Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats
Linda Tsan, Sandrine Chometton, Anna M.R. Hayes, Molly E. Klug, Yanning Zuo, Shan Sun, Lana Bridi, Rae Lan, Anthony A. Fodor, Emily E. Noble, Xia Yang, Scott E. Kanoski, Lindsey A. Schier
Linda Tsan, Sandrine Chometton, Anna M.R. Hayes, Molly E. Klug, Yanning Zuo, Shan Sun, Lana Bridi, Rae Lan, Anthony A. Fodor, Emily E. Noble, Xia Yang, Scott E. Kanoski, Lindsey A. Schier
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Research Article Development Neuroscience

Early-life low-calorie sweetener consumption disrupts glucose regulation, sugar-motivated behavior, and memory function in rats

Abstract

Low-calorie sweetener (LCS) consumption in children has increased dramatically due to its widespread presence in the food environment and efforts to mitigate obesity through sugar replacement. However, mechanistic studies on the long-term impact of early-life LCS consumption on cognitive function and physiological processes are lacking. Here, we developed a rodent model to evaluate the effects of daily LCS consumption (acesulfame potassium, saccharin, or stevia) during adolescence on adult metabolic, behavioral, gut microbiome, and brain transcriptomic outcomes. Results reveal that habitual early-life LCS consumption impacts normal postoral glucose handling and impairs hippocampal-dependent memory in the absence of weight gain. Furthermore, adolescent LCS consumption yielded long-term reductions in lingual sweet taste receptor expression and brought about alterations in sugar-motivated appetitive and consummatory responses. While early-life LCS consumption did not produce robust changes in the gut microbiome, brain region–specific RNA-Seq analyses reveal LCS-induced changes in collagen- and synaptic signaling–related gene pathways in the hippocampus and nucleus accumbens, respectively, in a sex-dependent manner. Collectively, these results reveal that habitual early-life LCS consumption has long-lasting implications for glucoregulation, sugar-motivated behavior, and hippocampal-dependent memory in rats, which may be based in part on changes in nutrient transporter, sweet taste receptor, and central gene pathway expression.

Authors

Linda Tsan, Sandrine Chometton, Anna M.R. Hayes, Molly E. Klug, Yanning Zuo, Shan Sun, Lana Bridi, Rae Lan, Anthony A. Fodor, Emily E. Noble, Xia Yang, Scott E. Kanoski, Lindsey A. Schier

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Figure 3

Early-life LCS consumption alters sugar taste responsiveness and reduces lingual sweet taste receptor expression.

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Early-life LCS consumption alters sugar taste responsiveness and reduces...
(A) Schematic displaying the use of the lickometer for analyses of ingestive responses to equimolar glucose and fructose solutions. (B–D) Whereas controls show equivalent short-term (first minute) ingestive responses for a glucose versus an equimolar but sweeter fructose solution, rats previously given daily LCS treatment show heightened responses for the fructose solution relative to glucose, regardless of sex (Experiment 1: CTL: n = 10 male, n = 10 female; LCS combined: ACE-K: n = 10 male, n = 10 female; saccharin: n = 10 male, n = 10 female; stevia, n = 10 male, n = 10 female). (E–G) Longer-term (30 minute) ingestive appetitive responses were higher for the glucose relative to the fructose solution in controls but not in LCS-exposed rats (E), an effect primarily driven by the males (F) but not females that displayed a ceiling effect in licking behavior (G). (H and I) Ingestive responding for the bitter tastant quinine, as measured by licks during the first minute of exposure (H), or whole-session consumption (I), was comparable between CTL and LCS-exposed animals (Experiment 1). (J–M) LCS-exposed rats also had reduced gene expression levels of the sweet taste receptors, T1R2 (J and K) and T1R3 (L and M) in the CV, regardless of sex (Experiment 3; CTL: n = 8 male, n = 8 female; ACE-K: n = 8 male, n = 8 female). Data are shown as means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001. A multifactor ANOVA with Sex (where included) and Group as the independent between-subjects variables were used to analyze the licking/ingestive tests (B–I) and Tas1r2 and Tas1r3 relative mRNA expression (J–M). Data were corrected for multiple comparisons using Sidak’s multiple-comparison test. CTL, control; LCS, low-calorie sweeteners; CV, circumvallate papillae of the tongue.