Endocrine fibroblast growth factors as regulators of metabolic homeostasis

Kurosu, Hiroshi; Kuro‐o, Makoto

doi:10.1002/biof.12

Cited by 38 publications

(34 citation statements)

References 78 publications

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“…Consistent with the fact that βKlotho is an obligate co-receptor for FGF19, mice lacking either βKlotho or FGF15 (the mouse ortholog of human FGF19) exhibited increased bile acid synthesis [30,34]. Thus, Klotho gene family may have evolved in the regulation of endocrine FGFs to confine their target organs in the redundant receptor-ligand system [45,[50][51][52].…”

Section: Discussionmentioning

confidence: 56%

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Klotho

Kuro‐o

2009

Pflugers Arch - Eur J Physiol

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229

171

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The klotho gene was identified as an "aging-suppressor" gene in mice that accelerates aging when disrupted and extends life span when overexpressed. It encodes a single-pass transmembrane protein and is expressed primarily in renal tubules. The extracellular domain of Klotho protein is secreted into blood and urine by ectodomain shedding. The two forms of Klotho protein, membrane Klotho and secreted Klotho, exert distinct functions. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for FGF23, a bone-derived hormone that induces phosphate excretion into urine. Mice lacking Klotho or FGF23 not only exhibit phosphate retention but also display a premature-aging syndrome, revealing an unexpected link between phosphate metabolism and aging. Secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface, including ion channels and growth factor receptors such as insulin/insulin-like growth factor-1 receptors. Potential contribution of these multiple activities of Klotho protein to aging processes is discussed.

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Section: Discussionmentioning

confidence: 56%

“…Furthermore, several mutations that affect expression and/or proteolytic degeneration of FGF23 have been identified in mice and humans, in which phosphatewasting phenotypes are associated with increased serum FGF23 levels [51,75]. These observations have established that FGF23 functions as a phosphaturic hormone.…”

Section: Function Of Membrane Klotho Proteinmentioning

confidence: 99%

Klotho

Kuro‐o

2009

Pflugers Arch - Eur J Physiol

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229

171

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“…Due to the lack of HBS in endocrine FGFs (including FGF15/19) these factors use a different mode of interaction with FGFRs that relies on the presence of alternative "binding-assisting" cell surface molecules. These accessory cell surface proteins belong to the so-called Klotho family [2,7].…”

Section: Endocrine Fgfs Signal Through Fgf Receptor/klotho Complexesmentioning

confidence: 99%

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

Jahn

Rau

Hermanns

et al. 2015

Cytokine & Growth Factor Reviews

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“…These metabolic responses of PPARa to fasting are mainly mediated by FGF21 (19,37,38,39). Several observations support this statement: i) PPARa agonist therapy, low-carbohydrate ketogenic diet and fasting induce hepatic expression, and circulating levels of FGF21 that are rapidly suppressed by refeeding (16); ii) FGF21 regulates fasting promoting lipolysis in WAT from murine adipocytes and ketogenesis in liver in response to fasting directly induced by PPARa (22,36,37), although this FGF21-induced lipolysis has not been demonstrated by others (40,41); iii) knockdown of FGF21 in the liver results in impaired ketogenesis and fatty acid oxidation in mice (16); iv) FGF21 reduces physical activity and promotes torpor in mice, a short-term hibernation state with the aim of saving energy by reducing physical activity and body temperature energy (37); and v) FGF21-overexpressing transgenic mice show reduced fat mass and resistance to obesity (19,38,39). These findings would demonstrate a role for the PPARa-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation (Fig.…”

Section: Adaptive Response To Fastingmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

Iglesias

Selgas

Romero

et al. 2012

European Journal of Endocrinology

101

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Fibroblast growth factor 21 (FGF21), a 181 amino acid circulating protein, is a member of the FGF superfamily, with relevant metabolic actions. It acts through the interaction with specific FGF receptors and a cofactor called β-Klotho, whose expression is predominantly detected in metabolically active organs. FGF21 stimulates glucose uptake in adipocytes via the induction of glucose transporter-1. This action is additive and independent of insulin. β-Cell function and survival are preserved, and glucagon secretion is reduced by this protein, thus decreasing hepatic glucose production and improving insulin sensitivity. Lipid profile has been shown to be improved by FGF21 in several animal models. FGF21 increases energy expenditure in rodents and induces weight loss in diabetic nonhuman primates. It also exerts favorable effects on hepatic steatosis and reduces tissue lipid content in rodents. Adaptive metabolic responses to fasting, including stimulation of ketogenesis and fatty acid oxidation, seem to be partially mediated by FGF21. In humans, serum FGF21 concentrations have been found elevated in insulin-resistant states, such as impaired glucose tolerance and type 2 diabetes. FGF21 levels are correlated with hepatic insulin resistance index, fasting blood glucose, HbA1c, and blood glucose after an oral glucose tolerance test. A relationship between FGF21 levels and long-term diabetic complications, such as nephropathy and carotid atheromatosis, has been reported. FGF21 levels decreased in diabetic patients after starting therapy with insulin or oral agents. Increased FGF21 serum levels have also been found to be associated with obesity. In children, it is correlated with BMI and leptin levels, whereas in adults, FGF21 levels are mainly related to several components of the metabolic syndrome. Serum FGF21 levels have been found to be elevated in patients with ischemic heart disease. In patients with renal disease, FGF21 levels exhibited a progressive increase as renal function deteriorates. Circulating FGF21 levels seem to be related to insulin resistance and inflammation in dialysis patients. In summary, FGF21 is a recently identified hormone with antihyperglycemic, antihyperlipidemic, and thermogenic properties. Direct or indirect potentiation of its effects might be a potential therapeutic target in insulin-resistant states.

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Endocrine fibroblast growth factors as regulators of metabolic homeostasis

Cited by 38 publications

References 78 publications

Klotho

Klotho

Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease

MECHANISMS IN ENDOCRINOLOGY: Biological role, clinical significance, and therapeutic possibilities of the recently discovered metabolic hormone fibroblastic growth factor 21

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