Glucose in the circulation plays an important role in the regulation of eating behavior. Animal studies indicate that a decrease in portal vein glycemic level stimulates feeding and this is prevented by elevated glucose in the system. These effects are abolished following selective ablation of hepatic vagal afferent fibers, suggesting the presence of glucose sensor in the portal vein. Currently, little is known about the nature of these sensors. We have recently identified the presence of glucose-excited (GluE) and glucose-inhibited (GluI) differentially distributed among gastric- and portal vein-projecting nodose neurons. Our preliminary data lets us hypothesize that the GluI neurons in the nodose ganglia innervating the portal vein are the glucose sensors mediating the satiety actions of glucose. These glucose sensing neurons are stimulated by portal vein hypoglycemia and inhibited by elevated glucose in the vessel. We further postulate that high glucose triggers cyclic AMP (cAMP) synthesis, which in turn activates a novel Epac-Rap-PLCe pathway to stimulate the calcium-sensitive 2 pore potassium channel TRESK resulting in hyperpolarization and suppression of feeding. To test this hypothesis, we plan to employ a variety of research tools including in vivo and in vitro electrophysiological recordings, calcium imaging studies, single cel RT-PCR, and signal transduction studies using pharmacological tools and small interfering RNA technology. In vivo intracellular recording and labeling studies will be used to demonstrate the GluI neurons are the portal vein glucose sensors mediating eating behavior. To dissect the signal transduction pathways utilized by GluI neurons, we plan to perform simultaneous calcium imaging studies and perforated patch electrophysiological recording of NG neurons. This allows us to correlate directly changes in intracellular Ca2+ concentration with an electrophysiological event and thus provides us with much more precise tools to dissect which molecules are involved in mediating Ca2+ signaling resulting in cellular hyperpolarization, a signature event for GluI neurons. The importance of Epac, Rap and PLCe in the signal transduction will be evaluated using siRNA technology. This study will be complemented by single cell PCR to identify the molecular imprint of signaling molecules and transmitter of this group of glucose sensors. Finally, we will perform feeding studies following silencing of key molecules in the cAMP-Epac-Rap-PLCe pathway. Understanding the signal transduction cascade utilized by the portal vein glucose sensor to regulate feeding behavior may provide insight as to why impaired glucose signaling occurs in obesity and patients with metabolic syndrome. Expression of Epac, Rap 2B, PLCe and TRESK in the nodose ganglia will be silenced by local application of specific siRNA of the molecule of interest into the nodose ganglia using electroporation.
Glucose in the circulation plays an important role in the regulation of eating behavior. However, little is known about the mechanism of glucose sensing and how the signal is transmitted to the hypothalamus to regulate feeding. Recently, we have identified a group of glucose-inhibited (GluI) neurons projecting to the portal vein, which we believe functions as glucose sensors mediating satiety actions of glucose. The purpose of this study is to understand the molecular and cellular actions of this group of specialized neurons and delineate the vagal-lateral hypothalamic circuit responsible for relaying information about glucose ingestion to control short-term feeding. This information may provide the foundation to understand why impaired glucose signaling occurs in obesity and patients with metabolic syndrome.
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