Obesity and Sex-Related Associations With Differential Effects of Sucralose vs Sucrose on Appetite and Reward Processing: A Randomized Crossover Trial

Importance Nonnutritive sweeteners (NNSs) are used as an alternative to nutritive sweeteners to quench desire for sweets while reducing caloric intake. However, studies have shown mixed results concerning the effects of NNSs on appetite, and the associations between sex and obesity with reward and appetitive responses to NNS compared with nutritive sugar are unknown. Objective To examine neural reactivity to different types of high-calorie food cues (ie, sweet and savory), metabolic responses, and eating behavior following consumption of sucralose (NNS) vs sucrose (nutritive sugar) among healthy young adults. Design, Setting, and Participants In a randomized, within-participant, crossover trial including 3 separate visits, participants underwent a functional magnetic resonance imaging task measuring blood oxygen level–dependent signal in response to visual cues. For each study visit, participants arrived at the Dornsife Cognitive Neuroimaging Center of University of Southern California at approximately 8:00amafter a 12-hour overnight fast. Blood was sampled at baseline and 10, 35, and 120 minutes after participants received a drink containing sucrose, sucralose, or water to measure plasma glucose, insulin, glucagon-like peptide(7-36), acyl-ghrelin, total peptide YY, and leptin. Participants were then presented with an ad libitum meal. Participants were right-handed, nonsmokers, weight-stable for at least 3 months before the study visits, nondieters, not taking medication, and with no history of eating disorders, illicit drug use, or medical diagnoses. Data analysis was performed from March 2020 to March 2021. Interventions Participants ingested 300-mL drinks containing either sucrose (75 g), sucralose (individually sweetness matched), or water (as a control). Main Outcomes and Measures Primary outcomes of interest were the effects of body mass index (BMI) status and sex on blood oxygen level–dependent signal to high-calorie food cues, endocrine, and feeding responses following sucralose vs sucrose consumption. Secondary outcomes included neural, endocrine, and feeding responses following sucrose vs water and sucralose vs water (control) consumption, and cue-induced appetite ratings following sucralose vs sucrose (and vs water). Results A total of 76 participants were randomized, but 2 dropped out, leaving 74 adults (43 women [58%]; mean [SD] age, 23.40 [3.96] years; BMI range, 19.18-40.27) who completed the study. In this crossover design, 73 participants each received water (drink 1) and sucrose (drink 2), and 72 participants received water (drink 1), sucrose (drink 2), and sucralose (drink 3). Sucrose vs sucralose was associated with greater production of circulating glucose, insulin, and glucagon-like peptide–1 and suppression of acyl-ghrelin, but no differences were found for peptide YY or leptin. BMI status by drink interactions were observed in the medial frontal cortex (MFC;Pfor interaction Conclusions and Relevance These findings suggest that female individuals and those with obesity may be particularly sensitive to disparate neural responsivity elicited by sucralose compared with sucrose consumption. Trial Registration ClinicalTrials.gov Identifier:NCT02945475