Non-Caloric Sweetener Effects on Brain Appetite Regulation in Individuals Across Varying Body Weights

Introduction: Sucralose is a non-caloric sweetener commonly consumed to provide sweet taste without calories. Yet, some studies suggest that non-caloric sweeteners stimulate appetite, possibly due to the delivery of a sweet taste without the post-ingestive metabolic signals that normally communicate with the hypothalamus to suppress hunger. We tested the hypothesis that acute consumption of the non-caloric sweetener, sucralose, would stimulate greater increases in hypothalamic blood flow, an MRI correlate of hunger, compared to caloric sugar (sucrose) and water, and would alter functional connectivity between the hypothalamus and other brain regions. Additionally, we expected sucrose, but not sucralose, to raise blood glucose levels, inversely affecting hypothalamic blood flow. We anticipated variations in hypothalamic responses based on weight status. Methods: Seventy-five young adults with healthy-weight, overweight, or obesity from a random-order crossover design study (NCT02945475) with acute consumption of a drink containing either 75g sucrose, sucralose (individually sweetness matched to sucrose), or plain water were included in this analysis to compare the effects of sucralose relative to sucrose and water on changes in hypothalamic blood flow, circulating glucose levels, and ratings of hunger. Hypothalamic blood flow (measured by pulsed arterial spin labeling perfusion MRI), hunger ratings, and glycemic responses were concurrently measured fasting, +10, and +35min after drink ingestion. As a secondary outcome, functional connectivity was performed using blood oxygen level-dependent (BOLD) fMRI to explore changes between the hypothalamus seed region and other brain areas after ingestion of sucralose relative to sucrose and water.Linear mixed-effects models were used for comparisons of drink contrasts. Linear regressions were used to examine associations between peripheral glucose levels, hypothalamic blood flow, and hunger ratings. Models were adjusted for age, sex, BMI, and race/ethnicity. Post hoc comparisons were adjusted for multiple comparisons using a Bonferroni correction. Results: There was a significant effect of drink on hypothalamic blood flow, adjusting for age, sex, BMI, and race/ethnicity (F = 5.05; p<.007). Compared to sucrose, intake of drinks sweetened with sucralose produced greater hypothalamic blood flow (Mean diff = .079, ± 0.03, p < .018) and greater hunger responses (Mean diff = .575 ± 0.16, p < .001). Sucralose vs water also increased hypothalamic blood flow (Mean diff = .078 ± 0.03, p < .019), but produced no difference in hunger ratings. Sucrose, but not sucralose, produced increases in peripheral glucose levels, which were associated with reductions in medial hypothalamic blood flow (beta =-.005 ± .002, p < .007). Sucralose, compared to sucrose and water, resulted in increased functional connections between the hypothalamus and brain regions involved in motivation and somatosensory processing. Conclusion: These results underscore the notable differences in sucralose, a non-caloric sweetener, on hypothalamic signaling pathways linked to appetite regulation when compared to sugar or water. The findings suggest that non-caloric sweeteners could affect key mechanisms in the hypothalamus responsible for appetite regulation.