Supplementation of oligofructose, but not sucralose, decreases high-fat diet induced body weight gain in mice independent of gustducin-mediated gut hormone release.

SCOPE: Enteroendocrine cells sense nutrients through taste receptors similar to those on the tongue. Sweet and fatty acid taste receptors (FFAR) coupled to the gustatory G-protein, gustducin, on enteroendocrine cells play a role in gut hormone release. We studied if supplementation of artificial (sucralose) or prebiotic (oligofructose; OFS) sweeteners target gustducin-mediated signaling pathways to alter gut hormone release and reduce obesity-associated disorders. METHODS AND RESULTS: Wild-type (WT) and α-gustducin knockout (α-gust-/- ) mice were fed a high-fat diet and gavaged once daily (8 wk) with water or equisweet concentrations of sweeteners. OFS but not sucralose decreased body weight gain (-19 ± 3%, p < 0.01), fat pad mass (-55 ± 6%, p < 0.001), and insulin resistance (-39 ± 5%, p < 0.001) independent of α-gustducin. Neither sweetener improved glucose intolerance, while solely OFS improved the disturbed colonic permeability. OFS decreased (-65 ± 8%, p < 0.001) plasma glucagon-like peptide 1 (GLP-1) but not ghrelin and peptide YY (PYY) levels in WT mice. Cecal acetate and butyrate levels were reduced by OFS in both genotypes suggesting enhanced uptake of SCFAs that may target FFAR2 (upregulated expression) in adipose tissue. CONCLUSION: OFS, but not sucralose, reduced body weight gain and decreased intestinal permeability, but not glucose intolerance. Effects were not mediated by altered gut hormone levels or gustducin-mediated signaling. Artificial sweeteners do not affect gut hormone levels and are metabolically inert in mice on a high-fat diet. In contrast, prebiotic oligosaccharides (OFS) prevent body weight gain but not glucose intolerance. Alterations in sweet and short-chain fatty acid receptors (FFAR) (studied in WT and α-gust-/- mice) that regulate gut hormone levels are not mandatory for the positive effects of OFS. Enhanced uptake of SCFAs may favor interaction with FFAR2/3 on adipose tissue to induce weight loss.