About GSBS   |  FAQ  |  Job Opportunities  |  Search UMDNJ
     




"THE ROLE OF NPY/AGRP-GI NEURONS IN INFLAMMATION-RELATED ANOREXIA"

by
Lihong Hao
Pharmacology & Physiology Program
M.S. 2005, Sun Yat-Sen University


Thesis Advisor: Vanessa H. Routh, Ph.D.
Professor
Department of Pharmacology & Physiology

Monday, August 18, 2014
1:00 P.M. , MSB H-609b


Abstract

Anorexia-cachexia syndrome is a serious complication of chronic disease (e.g., cancer). During anorexia-cachexia, the neuronal regulation of food intake is interrupted and the brain no longer responds to energy deficit. The mechanism(s) underlying anorexia-cachexia are unknown; however the orexigenic neuropeptide Y (NPY)-glucose-inhibited (GI) neurons which co-express Agouti-related peptide (AgRP) may play a role. NPY/AgRP neurons, which are located in the arcuate nucleus (ARC) within the ventromedial hypothalamus (VMH), are involved in regulation of food intake and energy balance. Approximately 40% of ARC NPY/AgRP neurons are GI neurons. GI neurons increase their activity in response to decreased glucose levels. Previous studies in our lab and others show that fasting increases c-fos expression in NPY neurons and enhances hypothalamic NPY release in response to decreased glucose. Fasting also increases the activation of NPY/AgRP-GI neurons by decreased glucose. Lipopolysaccharide (LPS) injection, an animal model of inflammation-induced anorexia, blocks fasting-induced c-fos expression in NPY/AgRP neurons. Thus, this thesis tests the hypothesis that LPS will also block the fasting enhanced activation of NPY/AgRP-GI neurons in response to decreased glucose. A corollary to this hypothesis is that the effects of LPS will be mediated via inflammatory cytokines. In order to test this hypotheses I used mice which expressed green fluorescent protein (GFP) on the NPY promoter (NPY-GFP mice) in order to visualize NPY-expressing neurons for electrophysiological and immunohistochemical experiments.
As shown by others, LPS injection reduced fasting-induced NPY c-fos activation. In line with this observation, LPS injection prevented the fasting enhanced response of NPY-GI neurons to decreased glucose from 2.5 mM to 0.5 mM. In contrast, in response to a glucose decrease from 2.5 mM to 0.1 mM, there was no significant difference in glucose sensitivity of NPY-GI neurons from fasted animals and fed animals, suggesting the response of NPY-GI neurons is maximal when glucose decreases to 0.1 mM and nutrient deprivation cannot elicit a further response. However, LPS blunts this maximal response. These data suggest that the glucose sensing ability of NPY/AgRP-GI neurons is impaired during LPS injection-induced anorexia.
Pretreating NPY-GFP mice with the nonspecific cytokine inhibitor pentoxyfilline (PTX) prevents the inhibitory effect of LPS on fasting-induced NPY neuronal c-fos activation. PTX also prevents the inhibitory effect of LPS on the response of NPY-GI neurons from fasted mice to decreased glucose. These data support the hypothesis that inflammatory cytokines mediate the effect of LPS on NPY/AgRP-GI neurons. To further test this hypothesis the glucose sensitivity of NPY/AgRP-GI neurons was evaluated in the presence of inflammatory cytokine tumor necrosis factor alpha (TNFá). As predicted, TNFá blocks the response of NPY/AgRP-GI neurons to decreased glucose. Interestingly, the effect of TNFá was mediated by a presynaptic mechanism.
In summary, reduced activation of NPY/AgRP-GI neurons by low glucose as a result of increased circulating inflammatory cytokines may contribute to the development of LPS-induced anorexia. Increased inflammatory cytokines are also believed to play a key role in the development of anorexia-cachexia in a number of chronic diseases including cancer as well as end-stage heart and kidney diseases. This suggests that we may be able to extend our findings to disease-related anorexia-cachexia. Therefore, we conclude that reduced activation of ARC NPY/AgRP-GI neurons by low glucose may play a role in the impaired detection of energy deficit which occurs in disease-related anorexia-cachexia. However, further work is needed in specific disease models in order to support this conclusion.


Return to Dissertation list

 

Newark Campus - Piscataway Campus - Stratford Campus
About GSBS - FAQ - Job Opportunities - Search UMDNJ