Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity

Tomlinson, Elizabeth; Fu, Ling; John, Linu M.; Hultgren, Bruce; Huang, Xiaojian; Renz, Mark; Stephan, Jean Philippe; Tsai, Saio Ping; Powell-Braxton, Lyn; French, Dorothy; Stewart, Timothy A.

doi:10.1210/endo.143.5.8850

Cited by 489 publications

(308 citation statements)

References 57 publications

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“…These negative findings raise the interesting possibility that FGF21 might induce Pgc1␣ through an indirect mechanism involving the central nervous system. FGF21 functions as a potent insulin sensitizer in various animal models of insulin resistance and diabetes (15,17,36,37). Our data suggest that FGF21 does not improve glycemic control by suppressing hepatic gluconeogenesis per se.…”

Section: Discussionmentioning

confidence: 73%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

639

570

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The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources. Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferatoractivated receptor ␥ coactivator protein-1␣ (PGC-1␣), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1␣ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis. These results reveal an unexpected relationship between FGF21 and PGC-1␣ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.lipid metabolism ͉ liver ͉ gluconeogenesis ͉ glycogenolysis ͉ ketogenesis I n mammals, the liver plays a crucial role in maintaining systemic energy balance during fasting and starvation through coordinate effects on carbohydrate and lipid metabolism. During the early stages of fasting, the liver mobilizes glucose from its glycogen stores. As fasting progresses and glycogen reserves are depleted, the liver oxidizes fat to provide both energy for gluconeogenesis and substrate for ketogenesis. This synchronization of hepatic lipid and carbohydrate metabolism is critical for the normal fasting response; disruption of either one of these pathways has profound effects on the other (1-4).Hormones such as glucagon, catecholamines, and glucocorticoids have important roles in controlling substrate utilization and maintaining energy balance during fasting. Recently, the hormone fibroblast growth factor 21 (FGF21) was shown to be induced in the liver during fasting (5-7). FGF21 is an unusual FGF family member in that it lacks the conventional heparinbinding domain (8) and thus can diffuse away from its tissue of origin and function as a hormone. FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with ␤-klotho, a membrane-spanning protein (9-14). Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor ␣ (PPAR␣) (5-7). FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis (5,6,15) and blocking the growth hormone signaling pathway (16). FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia (6). Pharmacologic administration of FGF21 to insulin-resistant rodents and monkeys improves glucose tolerance and reduces plasma insulin and triglyceride concentrations (15,17).Peroxisome proliferator-activated receptor ␥ coactivator protein-1␣ (PGC-1␣) is a transcriptional coactivator ...

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Section: Discussionmentioning

confidence: 73%

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Potthoff

Inagaki

Satapati

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

639

570

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“…Recently, FGF19 and FGF21 have emerged as candidate members of the FGF ligand family that have impact on the liver, although it is unclear whether the effect on hepatocytes is direct or indirect. Transgenic animals with FGF19 targeted to muscle exhibit an increased metabolic rate and decreased adiposity accompanied by a reduction in expression of liver acetyl CoA carboxylase 2 and triglyceride levels 36 and liver abnormalities associated with cancer in aging mice. 37 FGF21 appears to be specifically expressed in the liver 38 hepatocyte-specific FGFR4 functions and nonparenchymal cells of liver expressing other FGFR isotypes is under investigation.…”

Section: Discussionmentioning

confidence: 99%

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Wang

Jin

et al. 2003

The American Journal of Pathology

150

126

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Genomic ablation of hepatocyte-specific fibroblast growth factor receptor (FGFR)4 in mice revealed a role of FGF signaling in cholesterol and bile acid metabolism and hepatolobular restoration in response to injury without effect on liver development or hepatocyte proliferation. Although the potential role of all 23 FGF polypeptides in the liver is still unclear, the most widely studied prototypes, FGF1 and FGF2, are present and have been implicated in liver cell growth and function in vitro. To determine whether FGF1 and FGF2 play a role in response to injury and fibrosis, we examined the impact of both acute and chronic exposure to carbon tetrachloride (CCl 4 ) in the livers of FGF1-and FGF2-deficient mice. After acute CCl 4 exposure, FGF1(؊/؊)FGF2(؊/؊) mice exhibited an accelerated release of serum alanine aminotransferase similar to FGFR4 deficiency, but no effect on overall hepatolobular restoration or bile acid metabolism. The fibroblast growth factors (FGFs) comprise a family of 23 reported members that have varying affinities for variants of four different FGF receptor kinases (FGFR1 to FGFR4). 1-3 FGF1 and FGF2, the first two cloned members of the FGF family, 4,5 have received the most study, are widely expressed, and thus, predicted to be involved in tissue-specific functions and associated pathologies at their site of expression. 6,7 In vitro FGF1 affects cells of multiple origin whereas activity of FGF2 appears more limited to cells derived from mesenchyme and neuroectoderm. 8 FGF1 and FGF2 have been implicated in derivation of the liver from foregut endoderm. 9 However, mice lacking FGF1, FGF2, or both FGF1 and FGF2 are viable, fertile, and grossly indistinguishable from wild type (WT) except for modest defects in cardiovascular tissue, healing of skin wounds, and neuronal tissue. 3,10,11 This suggests that FGF1 and FGF2 alone are not essential for embryonic development or are compensated by other members of the extensive FGF ligand family. Consequently, FGF1-and FGF2-deficient animals are available for study of the role of the two factors in adult tissue homeostasis. Despite their ubiquity, little has emerged except for the modest effects of ablation of FGF1 and FGF2 in the cardiovascular, skin, and nervous systems.Although the levels of mRNA transcripts are low, longlived FGF1 and FGF2 polypeptides are present in the resting liver at significant levels. 12 This suggests that a significant reservoir of both ligands is present in the resting liver in an inactive state before activation and

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“…In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto and Yamashita, 2007;Liu and Quarles, 2007).…”

Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

“…In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al, 1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto et al, 2007;Liu et al, 2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or ␤Klotho, to activate FGFRs (Ogawa et al, 2007;Urakawa et al, 2006).…”

Section: Perspectivesmentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

356

313

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Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity

Cited by 489 publications

References 57 publications

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response

Role of Fibroblast Growth Factor Type 1 and 2 in Carbon Tetrachloride-Induced Hepatic Injury and Fibrogenesis

Functional evolutionary history of the mouse Fgf gene family

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