Hepatic gluconeogenesis is a main 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 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 ERK1/2, thereby stimulating the expression of corticotropin-releasing-hormone by activation of the transcription factor cAMP Response Element Binding protein (CREB). Therefore, FGF21 maintains glucose homeostasis during prolonged fasting by fine-tuning the inter-organ crosstalk between liver and brain.
- Received April 2, 2014.
- Accepted July 8, 2014.
- © 2014 by the American Diabetes Association.
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