FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway

Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
Cell metabolism (Impact Factor: 17.57). 06/2011; 13(6):729-38. DOI: 10.1016/j.cmet.2011.03.019
Source: PubMed


Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.

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    • "It has been reported recently that FGF-19 induces postprandial hepatic glycogen and protein synthesis through an insulin-independent pathway in vivo [3]. Furthermore, FGF-19 inhibits hepatic gluconeogenesis through inactivation of the transcription factor cAMP regulatory element binding protein (CREB) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) [4]. These findings suggest that FGF-19 may have a role in regulating postprandial glucose homeostasis. "
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    ABSTRACT: Background: We investigated factors associated with fibroblast growth factor 19 (FGF-19) increment after oral glucose loading (OGL) in human subjects. Methods: A total of 240 outpatients without known diabetes who were previously admitted for coronary angiography underwent an oral glucose tolerance test. FGF-19 increment (pg/ml) was calculated as FGF-19 2 h after OGL minus fasting FGF-19. Results: Overall, FGF-19 significantly increased after OGL (from 123 [78~201] to 141 [80~237], p=0.001). By age tertiles (≦54, 55~64, ≧65), FGF-19 significantly increased only in patients aged ≧65 (from 143 [98~209] to 189 [124~332], p<0.001). By glucose regulation status, FGF-19 significantly increased in patients with normal glucose tolerance (from 117 [78~211] to 153 [106~325], p=0.014) and in patients with prediabetes (from 117 [73~179] to 123 [70~204], p=0.043), but not in patients with diabetes (from 181 [102~243] to 178 [111~275], p=0.139). FGF-19 significantly increased in patients on statin treatment (from 120 [78~207] to 145 [86~264], p<0.001), but not in patients not on statin therapy (from 125 [86~196] to 128 [68~230] pg/ml, p=0.676). These findings remained significant after adjustment for confounders. Conclusions: FGF-19 increment after OGL was positively associated with age, and negatively associated with abnormal glucose regulation and statin treatment.
    Clinica chimica acta; international journal of clinical chemistry 09/2015; 450. DOI:10.1016/j.cca.2015.09.006 · 2.82 Impact Factor
    • "(M+3). WT and Mpc1 LivKO mice were administered U 13 Clactate and -pyruvate by intraperitoneal injection as performed previously (Potthoff et al., 2011). To capture flux data under near-equilibrium gluconeogenic conditions, livers were harvested and immediately freeze-clamped at 30 min post-injection , the expected time of plateau for blood glucose and lactate concentrations. "
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    ABSTRACT: Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D.
    Cell metabolism 09/2015; DOI:10.1016/j.cmet.2015.07.027 · 17.57 Impact Factor
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    • "By contrast, Ma et al. observed that FXR activation by CA suppressed the expression of multiple genes in the gluconeogenic pathway, including PEPCK, PGC-1α, and G-6-Pase [58]. Recent studies have also shown that mouse FGF15 and human FGF19, postprandial hormone induced by FXR, inhibit hepatic gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element binding protein (CREB) [59]. Nevertheless, a recent observation may provide a more reasonable illustration for the discrepancies that FXR activation exerts opposite effects during the transition from the unfed state to the fed state. "
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    ABSTRACT: Type 2 diabetes (T2D) is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR) and the liver X receptor (LXR) play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications.
    International Journal of Endocrinology 04/2014; 2014(5):751859. DOI:10.1155/2014/751859 · 1.95 Impact Factor
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