FGF21 Maintains Glucose Homeostasis by Mediating the Cross Talk Between Liver and Brain During Prolonged Fasting

Abstract

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 hepatocytesecreted 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 a (PPARa) 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 PPARa 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 PPARa 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 signalrelated 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.Hepatic gluconeogenesis is tightly controlled by counterregulatory hormones such as glucagon, cortisol, and insulin, via regulating the expression of key gluconeogenic enzymes, including glucose 6 phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Fibroblast growth factor 21 (FGF21), a metabolic regulator mainly secreted from the liver in response to fasting and starvation under the control of the nuclear receptor peroxisome proliferatoractivated receptor a (PPARa), plays a critical role in maintaining energy homeostasis and insulin sensitivity in both rodents and nonhuman primates (1-6). A therapeutic dose of FGF21 decreased blood glucose in diabetic animals without causing hypoglycemia (4). FGF21 has also been shown to act as a key downstream effector of PPARa, mediating several metabolic adaptation responses to starvation, including hepatic fatty acid oxidation, ketogenesis, and growth hormone resistance (1,2,7). In addition, FGF21 is implicated in hepatic gluconeogenesis, although it remains controversial whether hepatocytes are a direct action site of FGF21 (8,9). There is an obvious dichotomy between the effects of endogenous FGF21 and pharmacological actions of the recombinant peptide with respect to hepatic metabolism (4,6,9).FGF21 can cross the blood-brain barrier (10) and is detectable in both human and rodent cerebrospinal fluid (10,11). Continuous intracerebroventricular injection of FGF21 into obese rats increases energy e...

Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration

“…bFGF is another member of the FGF family, whose efficacy in promoting fibroblast-cell migration has been previously described (7). The functions of FGF21 in glucose homeostasis as well as in hepato-and cardioprotection have been reported (9)(10)(11). While it has been reported that FGF21 is highly expressed in the liver (8), the present study revealed that its expression was even higher in the injured skin of mice.…”

“…Initially, 1, a member of the FGF family, was reported to be preferentially expressed in the liver (8). However, recent studies have identified that FGF21 is inducible by starvation or certain drugs, and have reported on its diverse functions in glucose homeostasis as well as hepatoand cardioprotection (9)(10)(11). FGF19, FGF21 and FGF23 belong to the FGF19 sub-family.…”

Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome

“…Sirt 1 repression induces mitophagy with the development of MODS and may supersede the connections between diabetic genes (Type 1 and 2) and their associated diseases (Figure 2). Sirt 1 plays an important role in the regulation fibroblast growth factor 21 [82][83][84] and the apelinergic pathway [85] with connections to brain insulin resistance (stroke, dementia, AD) [86]. In Type 2 diabetes the relevance of stress, anxiety and hyperphagia are associated with defective apelinergic pathways [85] and severity of diabetes (post-transcriptional defect) associated with Sirt 1-apelinergic system defects in mental disorders [87].…”

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

“…Intracerebroventricular injection of FGF21 in Fgf21-KO mice restores the metabolic effects of FGF21 essentially through the corticotropinreleasing hormone (CRH) and the activation of CREB, which finally enhances hepatic gluconeogenesis and sympathetic nerve activity in BAT [56,61,62]. According to that, lack of KLB in the brain blunts these effects [56,60,61]. Finally, treatment with the b-blocker propranolol diminishes the effects of FGF21 when it is centrally administered but not when delivered peripherally [60].…”

“…FGF21 has the potential to act in the central nervous system (CNS) since FGFRs are widely expressed in this tissue and KLB is specifically expressed in the suprachiasmatic nucleus, the dorsal vagal complex of the hindbrain, the area postrema, the nucleus tractus solitari, the nodose ganglia, and the paraventricular nucleus [22,55,56]. Immunoblotting experiments have revealed that FGF21 is expressed in several regions of the brain, such as the substantia nigra, striatum, hippocampus, and cortex [57]; however, this growth factor also crosses the blood brain barrier and is present in the cerebrospinal fluid in a linear relationship with serum levels [58].…”