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Alexei Kharitonenkov,
James D Dunbar,
Holly A Bina,
Stuart Bright, Julie S Moyers,
Chen Zhang,
Liyun Ding,
Radmila Micanovic,
Sean F Mehrbod,
Michael D Knierman,
John E Hale,
Tamer Coskun,
Armen B Shanafelt
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ABSTRACT: Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that betaKlotho is an integral part of an activated FGF-21-betaKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking betaKlotho did not respond to FGF-21; the introduction of betaKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that betaKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, betaKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that betaKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects.
Journal of Cellular Physiology 05/2008; 215(1):1-7. · 3.87 Impact Factor
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Alexei Kharitonenkov,
James D. Dunbar,
Holly A. Bina,
Stuart Bright, Julie S. Moyers,
Chen Zhang,
Liyun Ding,
Radmila Micanovic,
Sean F. Mehrbod,
Michael D. Knierman,
John E. Hale,
Tamer Coskun,
Armen B. Shanafelt
[show abstract]
[hide abstract]
ABSTRACT: Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that βKlotho is an integral part of an activated FGF-21-βKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking βKlotho did not respond to FGF-21; the introduction of βKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that βKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, βKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that βKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects. J. Cell. Physiol. 215: 1–7, 2008. © 2007 Wiley-Liss, Inc.
Journal of Cellular Physiology 12/2007; 215(1):1 - 7. · 3.87 Impact Factor
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[show abstract]
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ABSTRACT: Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action.
Journal of Cellular Physiology 02/2007; 210(1):1-6. · 3.87 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARγ) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70S6K, SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARγ protein expression. Moreover, chronic activation of the PPARγ pathway in 3T3-L1 adipocytes with the PPARγ agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARγ, and further define FGF-21 mechanism of action. J. Cell. Physiol. 210: 1–6, 2007. © 2006 Wiley-Liss, Inc.
Journal of Cellular Physiology 12/2006; 210(1):1 - 6. · 3.87 Impact Factor
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ABSTRACT: Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeutic agents to target glucagon action as a treatment for Type 2 diabetes.
Expert opinion on therapeutic targets 07/2005; 9(3):593-600. · 3.72 Impact Factor
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Alexei Kharitonenkov,
Tatiyana L Shiyanova,
Anja Koester,
Amy M Ford,
Radmila Micanovic,
Elizabeth J Galbreath,
George E Sandusky,
Lisa J Hammond, Julie S Moyers,
Rebecca A Owens,
Jesper Gromada,
Joseph T Brozinick,
Eric D Hawkins,
Victor J Wroblewski,
De-Shan Li,
Farrokh Mehrbod,
S Richard Jaskunas,
Armen B Shanafelt
[show abstract]
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ABSTRACT: Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21-transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.
Journal of Clinical Investigation 07/2005; 115(6):1627-35. · 15.39 Impact Factor
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Kyle W Sloop,
Julia Xiao-Chun Cao,
Angela M Siesky,
Hong Yan Zhang,
Diane M Bodenmiller,
Amy L Cox,
Steven J Jacobs, Julie S Moyers,
Rebecca A Owens,
Aaron D Showalter, [......],
Achim Raap,
Jesper Gromada,
Brian R Berridge,
David K B Monteith,
Niels Porksen,
Robert A McKay,
Brett P Monia,
Sanjay Bhanot,
Lynnetta M Watts,
M Dodson Michael
[show abstract]
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ABSTRACT: Uncontrolled hepatic glucose production contributes significantly to hyperglycemia in patients with type 2 diabetes. Hyperglucagonemia is implicated in the etiology of this condition; however, effective therapies to block glucagon signaling and thereby regulate glucose metabolism do not exist. To determine the extent to which blocking glucagon action would reverse hyperglycemia, we targeted the glucagon receptor (GCGR) in rodent models of type 2 diabetes using 2'-methoxyethyl-modified phosphorothioate-antisense oligonucleotide (ASO) inhibitors. Treatment with GCGR ASOs decreased GCGR expression, normalized blood glucose, improved glucose tolerance, and preserved insulin secretion. Importantly, in addition to decreasing expression of cAMP-regulated genes in liver and preventing glucagon-mediated hepatic glucose production, GCGR inhibition increased serum concentrations of active glucagon-like peptide-1 (GLP-1) and insulin levels in pancreatic islets. Together, these studies identify a novel mechanism whereby GCGR inhibitors reverse the diabetes phenotype by the dual action of decreasing hepatic glucose production and improving pancreatic beta cell function.
Journal of Clinical Investigation 07/2004; 113(11):1571-81. · 15.39 Impact Factor
