The role of interferon regulatory factors in tanycytes during HFD-induced inflammation, obesity and glucose dysregulation

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Project Abstract The arcuate nucleus-median eminence complex (Arc-ME) is an evolutionarily conserved region of the hypothalamus that plays important roles in physiology and behavior, including control of appetite, energy balance, insulin sensitivity, fertility and lactation. In rodent models, the initiation of a high fat diet (HFD) rapidly induces inflammation specifically within Arc-ME, well in advance of inflammation observed in peripheral tissues. Genetic studies disrupting this inflammation protect from obesity, suggesting the inflammation is causal, and studies in humans show a correlation between arcuate inflammation and obesity. The arcuate has a unique anatomical relationship with bloodstream, as there is no classic endothelial Blood-Brain-Barrier (BBB) separating it from the median eminence, which is invaginated by fenestrated capillaries that are continuous with the peripheral circulation. Here, tanycytes, specialized ependymal cells found lining the ventricular wall of the basal hypothalamus, extend elaborate processes that separate the Arc and ME, thereby partitioning the ME, CSF, and brain parenchyma into distinct compartments. Studies of hypothalamic inflammation have not previously addressed a role for tanycytes, despite their unique localization. Using single cell RNA-seq, we observe that HFD induces an interferon response pathway specifically in 2 tanycytes, the subpopulation that contacts the peripheral circulation. We hypothesize that 2 tanycytes are sentinel cells that respond to signals associated with HFD by upregulating an inflammatory gene program and initiates hypothalamic inflammation. We propose to test this hypothesis by examining whether genetic models in which the interferon response program is specifically induced or disrupted in tanycytes is sufficient/necessary for induction of hypothalamic inflammation. We further propose to define specific interferon regulatory factor targets by which tanycytes elicit inflammation using a combination of transcriptional and epigenomic profiling within tanycytes and estimation of cell- cell communication from single cell sequencing of our perturbed models. Together, these studies will demonstrate a new role for tanycytes in initiating HFD-induced hypothalamic inflammation and identify specific molecular targets that enable them to do so. As 2 tanycytes are located outside of the BBB, they provide an attractive and specific target cell type modulating energy homeostasis against which to design therapeutics to combat obesity.