Administrative Supplement (Diversity) to Roles for Glucosensors in Taste Function

项目总结

PROJECT SUMMARY The typical Western diet is loaded with simple sugars, and their palatable taste is a predominant factor fueling excess calorie intake, body weight gain, and diabetes in the United States. A single heterodimeric G-protein coupled receptor (T1R2+T1R3) found in mammalian taste cells is widely considered the principal means through which all simple sugars are detected and promote consumption via the gustatory system. Yet, recent studies from our laboratory revealed that rodents come to respond more positively to the orosensory properties of glucose-containing sugars than other types of sweeteners. The preliminary findings in the parent R01 proposal and this application reveal that glucokinase, a phosphorylating enzyme involved in other glucosensing systems, is expressed in murine taste cells, is regulated by energy status, and diet. Activation of gustatory glucokinase bolsters glucose appetite, while silencing glucokinase impairs the ability to discriminate glucose from another sugar, fructose. Accordingly, our working hypothesis is that glucokinase is part of a T1R2+T1R3-independent taste receptor that transduces glucose-specific signals in the gustatory system. The overall goal of this administrative diversity supplement proposal, then, is to further clarify relative contributions of this novel gustatory glucosensor to the hedonic appeal of glucose-containing sugars. In Aim 1, we will determine which types of dietary sugars regulate glucokinase expression in the taste bud cells of sweet-sensitive mice, and, using a virogenetic silencing approach, will investigate whether lingual glucokinase is required for the hedonic appeal of glucose disaccharides. In Aim 2, we will combine genetic manipulation of taste receptor function with electrophysiology to determine how glucokinase-dependent taste signals are encoded at the first order central relay of the gustatory system in sweet-sensitive and sweet-insensitive mice, and how this information is reorganized after dietary exposure to simple sugars. The outcomes of these aims will help identify novel and potentially critical aspects of nutrient sensing, with the ultimate goal of identifying new strategies to curb appetite.