Type 2 diabetes (T2D) is among the most common and costly chronic diseases in the United States. Nearly 10% of Americans have T2D and a further 34% have prediabetes. The brain has increasing emerged as a promising target for the treatment of T2D. For example, our group has demonstrated in rodent models of T2D, that remission of diabetic hyperglycemia lasting for weeks or months can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). Injection of FGF1 into the brain induces sustained activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. ERK signaling is most highly induced in tanycytes which are specialized ependymo-glial cells that line the 3rd ventricle and are implicated in the central control of energy and glucose homeostasis. However, whether MAPK/ERK activation in tanycytes is required for sustained glucose lowering to occur in response to icv FGF1 is unknown. To begin testing of the hypothesis that activation of the MAPK/ERK pathway in tanycytes is necessary for sustained diabetic remission induced by FGF1, we proposed to inhibit the activation of MAPK/ERK pathway specifically in tanycytes by microinjection of a mouse MAPK shRNA silencing adenovirus into the 3rd ventricle 1 week prior to injecting FGF1. In preliminary studies in wild-type mice, I have shown that the ability of FGF1 to induce MAPK/ERK activation is blocked by prior injection of the MAPK shRNA silencing adenovirus. I will now take C57Bl/6J mice placed on high-fat diet to induce diabetic hyperglycemia and determine if pretreatment with the MAPK shRNA silencing adenovirus blocks the ability of icv FGF1 to induce diabetes remission. I predict that successful completion of this study will deepen our understanding of the pathogenesis of T2D, bringing us closer towards a treatment for this devastating disease.