Postingestive reward acts through behavioral reinforcement and is conserved in obesity and after bariatric surgery

Abstract

Postingestive nutrient stimulation conditions food preferences through striatal dopamine and may be associated with blunted brain responses in obesity. In a cross-sectional study, we tested flavor-nutrient conditioning (FNC) with maltodextrin-enriched yogurt, with maltodextrin previously optimized for concentration and dextrose equivalents (n = 57), and to mask texture cues (n = 102). After conditioning, healthy volunteers (n = 52) increased preference for maltodextrin-paired (+102 kcal, CS+), relative to control (+1.8 kcal, CS-) flavors, as assessed according to intake, but not pleasantness. In a clinical study (n = 61), behavioral conditioning without effects on pleasantness was confirmed across pre-bariatric candidates with obesity, weight-stable post-surgery patients, and healthy controls, without significant differences between groups. Striatal dopamine D2-like receptor (DD2lR) availability, assessed with [123I]IBZM SPECT, was reduced in the obesity group and strongly correlated with conditioning strength and a measure of restrained eating in patients with gastric bypass. These results show that postingestive nutrient stimulation influences human food choices through behavioral reinforcement, and is conserved in obesity and after bariatric surgery. Trial Registration: ISRCTN17965026: Dopaminergic neurotransmission in dietary learning and obesity.

Fig 1. Development of a novel FNC protocol.

(A) Intensity and pleasantness ratings of unflavored maltodextrin yogurt were tested across 3 different groups of healthy individuals, each at a different maltodextrin concentration (17%, 25%, or 33% w/v). In each group, participants consumed a base yogurt solution without maltodextrin and 3 solutions with maltodextrin at distinct dextrose equivalents (DE 4–7, DE 13–17, and DE 16.5–20). Intensity ratings of maltodextrin yogurts, normalized to ratings of base yogurt, varied according to DE (F_(2,72) = 3.4, P = 0.04), independently of the concentration tested (F_(2,36) = 0.5, P = 0.6; interaction: F_(4,72) = 0.7, P = 0.6; mixed-model two-way ANOVA; n = 39). (B) In 3-AFC tests, 1 or 2 of 3 yogurt samples contained maltodextrin (DE4-7), and the other(s) were control yogurts. The percentage of participants that detected maltodextrin was significantly above the chance level (94.4%, p < 0.0001; binominal test vs. 33%; n = 18). (C) In other 3-AFC tests, testing discrimination relative to CMC (0.4% w/v) rather than base yogurt, the higher concentrations of maltodextrin (25% and 33%) were identified significantly above chance (54.5%, P = 0.02, n = 22; 60%, P = 0.001, n = 25, respectively), while 17% maltodextrin was not discriminated from CMC (37.5%, P = 0.41, n = 24), as confirmed when yogurts were flavored (36.4%, P = 0.42, n = 33). (D) After conditioning, while intake of both CS+ and CS- flavors increased significantly (time: F_(1,51) = 17.1, P = 0.0001; stimulus: F_(1,51) = 1.2, P = 0.3; post hoc tests: CS⁺, P < 0.0001, CS^-_, P = 0.02), the interaction between factors suggested differential effects between stimuli (F_(1,51) = 4.3, P = 0.04; repeated measures two-way ANOVA; n = 52). (E) Post-conditioning, preference for CS⁺, as measured according to intake, increased significantly (t₍₅₁₎ = 2.6, P = 0.02, paired t test, n = 52). (F) In participants with low baseline intake preference for CS⁺ (≤50%), there was a significant post-conditioning increase in preference (t₍₂₇₎ = 3.7, P = 0.002, n = 28), but not in those with high baseline preference (>50%; t₍₂₃₎ = 0.08, P = 0.9, n = 24, one-sample t test vs. 0). (G) We found similar pleasantness ratings both for CS^- and CS⁺ before and after conditioning, and unchanged preference for CS⁺, as measured by pleasantness (H), irrespective of the baseline preference (I). Notes: In panels A, D, F, G, and I, data is presented as mean ± standard error of the mean (SEM). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001; ns P > 0.05. 3-AFC, 3-alternative forced-choice; CMC, carboxymethylcellulose; DE, dextrose equivalent; FNC, flavor-nutrient conditioning; gLMS/gLHS, general labeled magnitude/hedonic scales. The data supporting this figure is available in S1 Data.

Fig 2. Measures of FNC across the clinical study groups.

(A) ΔCS⁺ preference, measured by intake, across the clinical study groups. A one-way ANOVA revealed a nonsignificant group effect (F_{(2, 50)} = 1.9, P = 0.2) across healthy (n = 24), obese (n = 9), and surgical (n = 20) groups. (B) ΔCS⁺ preference, measured by pleasantness ratings, across the clinical study groups. A one-way ANOVA revealed a nonsignificant group effect (F_{(2, 50)} = 0.2, P = 0.8) across groups. Notes: Data is presented as mean ± SEM. FNC, flavor-nutrient conditioning; gLMS, general labeled magnitude scales; SEM, standard error of the mean. The data supporting this figure is available in S1 Data.

Fig 3. Striatal DD2lR availability in obesity and bariatric surgery and associations with postingestive conditioning and restrained eating.

(A) Average [¹²³I]IBZM group images in the striatal central transverse plane of healthy subjects (n = 21; upper panel), patients with obesity (n = 11; lower left panel), and surgical patients (n = 23; lower right panel). (B) There was a group effect for striatal DD2lR availability (F_{(2, 52)} = 9.81, P = 0.0002), with post hoc tests supporting lower striatal BP for the obesity group relative to both surgical (P = 0.0001) and healthy (P = 0.02) groups, but not between surgical and healthy groups (P = 0.19). (C) Association between striatal DD2lR availability and ΔCS⁺ preference (intake) across surgery types (Surgical group, r = −0.14, P = 0.6, n = 20; Bypass, r = −0.68, P = 0.02, n = 11; Sleeve, r = 0.49, P = 0.18, n = 9). (D) Association between striatal DD2lR availability and the Dutch Eating Behaviour Questionnaire—restrained eating scores across surgery types (Surgical group, r = 0.19, P = 0.4, n = 19; Bypass, r = 0.77, P = 0.01, n = 11; Sleeve, r = −0.26, P = 0.5, n = 8). Notes: In panel B, data is presented as the mean ± SEM. *P ≤ 0.05; ***P ≤ 0.001. The data supporting this figure is available in S1 Data. DD2lR, dopamine D2-like receptor; SEM, standard error of the mean.