The hypothalamic arcuate nucleus-median eminence (ARC-ME) is a target for sustained diabetes remission induced by fibroblast growth factor 1 (FGF1). To identify intracellular signaling cascades underlying this effect, we considered evidence that sustained signal transduction responses engaged by FGF1 are integrin-dependent. To determine if the sustained antidiabetic response of diabetic ob/ob mice to intracerebroventricular (icv) injection of FGF1 is also integrin-dependent, we investigated the response to a mutant FGF1 that is unable to activate integrin receptors (R50E FGF1). We found that although icv injection of R50E FGF1 mimics the transient anorexia, weight loss and blood glucose lowering responses induced by native FGF1 (P<0.001 vs. Veh for each), it fails to elicit sustained diabetes remission. Similarly, MAPK/ERK signaling is induced in the ARC-ME (primarily in tanycytes) for up to 24 h following a single icv FGF1 injection in both wild type and ob/ob mice, but the duration of this response is reduced by∼70% following icv R50E FGF1 injection (P<0.0001 vs. icv FGF1). We therefore hypothesized that owing to its integrin-dependent nature, FGF1-induced remission of diabetic hyperglycemia requires sustained activation of the MAPK/ERK signaling pathway in the ARC-ME. To test this hypothesis, 4 groups of diabetic ob/ob mice were studied. Each group received a single icv injection of either saline vehicle or recombinant FGF1 (3 µg), followed immediately by continuous icv infusion of either the MAPK inhibitor U0126 or its vehicle (DMSO) for 24 h. We report that the duration of the antidiabetic effect induced by icv FGF1 injection is attenuated by pharmacologic blockade of MAPK/ERK signaling. We conclude that the sustained remission of diabetic hyperglycemia induced by the central action of FGF1 depends upon its ability to activate hypothalamic MAPK/ERK signaling in a sustained manner.
J.M. Brown: None. B.N. Phan: None. H. Wasanwala: None. M.E. Matsen: None. A. Secher: Employee; Spouse/Partner; Gubra. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. J. Scarlett: None.
National Institutes of Health (K08DK114474, DK101997, DK083042, DK035816, P30DK017047, HL007312); University of Washington