Post-oral appetite stimulation by sugars and nonmetabolizable sugar analogs

Abstract

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...

Fructose- and glucose-conditioned preferences in FVB mice: strain differences in post-oral sugar appetition

“…Total 1-h intakes (oral ϩ IG) were high (ϳ4 g/h) in the first CSϪ training session, which may have precluded stimulation of intake by the IG sugar infusions in subsequent sessions. In a recent study, using a different 1-h training procedure, which produced low CSϪ baseline intakes (ϳ2 g/h), we observed rapid stimulation of CSϩ intake in B6 mice self-infusing glucose but not in mice self-infusing fructose (43). In addition, only glucose-trained B6 mice displayed a CSϩ preference in the two-choice test.…”

“…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 noncaloric 0.1% sucralose ϩ 0.1% saccharin solution (SϩS) (Sclafani A, Zukerman S, and Ackroff K, unpublished data).…”

The role of dopamine in the pursuit of nutritional value

“…In this situation glucose may be sensed by intestinal sodium-glucose cotransporter proteins (SGLT1 and/or 3) to drive conditioning. In support of this is a study showing that conditioned responses develop to intragastric infusions of the nonmetabolizable sugar analogue, α-methyl-D-glucopyranoside, which is a substrate for SGLT3 and that this effect is blocked by a SGLT1/3 antagonist [60]. As fructose is not a substrate for SGLTs this may explain its failure to induce conditioning in this paradigm.…”

“…These mechanisms certainly involve activation by proximal cues including orosensory stimulation, pre-absorptive mechanisms, and post-absorptive mechanisms [21,23,42,54,60]. Multiple hormones, among them ghrelin, insulin, amylin, and glucagon-like peptide 1, that are released peripherally interact either directly or indirectly with the mesolimbic dopamine pathway [15,[80][81][82][83][84].…”

“…Multiple hormones, among them ghrelin, insulin, amylin, and glucagon-like peptide 1, that are released peripherally interact either directly or indirectly with the mesolimbic dopamine pathway [15,[80][81][82][83][84]. Cells located both peripherally and centrally are able to respond to changes in glucose concentration including intestinal cells and dopamine neurons and their inputs [60,85,86].…”