An Action in the Hypothalamic Arcuate Nucleus Is Sufficient to Explain the Sustained Remission of Diabetes Induced by Central Administration of Fibroblast Growth Factor-1 (FGF-1)

Abstract

Our recent finding that a single intracerebroventricular (icv) injection of FGF-1 elicits sustained diabetes remission in rodent models of type 2 diabetes supports a growing consensus that the brain is a key target for diabetes drug development. The current work was undertaken to pinpoint the brain area responsible for this action of FGF-1. To this end, we considered the following preliminary findings: 1) both FGF Receptor 1 and integrin receptor αvβ3 (known to be involved in sustained FGF-1 signaling) are concentrated in the hypothalamic arcuate nucleus (ARC), 2) neuronal activation and sustained induction of the MAP Kinase / ERK pathway occurs in this brain area following icv FGF-1 injection, and 3) labeled FGF-1 is concentrated in this area following icv injection. We therefore hypothesized that in rodent models of T2D, an action in the ARC (a brain area known to participate in glucose homeostasis) mediates the sustained diabetes remission elicited by icv FGF-1 injection. To test this hypothesis, we investigated whether a single microinjection of a low dose of FGF-1 into the ARC (0.3 µg bilaterally, for a total of 0.6 µg) can mimic the response elicited by icv injection of a higher dose (3.0 µg). We report that in Zucker Diabetic Fatty rats, a single microinjection of FGF-1 bilaterally into the ARC (via an indwelling dual guide cannula) induced remission of hyperglycemia lasting >3 week, whereas intra-arcuate microinjection of saline vehicle was without effect (P<0.vs. Veh). Since icv injection of the same FGF-1 dose (0.6 µg) had no significant effect on glycemia, sustained diabetes remission induced by intra-ARC microinjection of FGF-1 cannot be explained by leakage into ventricular cerebrospinal fluid. We conclude that an action in the ARC is sufficient to explain the effect of FGF-1 to induce sustained diabetes remission. Disclosure J.M. Brown: None. J. Scarlett: None. M.E. Matsen: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. G.J. Morton: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.