Role of hypothalamic MAPK/ERK signaling and central action of FGF1 in diabetes remission

Jenny M. Brown, Marie A. Bentsen, Dylan M. Rausch, Bao Anh Phan, Danielle Wieck, Huzaifa Wasanwala, Miles E. Matsen, Nikhil Acharya, Nicole E. Richardson, Xin Zhao, Peng Zhai, Anna Secher, Gregory J. Morton, Tune H. Pers, Michael W. Schwartz, Jarrad M. Scarlett*

*Corresponding author for this work

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Abstract

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family, is induced for at least 24 h. Further, we show that this prolonged response is required for the sustained antidiabetic action of FGF1 since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

Original languageEnglish
Article number102944
JournaliScience
Volume24
Issue number9
Number of pages19
ISSN2589-0042
DOIs
Publication statusPublished - 2021

Bibliographical note

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Keywords

  • Diabetology
  • Molecular biology
  • Molecular neuroscience

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