Thursday, December 26, 2024
12/26/2024
PROJECT SUMMARY Obesity and diabetes are associated with the chronic overconsumption of high sugar foods and fluids, driven in large part by their palatable taste. A single heterodimeric G-protein coupled receptor (T1R2+3) found in mammalian taste cells is widely considered the principal means through which all simple sugars are detected and promote ingestion via the gustatory system. Yet, recent studies from our laboratory revealed that rodents come to respond more positively to the orosensory properties of glucose over fructose, when provided the opportunity to learn about their divergent metabolic consequences, and this phenomenon does not require the canonical T1R2+3 taste receptor. Collectively, these published studies point to the existence of a previously unknown taste receptor linked to glucose appetite. The preliminary findings included in this proposal now show that glucokinase, a phosphorylating enzyme involved in other glucosensing mechanisms, is expressed in murine taste cells. We further demonstrate that glucokinase levels in the taste tissue are regulated by energy state and dietary sugar exposure. Moreover, pharmacological activation of lingual glucokinase specifically bolsters licking behavior and neural responsiveness in the chorda tympani nerve for glucose, but not fructose or water. Our working hypothesis is that glucokinase is part of a T1R2+3-independent taste receptor that transduces glucose- specific signals in the gustatory system. The overall goal of this proposal is to further clarify the functional and molecular properties of this novel gustatory glucosensor. In Aim 1, we will combine genetic and pharmacological approaches to selectively disrupt and/or activate canonical “sweet” taste inputs and lingual glucokinase while measuring taste-driven licking for various “sweet” and “non-sweet” tastants in sugar-naïve and sugar-exposed mice. With immunoblot and qPCR, we will further quantify changes in glucokinase and other sensory mechanisms linked to glucokinase in taste tissue as a function of dietary sugar exposure. In Aim 2, we will combine genetic and pharmacological approaches to psychophysically assess the discriminability of glucose, fructose, and other tastants in a series of two response operant discrimination tasks in order to fully elucidate the behavioral outputs functionally linked to gustatory glucosensors. In Aim 3, we will combine genetic and pharmacological approaches with electrophysiology to determine how T1R2+3-independent, glucokinase-linked taste signals are neurally-transmitted from tongue to brain. The outcomes of these aims will identify novel and potentially critical aspects of nutrient sensing, with the ultimate goal of identifying potential new strategies to curb appetite.
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