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Alexei Kharitonenkov - One of the best experts on this subject based on the ideXlab platform.
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endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue
Scientific Reports, 2013Co-Authors: Derek Roberts, Alexei Kharitonenkov, Li-qun Zhang, Brian Zhang, Samuel M Hanson, Yan Chun Li, Yu H WuAbstract:Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho–PI3K–Akt1–BAD signaling network.
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FGF21 drives a shift in adipokine tone to restore metabolic health
Aging, 2013Co-Authors: Andrew C. Adams, Alexei KharitonenkovAbstract:Fibroblast growth factor 21 (FGF21) is a key metabolic regulator with significant potential to treat metabolic disease. Rather than traditional glucose or lipid centric therapies, FGF21 instead functions via expansive remodeling of whole body energy balance [1]. While FGF21's ability to ameliorate disease burden is well established in species ranging from mice to men, the mechanism(s) by which FGF21 is able to instigate the plethora of its in vivo actions have yet to be elucidated. Recently, adipose tissue has emerged as a critical target organ where FGF21 engages its primary receptor complex (FGFR1/KLB) [2, 3]. In fat, FGF21 acts as a metabolic rheostat serving to modulate secretion of adipokines which in turn mediate discrete aspects of FGF21-induced physiology. Supportive of this proposed mode of action is recent evidence demonstrating that adiponectin is not only a biomarker for FGF21 target engagement but is also essential for facilitating some of FGF21s downstream actions [4, 5]. Of critical importance, acute FGF21 signaling is not compromised in Adn−/− mice when compared to their WT counterparts. However, only in WT animals with intact adiponectin signaling is FGF21 able to trigger a cascade of metabolic events leading to correction of hyperglycemia and hyperinsulinemia. Correlated with the lack of improvement in glycemia and insulin sensitivity there was also lack of ceramide lowering in FGF21 treated Adn−/− animals. Supportive of partitioning of FGF21s metabolic endpoints, weight loss, elevated energy expenditure and reduced circulating lipids were yet evident FGF21-treated Adn−/− mice. Of note, induction of adiponectin is also a hallmark of another class of anti-diabetic therapeutics, the thiazoladinediones [6]. Indeed, it was recently suggested that FGF21 may play a role in mediating the physiological consequences of TZD treatment [7]. In concordance with this hypothesis, upon administration of either FGF21 or PPARγ ligands elevation of serum adiponectin reaches similar levels in mice. Nevertheless, TZDs mainly impact transcription of adiponectin gene while FGF21 functions as a potent adiponectin secretagogue [4, 5]. Furthermore, it has also recently been reported that in vivo the FGF21 & PPARγ pathways do not in fact intersect [8]. These distinctions are important in reconciling the lack of rosiglitazone-associated side effects such as adipose accrual and elevation of liver enzymes in FGF21 treated mice [4, 8]. Further work delineating additional downstream mediators of FGF21 action in adipose and other tissues will be critical to understanding of its mechanism of action and thus potentially yielding novel therapeutic avenues. Figure 1 Effects of chronic FGF21 treatment in vivo are mediated by specific hormonal pathways downstream of adipose tissue activation.
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the breadth of FGF21 s metabolic actions are governed by fgfr1 in adipose tissue
Molecular metabolism, 2013Co-Authors: Andrew C. Adams, Chaofeng Yang, Tamer Coskun, Christine C Cheng, Ruth E Gimeno, Yongde Luo, Alexei KharitonenkovAbstract:FGF21 is a multifunctional metabolic regulator. The co-factor βKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.
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Cardioprotective role of myocardial ischemia-induced hepatic FGF21
Cardiovascular Pathology, 2013Co-Authors: Shu Q. Liu, Alexei Kharitonenkov, Li-qun ZhangAbstract:Purpose: Myocardial ischemia activates innate protective mechanisms, enhancing cardiomyocyte tolerance to ischemia. Here, we demonstrate that the liver contributes to myocardial protection by up-regulating and releasing the secretory protein FGF21. Methods: Myocardial ischemia was induced in mice by ligating the LAD coronary artery. Myocardial infarction was assessed by histological assays. Left ventricular function was evaluated by echocardiography and hemodynamic analysis. The expression and activity of FGF21 and signaling molecules, including FGFR1, PI3K, Akt1, and BAD, were tested by immunoprecipitation/immunoblotting. The cardioprotective role of FGF21 was assessed in FGF21−/− and FGF21-Tg (overexpression) mice. The regulatory role of FGFR1, PI3K, and Akt1 was evaluated by siRNA-mediated gene silencing. Results: FGF21 was up-regulated in hepatocytes and serum from 0.5 to 3 days post myocardial ischemia. FGF21-/mice exhibited increased myocardial infarction, whereas FGF21-Tg mice showed reduced myocardial infarction compared to wild-type mice from 1 to 30 days, suggesting a cardioprotective role for FGF21. Administration of recombinant FGF21 to healthy mice or myocardial ischemia induced FGFR1 phosphorylation in cardiomyocytes. FGF21-/mice with myocardial ischemia exhibited reduced phosphorylation of FGFR1, PI3K, Akt1, and BAD in cardiomyocytes. siRNA-mediated FGFR1 gene silencing suppressed FGFR1 expression and reduced phosphorylation of PI3K, Akt1, and BAD, resulting in an increase in myocardial infarction. PI3K or Akt1 gene silencing reduced BAD phosphorylation and enhanced myocardial infarction, suggesting that BAD phosphorylation is required for effective cardioprotection. Conclusions: The liver contributes to myocardial protection by upregulating and releasing FGF21, and FGF21 activates the FGFR1-PI3KAkt1-BAD signaling pathway, enhancing myocardial tolerance to ischemic injury.
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fibroblast growth factor 21 FGF21 inhibits chondrocyte function and growth hormone action directly at the growth plate
Journal of Biological Chemistry, 2012Co-Authors: Shufang Wu, Alexei Kharitonenkov, Amy Levenson, Francesco De LucaAbstract:Fibroblast growth factor 21 (FGF21) modulates glucose and lipid metabolism during fasting. In addition, previous evidence indicates that increased expression of FGF21 during chronic food restriction is associated with reduced bone growth and growth hormone (GH) insensitivity. In light of the inhibitory effects on growth plate chondrogenesis mediated by other FGFs, we hypothesized that FGF21 causes growth inhibition by acting directly at the long bones' growth plate. We first demonstrated the expression of FGF21, FGFR1 and FGFR3 (two receptors known to be activated by FGF21) and β-klotho (a co-receptor required for the FGF21-mediated receptor binding and activation) in fetal and 3-week-old mouse growth plate chondrocytes. We then cultured mouse growth plate chondrocytes in the presence of graded concentrations of rhFGF21 (0.01–10 μg/ml). Higher concentrations of FGF21 (5 and 10 μg/ml) inhibited chondrocyte thymidine incorporation and collagen X mRNA expression. 10 ng/ml GH stimulated chondrocyte thymidine incorporation and collagen X mRNA expression, with both effects prevented by the addition in the culture medium of FGF21 in a concentration-dependent manner. In addition, FGF21 reduced GH binding in cultured chondrocytes. In cells transfected with FGFR1 siRNA or ERK 1 siRNA, the antagonistic effects of FGF21 on GH action were all prevented, supporting a specific effect of this growth factor in chondrocytes. Our findings suggest that increased expression of FGF21 during food restriction causes growth attenuation by antagonizing the GH stimulatory effects on chondrogenesis directly at the growth plate. In addition, high concentrations of FGF21 may directly suppress growth plate chondrocyte proliferation and differentiation.
Nobuyuki Itoh - One of the best experts on this subject based on the ideXlab platform.
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Roles of FGF Signals in Heart Development, Health, and Disease.
Frontiers in Cell and Developmental Biology, 2016Co-Authors: Nobuyuki Itoh, Yoshiaki Nakayama, Hiroya Ohta, Morichika KonishiAbstract:The heart provides the body with oxygen and nutrients and assists in the removal of metabolic waste through the blood vessels of the circulatory system. It is the first organ to form during embryonic morphogenesis. FGFs with diverse functions in development, health, and disease are signaling proteins, mostly as paracrine growth factors or endocrine hormones. The human/mouse FGF family comprises 22 members. Findings obtained from mouse models and human diseases with FGF signaling disorders have indicated that several FGFs are involved in heart development, health, and disease. Paracrine FGFs including FGF8, FGF9, FGF10, and FGF16 act as paracrine signals in embryonic heart development. In addition, paracrine FGFs including FGF2, FGF9, FGF10, and FGF16 play roles as paracrine signals in postnatal heart pathophysiology. Although FGF15/19, FGF21, and FGF23 are typical endocrine FGFs, they mainly function as paracrine signals in heart development or pathophysiology. In heart diseases, serum FGF15/19 levels or FGF21 and FGF23 levels decrease or increase, respectively, indicating their possible roles in heart pathophysiology. FGF2 and FGF10 also stimulate the cardiac differentiation of cultured stem cells and cardiac reprogramming of cultured fibroblasts. These findings provide new insights into the roles of FGF signaling in the heart and potential therapeutic strategies for cardiac disorders.
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Cardiac FGF21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts
Cardiovascular Research, 2015Co-Authors: Fabio Di Lisa, Nobuyuki ItohAbstract:Fibroblast growth factors (Fgfs) are signalling proteins of ∼150–300 amino acids with diverse functions, mainly in development and metabolism. The human/mouse Fgf family comprises 22 members. Fgfs can be classified as intracellular, paracrine, and endocrine Fgfs by their action mechanisms. Among Fgfs, Fgf2, Fgf16, FGF21, and Fgf23 have been shown to be cardiomyokines playing pathophysiological roles in the heart.1 Fgf2 and Fgf16 are paracrine Fgfs, which usually function in an autocrine/paracrine manner. In contrast, so far FGF21 and Fgf23 have been reported to function in an endocrine manner. Cardiac Fgf2 promotes cardiac hypertrophy and fibrosis by activating MAPK signalling through the activation of Fgf receptor (Fgfr). In contrast, cardiac Fgf16 may prevent them by competing with Fgf2 for the binding site of Fgfr. Although Fgf23 is an endocrine Fgf, cardiac Fgf23 induces cardiac hypertrophy by activating calcineurin/NFAT signalling in an autocrine/paracrine manner.1 FGF21 is usually known to be a hepatic hormone involved in the control of glucose, lipid, and energy metabolism. These actions of FGF21 are mediated by activating MAPK signalling through the activation of Fgfr in an endocrine manner.2 FGF21 is also produced in the heart and prevents cardiac hypertrophy by activating MAPK signalling through the activation of Fgfr.3 Cardiac FGF21 expression is induced by the protein deacetylase Sirt1,3 which protects against hypertrophy, ischaemia–reperfusion injury, and oxidative stress in the …
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Pathophysiological roles of FGF signaling in the heart
Frontiers in Physiology, 2013Co-Authors: Nobuyuki Itoh, Hiroya OhtaAbstract:Cardiac remodeling progresses to heart failure, which represents a major cause of morbidity and mortality. Cardiomyokines, cardiac secreted proteins, may play roles in cardiac remodeling. Fibroblast growth factors (FGFs) are secreted proteins with diverse functions, mainly in development and metabolism. However, some FGFs play pathophysiological roles in cardiac remodelling as cardiomyokines. FGF2 promotes cardiac hypertrophy and fibrosis by activating MAPK signaling through the activation of FGF receptor (FGFR) 1c. In contrast, FGF16 may prevent these by competing with FGF2 for the binding site of FGFR1c. FGF21 prevents cardiac hypertrophy by activating MAPK signaling through the activation of FGFR1c with β-Klotho as a co-receptor. In contrast, FGF23 induces cardiac hypertrophy by activating calcineurin/NFAT signaling without αKlotho. These FGFs play crucial roles in cardiac remodeling via distinct action mechanisms. These findings provide new insights into the pathophysiological roles of FGFs in the heart and may provide potential therapeutic strategies for heart failure.
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Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease
Cell and Tissue Research, 2010Co-Authors: Nobuyuki ItohAbstract:Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgf s identified in invertebrates and vertebrates, hormone-like Fgf s , Fgf15/19 , FGF21 , and Fgf23 , are vertebrate-specific. The ancestral gene of hormone-like Fgf s was generated from the ancestral gene of canonical Fgf s by gene duplication early in vertebrate evolution. Later, Fgf15/19 , FGF21 , and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgf s acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, FGF21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. FGF21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or FGF21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function.
Antonio Moschetta - One of the best experts on this subject based on the ideXlab platform.
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therapeutic potential of the endocrine fibroblast growth factors fgf19 FGF21 and fgf23
Nature Reviews Drug Discovery, 2016Co-Authors: Chiara Degirolamo, Carlo Sabba, Antonio MoschettaAbstract:As critical regulators of glucose and lipid metabolism, as well as vitamin D and phosphate homeostasis, the endocrine fibroblast growth factors (FGFs) have therapeutic potential in various chronic human diseases. Here, Moschetta and colleagues discuss the physiological roles of FGF19, FGF21 and FGF23, focusing on recent advances and the associated challenges in their therapeutic exploitation.
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Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23
Nature Reviews Drug Discovery, 2016Co-Authors: Chiara Degirolamo, Carlo Sabba, Antonio MoschettaAbstract:Endocrine fibroblast growth factors (FGFs) are critical regulators of glucose and lipid metabolism, and gatekeepers of vitamin D and phosphate homeostasis. Endocrine FGFs may serve as both risk factors and biomarkers of chronic metabolic disorders, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. The intestine-derived FGF19 is a critical regulator of both bile acid and glucose metabolism, and its pharmacological modulation has been proposed as a promising approach for the treatment of disorders related to the gut–liver axis, including cholestasis. The liver-derived hormone FGF21 is a master regulator of substrate turnover and orchestrates crosstalk between the liver, white adipose tissue, brain, pancreas and brown adipose tissue. FGF21 is rapidly emerging as an attractive target in the treatment of metabolic syndrome and type 2 diabetes. The bone-derived hormone FGF23 is the physiological regulator of phosphate and vitamin D serum levels and, along with its cofactor α-klotho, it could serve as an effective biomarker for prediction of outcome as well as treatment guidance in chronic kidney disease. A health-promoting activity of FGF23 has also been proposed. Pharmaceutical efforts are in progress to develop FGF analogues or mimetics that are devoid of mitogenic potential and risk of bone loss, and also endowed with a better pharmacokinetic profile. The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically. As critical regulators of glucose and lipid metabolism, as well as vitamin D and phosphate homeostasis, the endocrine fibroblast growth factors (FGFs) have therapeutic potential in various chronic human diseases. Here, Moschetta and colleagues discuss the physiological roles of FGF19, FGF21 and FGF23, focusing on recent advances and the associated challenges in their therapeutic exploitation.
Chaofeng Yang - One of the best experts on this subject based on the ideXlab platform.
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Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress
BMC gastroenterology, 2013Co-Authors: Chaofeng Yang, Fen Wang, Tao Lin, Pan You, Yanqing Huang, Xianhan Jiang, Cong Wang, Mong Hong LeeAbstract:FGF21 is a promising intervention therapy for metabolic diseases as fatty liver, obesity and diabetes. Recent results suggest that FGF21 is highly expressed in hepatocytes under metabolic stress caused by starvation, hepatosteatosis, obesity and diabetes. Hepatic FGF21 elicits metabolic benefits by targeting adipocytes of the peripheral adipose tissue through the transmembrane FGFR1-KLB complex. Ablation of adipose FGFR1 resulted in increased hepatosteatosis under starvation conditions and abrogation of the anti-obesogenic action of FGF21. These results indicate that FGF21 may be a stress responsive hepatokine that targets adipocytes and adipose tissue for alleviating the damaging effects of stress on the liver. However, it is unclear whether hepatic induction of FGF21 is limited to only metabolic stress, or to a more general hepatic stress resulting from liver pathogenesis and injury. In this survey-based study, we examine the nature of hepatic FGF21 activation in liver tissues and tissue sections from several mouse liver disease models and human patients, by quantitative PCR, immunohistochemistry, protein chemistry, and reporter and CHIP assays. The liver diseases include genetic and chemical-induced HCC, liver injury and regeneration, cirrhosis, and other types of liver diseases. We found that mouse FGF21 is induced in response to chemical (DEN treatment) and genetic-induced hepatocarcinogenesis (disruptions in LKB1, p53, MST1/2, SAV1 and PTEN). It is also induced in response to loss of liver mass due to partial hepatectomy followed by regeneration. The induction of FGF21 expression is potentially under the control of stress responsive transcription factors p53 and STAT3. Serum FGF21 levels correlate with FGF21 expression in hepatocytes. In patients with hepatitis, fatty degeneration, cirrhosis and liver tumors, FGF21 levels in hepatocytes or phenotypically normal hepatocytes are invariably elevated compared to normal health subjects. FGF21 is an inducible hepatokine and could be a biomarker for normal hepatocyte function. Activation of its expression is a response of functional hepatocytes to a broad spectrum of pathological changes that impose both cellular and metabolic stress on the liver. Taken together with our recent data, we suggest that hepatic FGF21 is a general stress responsive factor that targets adipose tissue for normalizing local and systemic metabolic parameters while alleviating the overload and damaging effects imposed by the pathogenic stress on the liver. This study therefore provides a rationale for clinical biomarker studies in humans.
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the breadth of FGF21 s metabolic actions are governed by fgfr1 in adipose tissue
Molecular metabolism, 2013Co-Authors: Andrew C. Adams, Chaofeng Yang, Tamer Coskun, Christine C Cheng, Ruth E Gimeno, Yongde Luo, Alexei KharitonenkovAbstract:FGF21 is a multifunctional metabolic regulator. The co-factor βKlotho (KLB) allows FGF21 to signal via FGF receptors. Given the widespread nature of FGFR expression and KLB presence in several organs, it remains unclear which tissue/FGFR isoform determine FGF21 action. Here we show that deletion of FGFR1 in fat (FR1KO) leads to a complete ablation of FGF21 stimulated transcriptional activity in this tissue. Furthermore, FR1KO mice showed no FGF21-mediated lowering of plasma glucose, insulin and triglycerides, altered serum levels of adipokines, no increase in energy expenditure, but preserved reductions in serum/liver FFAs as compared to wild type mice. Of importance, the anti-glycaemic actions of FGF19 were fully evident in FR1KO mice implying that FGF19 functions in a FGFR1/adipose independent manner. Taken together, our findings reveal the existence of an adipose FGFR1 driven axis of cross-tissue communication which defines several aspects of FGF21 biology and delineates mechanistic distinctions between FGF21 and FGF19.
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treating diabetes and obesity with an FGF21 mimetic antibody activating the βklotho fgfr1c receptor complex
Science Translational Medicine, 2012Co-Authors: Ian Foltz, Chaofeng Yang, Jennifer Weiszmann, Jamila Gupte, Jennitte Stevens, Chadwick T King, Wei Wang, Jiyun Sunny Chen, Noi Nuanmanee, Renee KomorowskiAbstract:Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to βKlotho with high affinity and specifically activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on βKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.
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differential specificity of endocrine fgf19 and FGF21 to fgfr1 and fgfr4 in complex with klb
PLOS ONE, 2012Co-Authors: Chaofeng Yang, Xiaokun Li, Fen Wang, Wallace L MckeehanAbstract:Background Recent studies suggest that betaKlotho (KLB) and endocrine FGF19 and FGF21 redirect FGFR signaling to regulation of metabolic homeostasis and suppression of obesity and diabetes. However, the identity of the predominant metabolic tissue in which a major FGFR-KLB resides that critically mediates the differential actions and metabolism effects of FGF19 and FGF21 remain unclear. Methodology/Principal Findings We determined the receptor and tissue specificity of FGF21 in comparison to FGF19 by using direct, sensitive and quantitative binding kinetics, and downstream signal transduction and expression of early response gene upon administration of FGF19 and FGF21 in mice. We found that FGF21 binds FGFR1 with much higher affinity than FGFR4 in presence of KLB; while FGF19 binds both FGFR1 and FGFR4 in presence of KLB with comparable affinity. The interaction of FGF21 with FGFR4-KLB is very weak even at high concentration and could be negligible at physiological concentration. Both FGF19 and FGF21 but not FGF1 exhibit binding affinity to KLB. The binding of FGF1 is dependent on where FGFRs are present. Both FGF19 and FGF21 are unable to displace the FGF1 binding, and conversely FGF1 cannot displace FGF19 and FGF21 binding. These results indicate that KLB is an indispensable mediator for the binding of FGF19 and FGF21 to FGFRs that is not required for FGF1. Although FGF19 can predominantly activate the responses of the liver and to a less extent the adipose tissue, FGF21 can do so significantly only in the adipose tissue and adipocytes. Among several metabolic and endocrine tissues, the response of adipose tissue to FGF21 is predominant, and can be blunted by the ablation of KLB or FGFR1. Conclusions Our results indicate that unlike FGF19, FGF21 is unable to bind FGFR4-KLB complex with affinity comparable to FGFR1-KLB, and therefore, at physiological concentration less likely to directly and significantly target the liver where FGFR4-KLB predominantly resides. However, both FGF21 and FGF19 have the potential to activate responses of primarily the adipose tissue where FGFR1-KLB resides.
Makoto Kuroo - One of the best experts on this subject based on the ideXlab platform.
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klotho and endocrine fibroblast growth factors markers of chronic kidney disease progression and cardiovascular complications
Nephrology Dialysis Transplantation, 2019Co-Authors: Makoto KurooAbstract:Three members of the fibroblast growth factor (FGF) family, FGF19, FGF21 and FGF23, are different from the other members in two major aspects. First, they are actually not growth factors but endocrine factors that regulate various metabolic processes. Second, their physiological receptors are not FGF receptors (FGFRs) but binary complexes of FGFRs and Klotho proteins. FGF23 and FGF21 have emerged as biomarkers that start increasing in early-stage chronic kidney disease (CKD). FGF23 is a bone-derived phosphaturic hormone that binds to the αKlotho-FGFR complex expressed in renal tubules to increase phosphate excretion per nephron. The FGF23 increase is deemed necessary to compensate for the decrease in the nephron number during CKD progression and to maintain the phosphate balance. However, the increase in phosphate excretion per nephron induces renal tubular damage and accelerates nephron loss. CKD progression is also associated with an increase in calciprotein particles (CPPs) in the blood. CPPs are calcium-phosphate nanoparticles with the ability to induce endothelial damage and inflammatory responses. The fact that serum CPP levels are correlated with vascular calcification/stiffness and mortality in CKD patients suggests that CPPs may serve as a 'pathogen' of cardiovascular complications. Like FGF23, FGF21 starts increasing in early-stage CKD. FGF21 is a liver-derived hormone that binds to the βKlotho-FGFR complex expressed in the central nervous system to induce stress responses, including activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis. Thus FGF21 and FGF23 are not merely biomarkers for CKD progression but potential pathogenic agents that accelerate CKD progression and aggravate cardiovascular complications.
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the klotho gene family as a regulator of endocrine fibroblast growth factors
Molecular and Cellular Endocrinology, 2009Co-Authors: Hiroshi Kurosu, Makoto KurooAbstract:The Klotho gene encodes a single-pass transmembrane protein and functions as an aging-suppressor gene, which extends lifespan when overexpressed and accelerates the development of aging-like phenotypes when disrupted in mice. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that regulates phosphate and vitamin D homeostasis. It has been shown that Klotho-deficient mice and Fgf23 knockout mice exhibit identical phenotypes. This observation led to the identification of Klotho as a cofactor essential for interactions between FGF23 and FGF receptors. In addition to the Klotho-FGF23 axis, recent studies has shown that betaKlotho, a Klotho family protein, also functions as a cofactor required for FGF19 and FGF21 signaling and determines the tissue-specific metabolic activities of FGF19 and FGF21. This review summarizes recent progress in understanding of Klotho and betaKlotho function in the regulation of tissue-specific metabolic activity of the endocrine fibroblast growth factors (FGF19, FGF21, and FGF23).
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tissue specific expression of βklotho and fibroblast growth factor fgf receptor isoforms determines metabolic activity of fgf19 and FGF21
Journal of Biological Chemistry, 2007Co-Authors: Hiroshi Kurosu, Mihwa Choi, Addie S Dickson, Anna V Eliseenkova, Yasushi Ogawa, Moosa Mohammadi, Regina Goetz, Kevin P Rosenblatt, Steven A. Kliewer, Makoto KurooAbstract:The fibroblast growth factor (FGF) 19 subfamily of ligands, FGF19, FGF21, and FGF23, function as hormones that regulate bile acid, fatty acid, glucose, and phosphate metabolism in target organs through activating FGF receptors (FGFR1–4). We demonstrated that Klotho and βKlotho, homologous single-pass transmembrane proteins that bind to FGFRs, are required for metabolic activity of FGF23 and FGF21, respectively. Here we show that, like FGF21, FGF19 also requires βKlotho. Both FGF19 and FGF21 can signal through FGFR1–3 bound by βKlotho and increase glucose uptake in adipocytes expressing FGFR1. Additionally, both FGF19 and FGF21 bind to the βKlotho-FGFR4 complex; however, only FGF19 signals efficiently through FGFR4. Accordingly, FGF19, but not FGF21, activates FGF signaling in hepatocytes that primarily express FGFR4 and reduces transcription of CYP7A1 that encodes the rate-limiting enzyme for bile acid synthesis. We conclude that the expression of βKlotho, in combination with particularFGFR isoforms, determines the tissue-specific metabolic activities of FGF19 and FGF21.