The brain is implicated in the antidiabetic effects of members of the fibroblast growth factor (FGF) peptide family. Previously, we reported that a single intracerebroventricular (icv) injection of FGF-1 induces remission of hyperglycemia that is sustained for weeks in rodent models of type 2 diabetes (T2D). The integrin receptor ανβ3 plays a key role in FGF-1 signaling, and crosstalk between ανβ3 and the FGF-1-FGF receptor (FGF-R) complex is necessary for increased DNA synthesis and proliferation in cultured cells. These cellular responses downstream of FGF-1-FGFR-ανβ3 result from sustained (e.g., lasting for 5 hours) activation of the extracellular signal-regulated kinase (ERK) signal transduction pathway. In cultured fibroblasts, prolonged ERK activation induced by FGF-1 is not replicated with a mutant FGF-1 peptide (R50E) that activates FGFR normally, but does not activate ανβ3 signaling. Similarly, we report that whereas icv FGF-1 (3 µg) induces phosphorylation of ERK1/2 at both early (20 minute) and late (5 hr) time points in hypothalamic punches obtained from wild type mice, icv injection of the same dose of R50E elicited this effect only at the early time point. Thus, R50E fails to activate hypothalamic FGF-1-FGFR-ανβ3 signaling in vivo. To investigate whether activation of ανβ3 is required for the prolonged antidiabetic effect of icv FGF-1, diabetic ob/ob mice received a single injection of either vehicle (Veh), recombinant FGF-1 (3 µg), or R50E (3 µg). Whereas R50E mimicked the effect of native FGF-1 to reduce food intake, body weight and blood glucose for the first week after icv injection (P<0.001 vs. Veh), the mutant peptide failed to elicit the sustained diabetes remission observed in animals receiving icv FGF-1. We conclude that signaling by the full FGF-1-FGFR-ανβ3 complex is necessary for the effect of FGF-1 signaling in the brain to elicit sustained remission of diabetic hyperglycemia in rodent models of T2D.


J. Scarlett: None. J.M. Brown: None. B.N. Phan: None. E.L. Khav: None. M.E. Matsen: None. N.K. Acharya: None. H.T. Nguyen: 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.

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