Neuroimaging Insights into the Effects of Non-Nutritive Sweeteners on Appetite Regulation: A Systematic Review.

Non-nutritive sweeteners (NNS) are increasingly used as low- or zero-calorie alternatives to sugar while maintaining sweetness. However, uncoupling sweet taste from caloric content may alter appetite regulation and promote food-seeking behavior, although the underlying neural mechanisms remain poorly understood. To address this, we conducted a systematic review in accordance with PRISMA guidelines. PubMed/MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched up to June 2025 using terms related to NNS, neuroimaging and appetite regulation. Of 137 screened records, 21 neuroimaging reports met predefined PICO-based eligibility criteria. Eligible reports included healthy adults across weight categories and examined artificial or naturally occurring NNS (e.g., sucralose, erythritol) compared with nutritive sweeteners (NS; e.g., sucrose) or non-sweet controls (e.g., water). Outcomes included appetite-related brain responses measured using functional magnetic resonance imaging (fMRI) or positron emission tomography (PET), as well as associations with gut hormones, glucose metabolism, and eating behavior. NNS and NS both engaged gustatory and reward-related brain regions, with some reports showing reduced activity and lower pleasantness ratings for NNS. Hypothalamic activity and functional connectivity were also modulated by NNS intake, with no observed associations between brain responses and gut hormones or glucose metabolism in the available reports. Overall, the evidence remains limited and varies by NNS type, dose, delivery method, habitual intake, sex, weight status, and metabolic state. Future studies should investigate acute and long-term NNS consumption under real-world conditions with greater ethnic and demographic diversity, accounting for individual variability to better inform dietary guidelines.