FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis

Nat Commun. 2015 Apr 28;6:6980. doi: 10.1038/ncomms7980.

Abstract

Fibroblast growth factor-1 (FGF1) and FGF19 have been shown to improve glucose metabolism in diabetic rodents, but how this occurs is unknown. Here to investigate the mechanism of action of these growth factors, we perform intracerebroventricular (i.c.v.) injections of recombinant FGF1 or FGF19 in an awake rat model of type 1 diabetes (T1D) and measure rates of whole-body lipolysis, hepatic acetyl CoA content, pyruvate carboxylase activity and hepatic glucose production. We show that i.c.v. injection of FGF19 or FGF1 leads to a ∼60% reduction in hepatic glucose production, hepatic acetyl CoA content and whole-body lipolysis, which results from decreases in plasma ACTH and corticosterone concentrations. These effects are abrogated by an intra-arterial infusion of corticosterone. Taken together these studies identify suppression of the HPA axis and ensuing reductions in hepatic acetyl CoA content as a common mechanism responsible for mediating the acute, insulin-independent, glucose-lowering effects of FGF1 and FGF19 in rodents with poorly controlled T1D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl Coenzyme A / metabolism
  • Adrenocorticotropic Hormone / antagonists & inhibitors
  • Animals
  • Corticosterone / antagonists & inhibitors
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism*
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / metabolism
  • Fibroblast Growth Factor 1 / pharmacology*
  • Fibroblast Growth Factor 1 / therapeutic use
  • Fibroblast Growth Factors / pharmacology*
  • Fibroblast Growth Factors / therapeutic use
  • Glucose / metabolism
  • Hypothalamo-Hypophyseal System / drug effects*
  • Injections, Intraventricular
  • Insulin / administration & dosage
  • Lipolysis / drug effects
  • Liver / metabolism
  • Male
  • Pituitary-Adrenal System / drug effects*
  • Pyruvate Carboxylase / metabolism
  • Rats, Sprague-Dawley

Substances

  • FGF19 protein, human
  • Insulin
  • Fibroblast Growth Factor 1
  • Fibroblast Growth Factors
  • Acetyl Coenzyme A
  • Adrenocorticotropic Hormone
  • Pyruvate Carboxylase
  • Glucose
  • Corticosterone