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HYPOTHALAMIC GLUCOSE-INHIBITED NEURONS:
COORDINATORS OF ENERGY HOMEOSTASIS

by
Beth Ann Murphy
Integrative Neuroscience

B.S., 1988, Muhlenberg College
M.S., 1992, Seton Hall University

Thesis Advisor: Vanessa H. Routh, Ph.D.
Associate Professor
Department: Pharmacology and Physiology

MSB, H-609B

Monday, January 5, 2009
2:00 p.m.


Abstract

Interactions between signals of peripheral energy status and the central nervous system (CNS) maintain energy homeostasis. Neuropeptide Y (NPY) is a potent orexigen, localized in hypothalamic arcuate neurons. Negative energy states (‘fasting’) stimulate NPY neurocircuitry in the hypothalamic arcuate nucleus (ARC) to correct energy deficits. A subpopulation of ARC-NPY neurons (~ 40%) are also glucose-inhibited (GI)-type glucose sensing neurons. Hence, they depolarize in response to decreased glucose. Because fasting enhances NPY neurotransmission, we hypothesize that fasting also decreases the glucose sensitivity of NPY-GI neurons causing them to become activated in response to smaller decreases in extracellular glucose. Using an in vitro hypothalamic explant system, we show that fasting enhances NPY release in response to reduced glucose. Using a membrane potential sensitive dye, we demonstrate that fasting also enhances depolarization of isolated NPY-GI neurons in response to reduced glucose. These data support our hypothesis that fasting decreases the glucose sensitivity of NPY-GI neurons. Therefore, decreased glucose sensitivity of NPY-GI neurons may lead to enhanced NPY release in response to decreased glucose and may contribute to overall stimulation of NPY neurotransmission during fasting. The reduction in extracellular leptin and glucose levels during fasting may play a role in the decreased glucose sensitivity of GI neurons. That is, leptin increases, while prolonged (1 hour) exposure to the lower glucose concentrations present in the brain during fasting decreases the glucose sensitivity of GI neurons. The effects of leptin and glucose on GI neurons are mediated by 5`AMP kinase (AMPK). During fasting reduced leptin and glucose levels increase AMPK activity. Our data indicate that this increase in AMPK activity decreases the glucose sensitivity of NPY-GI neurons. Thus, AMPK signaling is a pivotal player in controlling the response of GI neurons to reduced glucose.
Previously published data by our laboratory have shown that both AMPK activation and NO production are integral components of glucose sensing by GI neurons. The current studies suggest that positive feedback between AMPK and NO signaling regulates glucose sensing in GI neurons. First, we confirmed that AMPK activation is required for nNOS phosphorylation and NO production in GI neurons. We then extended these findings to show that nNOS and sGC are needed for GI neurons to depolarize in response to decreased glucose and the AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta -D-ribofuranoside (AICAR). Furthermore, downstream activation of AMPK by the NO-sGC signaling pathway is necessary for depolarization of GI neurons in response to decreased glucose. These data suggest that AMPK-NO-AMPK signaling is an important component in glucose sensing by GI neurons. Finally, our data suggest that the cystic fibrosis transmembrane regulator (CFTR) chloride conductance is the final target of the AMPK-NO-AMPK signaling pathway in GI neurons.
In conclusion, changes in leptin and glucose associated with fasting increase AMPK activity in GI neurons. This increase in AMPK activity mediates the fasting-induced decrease in the glucose sensitivity of GI and NPY-GI neurons. Decreased glucose sensitivity of NPY-GI neurons is a putative mediator of the increased hypothalamic NPY release seen during fasting. Finally, glucose sensing in GI neurons is mediated by positive feedback between AMPK and NO signaling. This AMPK-NO-AMPK signaling pathway may be a target for normalizing the glucose sensitivity of GI neurons when energy homeostasis is disturbed under conditions such as obesity and diabetes.


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