Early-life influences of low-calorie sweetener consumption on sugar taste

Abstract

Children and adolescents are the highest consumers of added sugars, particularly from sugar-sweetened beverages (SSB). Regular consumption of SSB early in life induces a variety of negative consequences on health that can last into adulthood. Low-calorie sweeteners (LCS) are increasingly used as an alternative to added sugars because they provide a sweet sensation without adding calories to the diet. However, the long-term effects of early-life consumption of LCS are not well understood. Considering LCS engage at least one of the same taste receptors as sugars and potentially modulate cellular mechanisms of glucose transport and metabolism, it is especially important to understand how early-life LCS consumption impacts intake of and regulatory responses to caloric sugars. In our recent study, we found that habitual intake of LCS during the juvenile-adolescence period significantly changed how rats responded to sugar later in life. Here, we review evidence that LCS and sugars are sensed via common and distinct gustatory pathways, and then discuss the implications this has for shaping sugar-associated appetitive, consummatory, and physiological responses. Ultimately, the review highlights the diverse gaps in knowledge that will be necessary to fill to understand the consequences of regular LCS consumption during important phases of development.

Keywords: Adolescence; Artificial sweetener; Cephalic phase; Glucose metabolism; Gustatory; Ingestive behavior; Sugar consumption; Sweet.

Figure 1.. Effects of Early-Life Low-Calorie Sweetener Consumption on Sugar-Motivated Behaviors, Glucoregulation, and Memory in Rats.

Overview of the major findings of the Tsan et al. (2022) study (21): In Experiment 1, male and female rats were offered one of three LCS (Acesulfame potassium, Saccharin, or Stevia) to drink at the FDA’s acceptable daily intake level (mg/kg) or water (Control) from postnatal (PN) days 26–77 in the home cage. Starting at PN 62, all rats were tested for their hippocampal-dependent contextual episodic memory in the novel object in context recognition task, and then, for spatial memory in the Barnes Maze, after which (on PN 77), fecal samples were collected for microbiome analyses with 16S RNA-sequencing. Starting at PN 89, all rats were tested for consummatory responses to two metabolically distinct caloric sugars, 0.56 M glucose and fructose, in 30-minute intake tests. This was followed by intake tests with a polysaccharide, a bitterant, and lithium chloride (not shown). At PN 110–111, all rats were tested for anxiety-like behaviors in the Zero Maze. Following that, at PN 151, the willingness to work for sucrose pellets, then high fat pellets, was assessed with an operant progressive ratio task. Long term consumption of added sugar (11% sucrose) was measured in the home cage from PN 165–193, followed by body composition measurements with NMR at PN 194. The major outcomes are highlighted under the black titles, with analyses conducted with both sexes combined (All) and each sex separately, where applicable. Generally speaking, no differences were found among the three LCS (but see (21), for more detail). Arrows indicate direction of significant differences of the combined LCS group versus the control group. n.s. indicates no significant differences detected between the respective LCS and control group, with an asterisk indicating phenomena where no effect was noted in the Control (female) group. In Experiments 2–4, assessment of underlying cellular or physiological mechanisms were investigated in male and/or female rats that were provided with a representative LCS, Acesulfame potassium (ACE-K), at the same dose noted above, during the juvenile-adolescence period (full details provided in (21)). These are indicated in the gray titles, and included oral and intragastric glucose tolerance tests, RT-qPCR on genes of interest in the circumvallate taste tissue and duodenal villi, fasting insulin levels (no differences, not shown), and RNA-sequencing of dorsal hippocampus and nucleus accumbens.

Figure 2.. Overview of Sugar Sensing in the Peripheral Gustatory System.

The sensory end organ of the gustatory system comprises specialized epithelial cells clustered in buds of ~50–100 cells and distributed in papillae across the tongue (fungiform, circumvallate, and foliate, shown in panel A) and in the soft palate and larynx (not shown). There are three major types of taste cells within each bud. Among these, Type II cells express one of three known G protein coupled receptors at their apical membrane (for sweet, umami, or bitter). The sweet receptor is made up of two proteins, named T1R2 and T1R3, that form a heterodimeric complex, and broadly bind simple sugars, low calorie sweeteners, and some D-amino acids (shown in panel B). Activation of the T1R2+T1R3 initiates a canonical signaling cascade, illustrated in panel B, ultimately leading to the release of ATP. Type III cells are outfitted to respond to salts and acids and form a synaptic connection with cranial nerve afferents. Type II cells may communicate with intragemmal nerve fibers or via Type III cells through a paracrine-like mechanism. Recent studies have shown that Type II and III taste cells also express various signaling intermediaries associated with sugar sensing. This includes transceptor (e.g., sodium glucose linked transporter 1, SGLT1) and metabolic glucose detectors (e.g., glucokinase, GCK), as illustrated in panel C, though the precise intracellular cascades associated with these remain to be determined. This importantly also includes digestive enzymes on the apical membrane, such as sucrase isomaltase (SI) and maltase glucoamylase (MGAM), that cleave complex saccharides to free glucose and/or fructose units. More information about the known expression patterns and function of these alternative sugar sensing systems in the taste bud cells is shown in Figure 3.

Figure 3.. Alternative Sugar Sensing Pathways in the Gustatory System.

Both Type II and Type III cells express molecular machinery involved in glucose sensing and signaling. Within the Type II cells, these seem to be largely co-expressed with T1R3, one of the proteins involved in sweet reception. Panel A highlights the intermediaries present in T1R3+ taste cells and/or in presumptive Type III taste cells, with the black font indicating ones with known roles in behavioral or physiological aspects of taste and gray font indicating ones whose role remains to be empirically tested. The taste papillae where protein or transcript has been detected is noted in the superscript, along with the corresponding citations. Panel B summarizes published roles for these alternative sugar sensors among the three domains of taste function, with corresponding citations in superscript. To date, the sodium glucose-linked transporter 1 (SGLT1) and glucokinase (GCK) contribute to consummatory/motivational aspects of glucose taste, though it is unknown if they collaborate or work separately in these phenomena (24, 135). SGLT1 has also been implicated in glucose detection in humans (66). The sulfonylurea receptor 1 (SUR1) is suggested to facilitate the cephalic phase insulin response to glucose-containing sugars (68).

Figure 4.. Effects of Early-life ACE-K Consumption on the Expression of Sweet Taste Receptors and SGLT1 in the Taste Tissue.

Panel A shows a decrease in Tas1r2 (left) and Tas1r3 (right) mRNA expression in the circumvallate papillae of adult male and female rats previously exposed during juvenile phase to the low-calorie sweetener acesulfame potassium (ACE-K) compared to water (CTL). These data have been previously published in (21). However, the male and female data have been analyzed separately here, and a student t-test has been used for the statistical significance. Panel B shows a reduction in Sglt1 mRNA expression in the same samples as panel A when the sexes are combined, and more specifically in the female group. A positive correlation between Tas1r and Sglt1 mRNA expression was observed only in female group (panel C), and no correlation was observed in male rats (panel D). * p < 0.05; ** p < 0.01

Figure 5.. Effects of Early-Life ACE-K Consumption on the Expression of SUR1 in the Taste Tissue.

Panel A shows no difference in Sur1 mRNA expression in the same samples than Figure 4 when the sexes are combined or analyzed separately. No correlation between Tas1r and Sur1 mRNA expression was observed in female (panel B) and male (panel C) rats. Sur1 mRNA expression for one CTL male rat sample could not be detected during the qPCR analysis.