FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting

Qingning Liang, Ling Zhong, Jialiang Zhang, Yu Wang, Stefan R. Bornstein, Christopher Triggle, Hong Ding, Karen S L Lam, Aimin Xu

Research output: Contribution to journalArticle

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Abstract

Hepatic gluconeogenesis is amain source of blood glucose during prolonged fasting and is orchestrated by endocrine and neural pathways. Here we show that the hepatocyte-secreted hormone fibroblast growth factor 21 (FGF21) induces fasting gluconeogenesis via the brain-liver axis. Prolonged fasting induces activation of the transcription factor peroxisome proliferator-activated receptor α (PPARα) in the liver and subsequent hepatic production of FGF21, which enters into the brain to activate the hypothalamic-pituitary-adrenal (HPA) axis for release of corticosterone, thereby stimulating hepatic gluconeogenesis. Fasted FGF21 knockout (KO) mice exhibit severe hypoglycemia and defective hepatic gluconeogenesis due to impaired activation of the HPA axis and blunted release of corticosterone, a phenotype similar to that observed in PPARα KO mice. By contrast, intracerebroventricular injection of FGF21 reverses fasting hypoglycemia and impairment in hepatic gluconeogenesis by restoring corticosterone production in both FGF21 KO and PPARα KO mice, whereas all these central effects of FGF21 were abrogated by blockage of hypothalamic FGF receptor-1. FGF21 acts directly on the hypothalamic neurons to activate the mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thereby stimulating the expression of corticotropin-releasing hormone by activation of the transcription factor cAMP response element binding protein. Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine tuning the interorgan cross talk between liver and brain.

Original languageEnglish
Pages (from-to)4064-4075
Number of pages12
JournalDiabetes
Volume63
Issue number12
DOIs
Publication statusPublished - 1 Dec 2014

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Fasting
Homeostasis
Gluconeogenesis
Glucose
Liver
Brain
Peroxisome Proliferator-Activated Receptors
Corticosterone
Knockout Mice
Hypoglycemia
Transcription Factors
Fibroblast Growth Factor 1
Fibroblast Growth Factor Receptors
Neural Pathways
Cyclic AMP Response Element-Binding Protein
fibroblast growth factor 21
Corticotropin-Releasing Hormone
Mitogen-Activated Protein Kinases
Blood Glucose
Hepatocytes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. / Liang, Qingning; Zhong, Ling; Zhang, Jialiang; Wang, Yu; Bornstein, Stefan R.; Triggle, Christopher; Ding, Hong; Lam, Karen S L; Xu, Aimin.

In: Diabetes, Vol. 63, No. 12, 01.12.2014, p. 4064-4075.

Research output: Contribution to journalArticle

Liang, Qingning ; Zhong, Ling ; Zhang, Jialiang ; Wang, Yu ; Bornstein, Stefan R. ; Triggle, Christopher ; Ding, Hong ; Lam, Karen S L ; Xu, Aimin. / FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. In: Diabetes. 2014 ; Vol. 63, No. 12. pp. 4064-4075.
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