ObjectiveBeyond 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.MethodsUsing 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.ResultsSTR 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.ConclusionsOur 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.

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Pratley RE, Kyriazis GA. Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity. Am J Physiol Endocrinol Metab 310: E688 -E698, 2016. First published February 16, 2016 doi:10.1152/ajpendo.00484.2015.-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. sweet taste receptors; obesity; hyperinsulinemia; body composition; diabetes OBESITY AND ITS COMORBIDITIES have become a global epidemic (37). In the United States alone, about two thirds of all adults are overweight and one third are classified as obese (12). Obesity is associated with an increased risk for the development of insulin resistance and type 2 diabetes (T2D) (21,38). Although the etiology of obesity is a complex interplay of environmental and genetic components, it is largely linked to excessive caloric intake and decreased physical activity (13). Disturbances in energy balance induce the activation of cellular biochemical sensors that attempt to restore homeostasis by the activation of metabolic, hormonal, and neuronal pathways. For instance, glucose influx and metabolism causes the accumulation of malonyl coenzyme A (CoA), which inhibits lipid oxidation in favor of triglyceride synthesis and glucose oxidation (35,44). Nevertheless, the range and nature of nutrientsensing pathways that regulate adaptive responses to nutrient surplus and their role in the development of obesity are not completely understood.A series of G protein-coupled rec...