REVISED 1 Post - oral appetite stimulation by sugars and non - metabolizable sugar analogs 2 in mice : Role of intestinal

18 Post-oral sugar actions enhance the intake of and preference for sugar-rich foods, a process 19 referred to as appetition. Here we investigated the role of intestinal sodium glucose co20 transporters (SGLTs) in sugar appetition in C57BL/6J mice using sugars and non-metabolizable 21 sugar analogs that differ in their affinity for SGLT1 and SGLT3. In Experiments 1 and 2 food22 restricted mice were trained (1 h/day) to consume a flavored saccharin solution (CS-) paired with 23 intragastric (IG) self-infusions of water and a different flavored solution (CS+) paired with 24 infusions of 8 or 12% sugars (glucose; fructose; galactose) or sugar analogs (α-methyl-D25 glucopyranoside, MDG; 3-O-methyl-D-glucopyranoside: OMG). Subsequent two-bottle CS+ vs. 26 CSchoice tests were conducted without co-infusions. Infusions of the SGLT1 ligands glucose, 27 galactose, MDG and OMG stimulated CS+ licking above CSlevels. However, only glucose, 28 MDG and galactose conditioned significant CS+ preferences, with the SGLT3 ligands (glucose, 29 MDG) producing the strongest preferences. Fructose, which is not a ligand for SGLTs, failed to 30 stimulate CS+ intake or preference. Experiment 3 revealed that IG infusion of MDG + phloridzin 31 (an SGLT1/3 antagonist) blocked MDG appetition, whereas phloridzin had minimal effects on 32 glucose-induced appetition. However, adding phloretin (a GLUT2 antagonist) to the glucose + 33 phloridzin infusion blocked glucose appetition. Taken together, these findings suggest that 34 humoral signals generated by intestinal SGLT1 and SGLT3, and to a lesser degree GLUT2, 35 mediate post-oral sugar appetition in mice. The MDG results indicate that sugar metabolism is 36 not essential for the post-oral intake stimulating and preference conditioning actions of sugars in 37 mice. 38