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...

Among the 22 fibroblast growth factors (FGFs), FGF21 has now emerged as a key metabolic regulator. However, the mechanism whereby FGF21 mediates its metabolic actions per se remains largely unknown. Here, we show that FGF21 represses mammalian target of rapamycin complex 1 (mTORC1) and improves insulin sensitivity and glycogen storage in a hepatocyte-autonomous manner. Administration of FGF21 in mice inhibits mTORC1 in the liver, whereas FGF21-deficient mice display pronounced insulin-stimulated mTORC1 activation and exacerbated hepatic insulin resistance (IR). FGF21 inhibits insulin- or nutrient-stimulated activation of mTORC1 to enhance phosphorylation of Akt in HepG2 cells at both normal and IR condition. TSC1 deficiency abrogates FGF21-mediated inhibition of mTORC1 and augmentation of insulin signaling and glycogen synthesis. Strikingly, hepatic βKlotho knockdown or hepatic hyperactivation of mTORC1/ribosomal protein S6 kinase 1 abrogates hepatic insulin-sensitizing and glycemic-control effects of FGF21 in diet-induced insulin-resistant mice. Moreover, FGF21 improves methionine- and choline-deficient diet-induced steatohepatitis. Conclusions: FGF21 acts as an inhibitor of mTORC1 to control hepatic insulin action and maintain glucose homeostasis, and mTORC1 inhibition by FGF21 has the therapeutic potential for treating IR and type 2 diabetes.

The present study was undertaken to investigate the gender-related liver injury induced by Dioscorea bulbifera L. (DB), a traditional medicinal plant, in mice, and further explored its hepatotoxic chemical compound. Serum and liver tissue samples were collected at 0, 4, 8, 12 h, after mice were administrated orally with 640 mg/kg ethyl acetate extracts (EF) isolated from DB. After treatments, serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were both significantly elevated. Liver lipid peroxidation (LPO) level increased, while glutathione amounts, glutathione- S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT) activities all decreased in the time-dependent manner. Further analysis demonstrated that ALT and AST activities in female mice were significantly lower than those in male. Meanwhile, liver glutathione amounts and CAT activity in female mice after giving EF for 12 h were both higher than those in male. Further, comparing the liver injury induced by Diosbulbin B isolated from DB with that induced by EF on the basis of chemical analysis for the amounts of Diosbulbin B in EF of DB, we found that Diosbulbin B could be the main hepatotoxic chemical compound in DB. Taken together, our results show that DB can induce gender-related liver oxidative stress injury in mice, and its main hepatotoxic chemical compound is Diosbulbin B, for the first time.