We hypothesize that hypothalamic inflammation associated with high fat feeding arises as a result of Toll-like receptor (TLR) signaling in a specialized cell type lining the inferolateral walls of the third ventricle, the alpha tanycyte. We propose that the activation of NF-?B in these cells releases inflammatory mediators into feeding-related centers in the mediobasal hypothalamus, increasing feeding and/or altering the sensitivity of arcuate/ventromedial nucleus neurons to leptin and/or insulin. To test this hypothesis, RNA-Seq analysis will be used to identify the complete gene expression profile of alpha tanycytes in response to a HFD, with particular emphasis given to the identification of genes and pathways involved in inflammation. Based on this analysis, the effect of a HFD on food intake, energy expenditure, glucose homeostasis, leptin and insulin sensitivity, and other parameters of hypothalamic inflammation will be studied in transgenic animals with conditional KO in alpha tanycytes of selected genes identified in the RNA-Seq analysis. We propose that these studies will demonstrate a critical role of tanycytes in the pathophysiology of hypothalamic inflammation associated with high fat feeding, uncovering new knowledge in understanding the pathogenesis of obesity and a potentially new pharmacologic target for the treatment of obesity.
Improvements in long-term management of obesity are clearly needed to reduce the risk of associated morbidities, and elucidating mechanisms involved in the regulation of appetite and satiety will allow the development of new targets and molecular interventions for the treatment of obesity. We propose that tanycytes, a specialized ependymal cell located in the wall of the third ventricle, contribute to hypothalamic inflammation in response to high fat feeding by the release of inflammatory mediators into the adjacent hypothalamus, increasing feeding and altering the sensitivity of arcuate/ventromedial nucleus neurons to leptin and insulin.