taste, odor, and mouth feel) that contribute to the identification and hedonic evaluation of food flavor. Considerable progress has been made in identifying the taste receptors that respond to sugar, fat, and amino acids that provide attractive sweet, fatty, and umami flavors to foods (8). The appetite for such foods is further enhanced by the post-oral actions of ingested nutrients (50). This is demonstrated in laboratory rodents by the intake stimulation and learned preferences for arbitrary flavors (conditioned stimuli, CS) that are paired with gastric or intestinal infusions of sugar, fat, and proteins (or glutamate) (50). However, relatively little is known about the sites and identities of the sensors that mediate the post-oral appetite-stimulating actions of nutrients, a process we refer to as appetition (48). In the case of sugars, several findings implicate the upper small intestine as a primary site of a...
-Although widely assumed to have only satiating actions, nutrients in the gut can also condition increases in intake in some cases. Here we studied the time course of post-oral nutrient stimulation of ingestion in food-restricted C57BL/6J mice. In experiment 1, mice adapted to drink a 0.8% sucralose solution 1 h/day, rapidly increased their rate of licking (within 4 -6 min) when first tested with an 8% glucose solution and even more so in tests 2 and 3. Other mice decreased their licking rate when switched from sucralose to 8% fructose, a sugar that is sweet like glucose but lacks positive post-oral effects in mice. The glucose-stimulated drinking is due to the sugar's post-oral rather than taste properties, because sucralose is highly preferred to glucose and fructose in brief choice tests. A second experiment showed that the glucose-stimulated ingestion is associated with a conditioned flavor preference in both intact and capsaicin-treated mice. This indicates that the post-oral stimulatory action of glucose is not mediated by capsaicin-sensitive visceral afferents. In experiment 3, mice consumed flavored saccharin solutions as they self-infused water or glucose via an intragastric (IG) catheter. The glucose self-infusion stimulated ingestion within 13-15 min in test 1 and produced a conditioned increase in licking that was apparent in the initial minute of tests 2 and 3. Experiment 4 revealed that IG self-infusions of a fat emulsion also resulted in post-oral stimulation of licking in test 1 and conditioned increases in tests 2 and 3. These findings indicate that glucose and fat can generate stimulatory post-oral signals early in a feeding session that increase ongoing ingestion and condition increases in flavor acceptance and preference revealed in subsequent feeding sessions. The test procedures developed here can be used to investigate the peripheral and central processes involved in stimulation of intake by post-oral nutrients.conditioned flavor acceptance and preference; fructose; sucralose; capsaicin deafferentation; intragastric infusion THE OROSENSORY AND POST-ORAL nutritional properties of foods are important determinants of food intake and preference. The flavors of palatable foods, i.e., their taste, odor, and texture, stimulate feeding, whereas post-oral signals are often assumed to have only inhibitory action via satiation signals that terminate a feeding bout and satiety signals that suppress postmeal eating (10,24,56). However, there is extensive evidence that nutrients can have other post-oral effects that condition food preferences and, in some cases, increase intake (42). This has been demonstrated, for example, by studies in which rodents are trained to drink a flavored nonnutritive solution paired with intragastric (IG) self-infusion of a nutrient. Typically, animals are given multiple training trials with one flavor (the conditioned stimulus or CSϩ) paired with a concurrent IG nutrient self-infusion and a second flavor (CSϪ) paired with IG water self-infusion on alternate training days. T...
Trpm5 and alpha-gustducin are key to the transduction of tastes of sugars, amino acids, and bitter compounds. This study investigated the role of these signaling proteins in the preference for fat, starch, and starch-derived polysaccharides (Polycose), using Trpm5 knockout (Trpm5 KO) and alpha-gustducin knockout (Gust KO) mice. In initial two-bottle tests (24 h/day), Trpm5 KO mice showed no preference for soybean oil emulsions (0.313-2.5%), Polycose solutions (0.5-4%), or starch suspensions (0.5-4%). Gust KO mice displayed an attenuated preference for Polycose, but their preferences for soybean oil and starch were comparable to those of C57BL/6J wild-type (WT) mice. Gust KO mice preferred starch to Polycose, whereas WT mice had the opposite preference. After extensive experience with soybean oil emulsions (Intralipid) and Polycose solutions, the Trpm5 KO mice developed preferences comparable to the WT mice, although their absolute intakes remained suppressed. Similarly, Gust KO mice developed a strong Polycose preference with experience, but they continued to consume less than the WT mice. These results implicate alpha-gustducin and Trpm5 as mediators of polysaccharide taste and Trpm5 in fat taste. The disruption in Polycose, but not starch, preference in Gust KO mice indicates that distinct sensory signaling pathways mediate the response to these carbohydrates. The experience-induced rescue of fat and Polycose preferences in the KO mice likely reflects the action of a postoral-conditioning mechanism, which functions in the absence of alpha-gustducin and Trpm5.
In a recent study, intragastric (IG) self-infusion of 16% glucose stimulated 1-h intake and conditioned a preference for a flavored saccharin solution in C57BL/6J mice (Zukerman et al., 2011). Experiment 1 of the present study presents a concentration-response analysis of IG glucose-induced intake stimulation monitored by recording licking response every min of the 1 h/day sessions. Separate groups of food-restricted mice consumed a flavored saccharin solution (the CS−) paired with IG self-infusions of water (Test 0) followed by a different flavored solution (the CS+) paired with IG self-infusions of 2, 4, 8, 16, or 32% glucose (Tests 1–3). Following additional CS− and CS+ training sessions, a two-bottle CS+ vs. CS− choice test was conducted without infusions. Self-infusions of 8%, 16% or 32% glucose stimulated CS+ licking within 12 min of the first test session and even earlier in subsequent test sessions, and also conditioned significant CS+ preferences in the two-bottle test. The stimulation of early licking and CS+ preference increased as a function of glucose concentration. The amount of glucose solute self-infused increased with sugar concentration as did post-infusion blood glucose levels. The 2% glucose infusion did not stimulate CS+ intake and the 2% and 4% infusions failed to produce a CS+ preference in the 1-h test. Experiment 2 revealed that intraperitoneal self-infusions of 8% glucose, unlike IG glucose self-infusions, failed to stimulate CS+ licking or preference despite producing maximal increases in blood glucose levels. Taken together, these and other findings suggest that glucose rapidly produces concentration-dependent intestinal signals that stimulate intake and condition flavor preferences while postoral satiation signals limit total amounts consumed.
In addition to orosensory signals, postoral actions of fat stimulate appetite and condition flavor preferences, but the gut sensors mediating these responses are unknown. Here, we investigated the role of the fatty acid sensors GPR40 and GPR120 in postoral and oral preferences for a soybean oil emulsion (Intralipid). Mice were trained to drink a flavored solution (CS+) paired with intragastric (IG) oil infusions and another flavored solution (CS-) paired with water infusions. Knockout (KO) mice missing GPR40 or GPR120 sensors increased their CS+ intake in one-bottle tests (1 h/day) but less so than wild-type (WT) mice. The KO mice also preferred the CS+ to CS- in a two-bottle test, but the preference was attenuated in GPR40 KO mice. Double-knockout (DoKO) mice missing both GPR40 and GPR120 displayed attenuated stimulation of CS+ intake and only a marginal CS+ preference. The DoKO mice developed a more substantial CS+ preference when tested 24 h/day, although weaker than that of WT mice. The DoKO mice also consumed less of the CS+ paired with IG Intralipid, as well as less Intralipid in oral tests. However, DoKO mice, like GPR40 KO and GPR120 KO mice did not differ from WT mice in their preference for Intralipid over water at 0.001%-20% concentrations. In contrast to prior results obtained with mice missing the CD36 fatty acid sensor, these findings indicate that, together, GPR40 and GPR120 play a critical role in the postoral stimulation of appetite by fat but are not essential for oral fat preferences.
Recent studies suggest that because of their energy value, sugars are more rewarding than non-caloric sweeteners. However, intragastric infusion data indicate that sugars differ in their postoral appetite-stimulating effects. We therefore compared the preference for isocaloric 8% sucrose, glucose, and fructose solutions with that of a non-caloric sweetener solution (0.8% sucralose) in C57BL/6J mice. Brief 2-bottle tests indicated that sucralose was isopreferred to sucrose but more preferred than glucose or fructose. Yet, in long-term tests, the mice preferred sucrose and glucose, but not fructose to sucralose. Additional experiments were conducted with a non-caloric 0.1% sucralose + 0.1% saccharin mixture (S + S), which does not have the postoral inhibitory effects of 0.8% sucralose. The S + S was preferred to fructose in brief and long-term choice tests. S + S was also preferred to glucose and sucrose in brief tests, but the sugars were preferred in long-term tests. In progressive ratio tests, non-deprived and food-deprived mice licked more for glucose but not fructose than for S + S. These findings demonstrate that the nutrient-specific postoral actions, not calories per se, determine the avidity for sugar versus non-caloric sweeteners. Furthermore, sweet taste intensity and potential postoral inhibitory actions must be considered in comparing non-caloric and caloric sweeteners.
Recent studies indicate that, unlike glucose, fructose has little or no post-oral preference conditioning actions in C57BL/6J (B6) mice. The present study determined whether this is also the case for FVB mice, which overconsume fructose relative to B6 mice. In experiment 1, FVB mice strongly preferred a noncaloric 0.1% sucralose ϩ 0.1% saccharin (SϩS) solution to 8% fructose in a 2-day choice test but switched their preference to fructose after separate experience with the two sweeteners. Other FVB mice displayed a stronger preference for 8% glucose over SϩS. In a second experiment, ad libitum-fed FVB mice trained 24 h/day acquired a significant preference for a flavor (CSϩ) paired with intragastric (IG) selfinfusions of 16% fructose over a different flavor (CSϪ) paired with IG water infusions. IG fructose infusions also conditioned flavor preferences in food-restricted FVB mice trained 1 h/day. IG infusions of 16% glucose conditioned stronger preferences in FVB mice trained 24-or 1 h/day. Thus, fructose has post-oral flavor conditioning effects in FVB mice, but these effects are less pronounced than those produced by glucose. Further studies of the differential post-oral conditioning effects of fructose and glucose in B6 and FVB mice should enhance our understanding of the physiological processes involved in sugar reward.post-oral flavor conditioning; sucralose; saccharin; C57BL/6J mice IT IS WELL ESTABLISHED THAT inbred mouse strains differ in their taste responses to caloric and noncaloric sweeteners. This is due, in part, to allelic variations in the Tas1r3 gene that encodes the T1r3 sweet taste receptor protein (6,25). Mouse strains with the Sac B variant of the Tas1r3 gene are more sensitive to sugars (e.g., sucrose) and noncaloric sweeteners (e.g., saccharin) than are strains with the Sac D variant. In addition, sugar intake and preference are stimulated by the post-oral actions of sugars, a process referred to as appetition to distinguish it from the satiation process that inhibits sugar intake (27). Appetition is demonstrated by the intake and preference-stimulating effects of intragastric (IG) sugar infusions in mice and rats (3,21,27,30). Conceivably, strain differences in post-oral sugar appetition may contribute to variations in sugar intake in mice, but this has yet to be documented. One study reported mouse strain differences in sugar-conditioned flavor preferences, but because the sugars were orally consumed, the conditioning effects may have been mediated by the taste and/or post-oral actions of the sugars (24). In another study, we compared IG sucrose conditioning in The present study sought evidence for strain differences in the post-oral conditioning response to glucose and fructose, the constituent monosaccharide sugars of sucrose. B6 mice acquire strong preferences for flavors paired with IG glucose infusions but fail to prefer flavors paired with isocaloric fructose infusions (29, 43). Related findings were obtained with B6 mice given oral choice tests with 8% glucose or 8% fructose vs. a ...
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