| Abstract No.: | A-E1162 |
| Country: | Canada |
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| Title: | ROLE OF NEUROPEPTIDE Y INHIBITION ON ENERGY BALANCE AT THE VENTROMEDIAL HYPOTHALAMIC NUCLEUS |
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| Authors/Affiliations: | 1 Melissa Chee*; 1 William Colmers;
1 University of Alberta, Edmonton, AB, Canada
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| Content: | Animals with lesions to the ventromedial nucleus (VMN) of the hypothalamus are hyperphagic and obese, suggesting that ongoing activity in VMN neurons tonically inhibits feeding behaviour. The VMN contains specialized, glucosensitive neurons that are regulated by physiological changes in blood glucose levels. Furthermore, it is rich in receptor expression for many anorexigenic and/or orexigenic peptides that suppresses and stimulates food intake, respectively. One of the most potent orexigens is Neuropeptide Y (NPY), especially when directly applied to the VMN. The OBJECTIVES are to identify the population of VMN neurons that are NPY-sensitive, to determine the cellular and molecular mechanisms underlying NPY actions, and to determine how NPY-signaling interacts with the glucose-sensitive mechanism of the VMN neuron. The MATERIALS AND METHODS involve visualized-patch electrophysiological recordings from VMN neurons in acute mouse brain slices to monitor the neuronal properties that are affected by NPY. Additionally, we use pharmacological tools to identify the cellular mechanisms and receptor properties mediating the actions of NPY. Overall, the RESULTS indicate that NPY inhibits VMN neurons located in the dorsomedial and central subdivision of the VMN. The inhibitory NPY effects are mediated solely by the NPY Y1 receptor subtype as co-application of NPY with the selective Y1 receptor antagonist BIBO 03304 completely blocked the actions of NPY. The effects of NPY are concentration-dependent and are enhanced with increasing concentrations of NPY application (30 – 500 nM). At 500 nM, NPY activated an inwardly-rectifying potassium conductance that decreased the input resistance of the VMN neuron by 44 +/- 5 % (n=13) and induced a strong 13 +/- 1 mV (n=13) membrane hyperpolarization that is reversible upon washout. These underlying changes suppressed the excitability of the VMN neuron in a concentration-dependent manner. NPY application increased the rheobase – current required for action potential firing – by up to 35 +/- 7 pA (n=11; 500 nM NPY) and increased the latency of action potential firing, suggesting that NPY reduces the excitability of VMN neurons. Furthermore, about 70% of NPY-sensitive neurons are also glucosensitive (uniformly excited by reduced glucose concentration), and about 80% of glucosensitive neurons are also NPY-sensitive. The effects of NPY are independent of the extracellular glucose concentration (0.5 – 10 mM) and persist even during neuronal activation induced by decreasing extracellular glucose. The concurrent sensitivity to NPY in glucosensitive VMN neurons supports our CONCLUSION that there is a convergence of neural and metabolic signals onto the output of the VMN. It also indicates the physiological relevance of NPY’s actions on these VMN neurons. The inhibitory actions of NPY on VMN neurons are consistent with lesion studies suggesting that a reduction in VMN output, such as by the actions of NPY, can potently modulate feeding behaviour.
This study is supported by the Canadian Institute of Health Research, Queen Elizabeth II Graduate Scholarship and Hotchkiss Brain Institute Obesity: A Brain Disorder Research Studentship.
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