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Background Non-caloric artificial sweeteners (NCAS) are widely used as a substitute for dietary sugars to control body weight or glycemia. Paradoxically, some interventional studies in humans and rodents have shown unfavorable changes in glucose homeostasis in response to NCAS consumption. The causative mechanisms are largely unknown, but adverse changes in gut microbiota have been proposed to mediate these effects. These findings have raised concerns about NCAS safety and called into question their broad use, but further physiological and dietary considerations must be first addressed before these results are generalized. We also reasoned that, since NCAS are bona fide ligands for sweet taste receptors (STRs) expressed in the intestine, some metabolic effects associated with NCAS use could be attributed to a common mechanism involving the host. Results We conducted a double-blind, placebo-controlled, parallel arm study exploring the effects of pure saccharin compound on gut microbiota and glucose tolerance in healthy men and women. Participants were randomized to placebo, saccharin, lactisole (STR inhibitor), or saccharin with lactisole administered in capsules twice daily to achieve the maximum acceptable daily intake for 2 weeks. In parallel, we performed a 10-week study administering pure saccharin at a high dose in the drinking water of chow-fed mice with genetic ablation of STRs (T1R2-KO) and wild-type (WT) littermate controls. In humans and mice, none of the interventions affected glucose or hormonal responses to an oral glucose tolerance test (OGTT) or glucose absorption in mice. Similarly, pure saccharin supplementation did not alter microbial diversity or composition at any taxonomic level in humans and mice alike. No treatment effects were also noted in readouts of microbial activity such as fecal metabolites or short-chain fatty acids (SCFA). However, compared to WT, T1R2-KO mice were protected from age-dependent increases in fecal SCFA and the development of glucose intolerance. Conclusions Short-term saccharin consumption at maximum acceptable levels is not sufficient to alter gut microbiota or induce glucose intolerance in apparently healthy humans and mice. Trial registration Trial registration number NCT03032640, registered on January 26, 2017.

Objective Beyond the taste buds, sweet taste receptors (STRs; T1R2/T1R3) are also expressed on enteroendocrine cells, where they regulate gut peptide secretion but their regulatory function within the intestine is largely unknown. Methods Using T1R2-knock out (KO) mice we evaluated the role of STRs in the regulation of glucose absorption in vivo and in intact intestinal preparations ex vivo. Results STR signaling enhances the rate of intestinal glucose absorption specifically in response to the ingestion of a glucose-rich meal. These effects were mediated specifically by the regulation of GLUT2 transporter trafficking to the apical membrane of enterocytes. GLUT2 translocation and glucose transport was dependent and specific to glucagon-like peptide 2 (GLP-2) secretion and subsequent intestinal neuronal activation. Finally, high-sucrose feeding in wild-type mice induced rapid downregulation of STRs in the gut, leading to reduced glucose absorption. Conclusions Our studies demonstrate that STRs have evolved to modulate glucose absorption via the regulation of its transport and to prevent the development of exacerbated hyperglycemia due to the ingestion of high levels of sugars., Highlights • The intestinal T1R2 receptor enhances glucose absorption in vivo and ex vivo. • Pharmacological inhibition of STRs reduces glucose flux in human intestinal preparations. • T1R2 regulates glucose absorption dependent on GLUT2 activity in enterocytes. • GLP-2 mediates the effects of T1R2 signaling through activation of enteric neurons. • High sucrose diet rapidly downregulates STRs leading to reduced glucose absorption.

Background: Glucose is a natural ligand for sweet taste receptors (STRs) that are expressed on the tongue and in the gastrointestinal tract. Whether STRs directly contribute to the regulation of glucose homeostasis in response to glucose ingestion is unclear.Objective: We sought to determine the metabolic effects of the pharmacologic inhibition of STRs in response to an oral glucose load in healthy lean participants.Design: Ten healthy lean participants with a body mass index (in kg/m2) of 22.4 ± 0.8 were subjected to an oral-glucose-tolerance test (OGTT) on 4 separate days with the use of a randomized crossover design. Ten minutes before the 75-g OGTT, participants consumed a preload solution of either 300 parts per million (ppm) saccharin or water with or without the addition of 500 ppm lactisole, a human-specific inhibitor of STRs. When present, lactisole was included in both the preload and OGTT solutions. We assessed plasma responses of glucose, insulin, C-peptide, glucagon, glucagon-like peptides 1 and 2, gastric inhibitory peptide, acetaminophen, and 3-O-methylglucose. With the use of mathematical modeling, we estimated gastric emptying, glucose absorption, β-cell function, insulin sensitivity and clearance, and the portal insulin:glucagon ratio.Results: The addition of lactisole to the OGTT caused increases in the plasma responses of insulin (P = 0.012), C-peptide (P = 0.004), and the insulin secretory rate (P = 0.020) compared with the control OGTT. The addition of lactisole also caused a slight reduction in the insulin sensitivity index independent of prior saccharin consumption (P < 0.025). The ingestion of saccharin before the OGTT did not alter any of the measured variables but eliminated the effects of lactisole on the OGTT.Conclusion: The pharmacologic inhibition of STRs in the gastrointestinal tract alters insulin responses during an oral glucose challenge in lean healthy participants. This trial was registered at clinicaltrials.gov as NCT02835859.

Over one third of U.S. youth are overweight or obese. Treatments typically have had unreliable effects, inconsistently incorporating behavior-change theory. After-school care might be a viable setting for health behavior-change programs. We evaluated effects of two consecutive 12-week segments of a revised self-efficacy/social cognitive theory-based physical activity and nutrition treatment on fitness levels, body mass index (BMI), and targeted psychosocial factors in after-school care participants, ages 5–8 years. Changes in physiological measures, exercise self-efficacy (ESE), and physical self-concept over 9 months were contrasted in experimental (n = 72) vs. typical-care (n = 42) groups. Mediation of the group–BMI change relationship by the psychosocial factors was also assessed. Improvements in physiological measures and ESE were significantly greater in the experimental group. ESE change completely mediated the association of treatment type with BMI change. The experimental group demonstrated significantly greater improvements in the physiological measures, with its treatment’s theoretical basis and application within after-school care supported.

Animal coloration has multiple functions including thermoregulation, camouflage, and social signaling, and the requirements of each function may sometimes conflict. Many terrestrial ectotherms accommodate the multiple functions of color through color change. However, the relative importance of these functions and how color-changing species accommodate them when they do conflict are poorly understood because we lack data on color change in the wild. Here, we show that the color of individual radio-tracked bearded dragon lizards, Pogona vitticeps, correlates strongly with background color and less strongly, but significantly, with temperature. We found no evidence that individuals simultaneously optimize camouflage and thermoregulation by choosing light backgrounds when hot or dark backgrounds when cold. In laboratory experiments, lizards showed both UV-visible (300-700 nm) and near-infrared (700-2,100 nm) reflectance changes in response to different background and temperature treatments, consistent with camouflage and thermoregulatory functions, respectively, but with no interaction between the two. Overall, our results suggest that wild bearded dragons change color to improve both thermoregulation and camouflage but predominantly adjust for camouflage, suggesting that compromising camouflage may entail a greater potential immediate survival cost.

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas, and adipose tissue suggests a physiological contribution to whole body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by overnutrition and subsequent obesity. Here, we investigated the effects of high-fat/low-carbohydrate (HF/LC) diet on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein T1R2. We assessed body composition, energy balance, glucose homeostasis, and tissue-specific nutrient metabolism in T1R2 knockout (T1R2-KO) mice fed a HF/LC diet for 12 wk. HF/LC diet-fed T1R2-KO mice gained a similar amount of body mass as did WT mice, but had reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice were also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs ( T1r2/T1r3) were upregulated in the adipose tissue of WT mice in response to HF/LC diet, and their expression positively correlated with fat mass and glucose intolerance. The chemosensory receptor T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.

β-Cells rapidly secrete insulin in response to acute increases in plasma glucose but, upon further continuous exposure to glucose, insulin secretion progressively decreases. Although the mechanisms are unclear, this mode of regulation suggests the presence of a time-dependent glucosensory system that temporarily attenuates insulin secretion. Interestingly, early-stage β-cell dysfunction is often characterized by basal (ie, fasting) insulin hypersecretion, suggesting a disruption of these related mechanisms. Because sweet taste receptors (STRs) on β-cells are implicated in the regulation of insulin secretion and glucose is a bona fide STR ligand, we tested whether STRs mediate this sensory mechanism and participate in the regulation of basal insulin secretion. We used mice lacking STR signaling (T1R2−/− knockout) and pharmacologic inhibition of STRs in human islets. Mouse and human islets deprived of STR signaling hypersecrete insulin at short-term fasting glucose concentrations. Accordingly, 5-hour fasted T1R2−/− mice have increased plasma insulin and lower glucose. Exposure of isolated wild-type islets to elevated glucose levels reduced STR expression, whereas islets from diabetic (db/db) or diet-induced obese mouse models show similar down-regulation. This transcriptional reprogramming in response to hyperglycemia correlates with reduced STR function in these mouse models, leading to insulin hypersecretion. These findings reveal a novel mechanism by which insulin secretion is physiologically regulated by STRs and also suggest that, during the development of diabetes, STR function is compromised by hyperglycemia leading to hyperinsulinemia. These observations further suggest that STRs might be a promising therapeutic target to prevent and treat type 2 diabetes.