FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.
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.
1] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [2] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [3] Department of Cellular &Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Rachel J
RJ
Perry
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [2] Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Sangwon
S
Lee
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [2] Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Lie
L
Ma
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Dongyan
D
Zhang
1] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [2] Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Joseph
J
Schlessinger
1] Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [2] Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA [3] Department of Cellular &Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Gerald I
GI
Shulman
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors; D000818:Animals; D003345:Corticosterone / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology* / Q000627:therapeutic use; D005346:Fibroblast Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D007276:Injections, Intraventricular; D007328:Insulin / Q000008:administration & dosage; D008066:Lipolysis / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D011766:Pyruvate Carboxylase / Q000378:metabolism; D017207:Rats, Sprague-Dawley
C117476:FGF19 protein, human; D007328:Insulin; D016220:Fibroblast Growth Factor 1; D005346:Fibroblast Growth Factors; D000105:Acetyl Coenzyme A; D000324:Adrenocorticotropic Hormone; D011766:Pyruvate Carboxylase; D005947:Glucose; D003345:Corticosterone