1523-P: Anorexia Induced by the Central Action of Fibroblast Growth Factor 1 (FGF1) Is Dependent on Activation of Parabrachial CGRP Neurons

Intracerebroventricular (icv) injection of FGF1 induces remission of hyperglycemia that is sustained for weeks across multiple rodent models of type 2 diabetes. However, in addition to sustained remission of hyperglycemia, we and others have shown that icv FGF1 injection also induces a transient but potent anorexic response that has hindered efforts to translate these findings towards the clinic. Recently, our group reported that the activity of orexigenic AgRP neurons is inhibited following icv FGF1 injection, both in vivo and after bath application of FGF1 in an ex vivo brain slice preparation. Previous work by other groups has established that neurons located in the parabrachial nucleus (PBN) that express calcitonin gene-related peptide (CGRPPBN neurons) are highly anorexigenic when activated and are innervated by and tonically inhibited by GABAergic projections from AgRP neurons. Based on these findings, we hypothesized that FGF1-induced anorexia involves CGRPPBN neuron activation. To test this hypothesis, we employed CalcaCre:GFP/+ transgenic mice, which express GFP fused to Cre recombinase driven by the CGRP-encoding gene Calca. We first found that CGRPPBN neurons are robustly activated following icv FGF1 injection (based on detectable c-Fos staining). We next found that the anorexic response to icv FGF1 injection was blunted by 50% by continuous subcutaneous infusion of the GABAA receptor agonist Bretazenil via osmotic minipump at a dose that does not affect intake in control mice. Finally, we bilaterally infected CGRPPBN neurons with either AAV1-DIO-hM4Di:mCherry or AAV1-DIO-mCherry control virus and observed that inhibition of CGRPPBN neurons following administration of CNO fully reversed FGF1-induced anorexia in hM4Di-bearing mice, while anorexia remained intact in the mCherry control group. Together, these data suggest that FGF1-induced anorexia results from reduced GABAergic inhibition of CGRPPBN neurons. Disclosure J.M. Scarlett: None. C. Bryan: None. I.K. Redford: None. K.M. Alonge: None. G.J. Morton: Research Support; Novo Nordisk A/S. M.W. Schwartz: None. Funding NIH (DK114474, DK128383DoD, W81XWH2110635); GJM (DK089056, DK124238MWS, DK101997, DK083042)