JCI Insight (Sep 2022)

Sustained inhibition of NPY/AgRP neuronal activity by FGF1

  • Eunsang Hwang,
  • Jarrad M. Scarlett,
  • Arian F. Baquero,
  • Camdin M. Bennett,
  • Yanbin Dong,
  • Dominic Chau,
  • Jenny M. Brown,
  • Aaron J. Mercer,
  • Thomas H. Meek,
  • Kevin L. Grove,
  • Bao Anh N. Phan,
  • Gregory J. Morton,
  • Kevin W. Williams,
  • Michael W. Schwartz

Journal volume & issue
Vol. 7, no. 17

Abstract

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In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

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