Over 500 million adults worldwide have type II diabetes (T2D), which has caused 6.7 million deaths in 2021 alone. Yet, accessible and sustainable treatments remain limited and many address the symptoms of the disease rather than the root causes, one of which is insulin sensitivity. Recent research shows that therapies targeting glucose-regulating mechanisms in the brain that do not directly affect insulin secretion can enhance diabetes remissions in T2D rodent models. Such treatments may revolutionize diabetes treatment and public health. The Scarlett Lab’s previous studies show that exogenous intracerebroventricular administration of hypothalamic fibroblast growth factor 1 (FGF1) resulted in sustained hyperglycemic remission and increased insulin sensitivity in the mediobasal hypothalamus (MBH), suggesting that FGF1 signaling in the brain impacts glucose metabolism. FGF1 is also endogenously expressed in the MBH, but the functional role of endogenous FGF1 is still unknown. Thus, I hypothesize that endogenous FGF1 signaling in the MBH regulates glucose and energy homeostasis. To test this, I utilize adenosine-associated virus as a vector for gene editing therapy to knock out the Fgf1 gene from the MBH in adult male Fgf1-floxed mice. I then monitor food intake, body weight, and blood glucose levels; perform insulin and glucose tolerance tests; and measure insulin and glucagon levels using enzyme-linked immunosorbent assay. Finally, I use immunohistochemical analysis at the end of the experiment to validate Fgf1 knockout. Based on pilot studies, I expect to observe that MBH Fgf1 knockout significantly increases body weight and impairs glucose tolerance and insulin sensitivity. Follow-up work can elaborate on investigating the effect of a high-fat diet on FGF1 signaling and function. This project illuminates the functional role of endogenous FGF1 signaling in regulating glucose and energy homeostasis and contributes to the development of novel therapeutic strategies to treat diabetes and obesity.

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.