Understanding the Molecular Basis for FGF15/19 and FGF21 Actions on Energy Homeostasis
type: CreativeWork
description: Insulin and glucagon have long been known to play essential roles in controlling energy balance during the fed and fasted states, respectively. Recently, additional metabolic hormones have been discovered within a subfamily of the fibroblast growth factor superfamily. The FGF15/19 subfamily is composed of atypical FGFs lacking the heparin-binding domain, which enables them to act in an endocrine fashion by diffusing away from their tissues of origin. They signal through cell-surface receptors complexed with β-Klotho, a membrane-spanning protein, to mediate signaling cascades that lead to physiological responses. One member, FGF19, causes reduced glucose and insulin levels with enhanced insulin sensitivity when expressed in transgenic mice. Another member, FGF21, has been shown to act as an insulin sensitizer pharmacologically by improving glucose tolerance and reducing insulin. The prevalence of metabolic disorders (e.g. type 2 diabetes) in today’s society has led to the investigation of these two endocrine FGFs for use in a clinical setting. However, the mechanisms underlying these responses have not been characterized. To elucidate the mechanisms utilized by FGF15/19, we used several animal models to show a role for FGF15/19 in regulating hepatic glucose production. Like insulin, FGF15/19 represses gluconeogenesis. Specifically, FGF15/19 inhibits expression of the transcriptional coactivator PGC1α, a key regulator of gluconeogenic gene expression. The repressive effect of FGF15/19 on gluconeogenic gene expression is lost when PGC1α is overexpressed. FGF15/19 causes the dephosphorylation and inactivation of the transcription factor CREB, thereby blunting its ability to bind and induce the PGC1α promoter. The results demonstrated that FGF15/19 works subsequent to insulin as a postprandial regulator of gluconeogenesis through inhibition of the CREB/ PGC1α pathway. To fully understand the effects of FGF21, we began studying the downstream kinase signaling cascades and…
abstract: Insulin and glucagon have long been known to play essential roles in controlling energy balance during the fed and fasted states, respectively. Recently, additional metabolic hormones have been discovered within a subfamily of the fibroblast growth factor superfamily. The FGF15/19 subfamily is composed of atypical FGFs lacking the heparin-binding domain, which enables them to act in an endocrine fashion by diffusing away from their tissues of origin. They signal through cell-surface receptors complexed with β-Klotho, a membrane-spanning protein, to mediate signaling cascades that lead to physiological responses. One member, FGF19, causes reduced glucose and insulin levels with enhanced insulin sensitivity when expressed in transgenic mice. Another member, FGF21, has been shown to act as an insulin sensitizer pharmacologically by improving glucose tolerance and reducing insulin. The prevalence of metabolic disorders (e.g. type 2 diabetes) in today’s society has led to the investigation of these two endocrine FGFs for use in a clinical setting. However, the mechanisms underlying these responses have not been characterized. To elucidate the mechanisms utilized by FGF15/19, we used several animal models to show a role for FGF15/19 in regulating hepatic glucose production. Like insulin, FGF15/19 represses gluconeogenesis. Specifically, FGF15/19 inhibits expression of the transcriptional coactivator PGC1α, a key regulator of gluconeogenic gene expression. The repressive effect of FGF15/19 on gluconeogenic gene expression is lost when PGC1α is overexpressed. FGF15/19 causes the dephosphorylation and inactivation of the transcription factor CREB, thereby blunting its ability to bind and induce the PGC1α promoter. The results demonstrated that FGF15/19 works subsequent to insulin as a postprandial regulator of gluconeogenesis through inhibition of the CREB/ PGC1α pathway. To fully understand the effects of FGF21, we began studying the downstream kinase signaling cascades and…
author: Boney-Montoya, Jamie
language: en
keywords: Fibroblast Growth Factors, Glucose, Cyclic AMP Response Element-Binding Protein
date published: 2012-07-09T16:45:30Z
date modified: 2026-07-24T05:52:26Z
provider: University of Texas Southwestern Medical Center
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Texas Southwestern Medical Center

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152.5/986