1532-P: Expression of Fibroblast Growth Factor-1 by Medial Hypothalamic Neurons Is Required for Normal Glucose and Energy Homeostasis

The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. As one example, our group and others have shown that a single intracerebroventricular (icv) injection of fibroblast growth factor-1 (FGF1) induces both transient anorexia and weight loss and sustained remission of diabetic hyperglycemia in rodent models of type 2 diabetes (T2D). These pharmacological responses are mediated by FGF1’s action in the mediobasal hypothalamus (MBH), which includes both arcuate (ARC) and ventromedial hypothalamic nuclei (VMN). FGF1 is endogenously expressed in the MBH and based on both RT-PCR and western blot analysis of MBH punches from male C57Bl/6J mice, we report that Fgf1 mRNA levels were reduced by 33%, (p<0.01) and FGF1 protein levels were reduced by 39%, (p<0.01) during fasting while both were restored to baseline within 2 hours of refeeding. Given the key role played by the VMN neurons in both energy and glucose homeostasis, we sought to determine if endogenous VMN FGF1 signaling participates in these processes. We deleted FGF1 from MBH neurons by microinjecting either control AAV1-CAG-GFP or AAV1-hSyn-Cre-WPRE.hGH directed towards the bilateral MBH of adult male FGF1 floxed (FGF1^fl/fl) mice. We found that although daily food intake tended to be higher following targeted deletion of FGF1, the effect did not achieve statistical significance. In contrast, this intervention caused significant weight gain (characterized by increases of both lean and fat mass), glucose intolerance, and pronounced disruption of dark/light cycle feeding, energy expenditure, and locomotion patterns. Together, these preliminary findings support the conclusion that expression of FGF1 by neurons in the MBH is required for normal energy and glucose homeostasis.