Circulating Fibroblast Growth Factor-23 Is Associated With Fat Mass and Dyslipidemia in Two Independent Cohorts of Elderly Individuals

Objective—Disturbances in mineral metabolism define an increased cardiovascular risk in patients with chronic kidney disease. Fibroblast growth factor-23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and has recently been implicated as a putative pathogenic factor in cardiovascular disease. Because other members of the FGF family play a role in lipid and glucose metabolism, we hypothesized that FGF23 would associate with metabolic factors that predispose to an increased cardiovascular risk. The goal of this study was to investigate the relationship between FGF23 and metabolic cardiovascular risk factors in the community. Methods and Results—Relationships between serum FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass were examined in 2 community-based, cross-sectional cohorts of elderly whites (Osteoporotic Fractures in Men Study: 964 men aged 75±3.2; Prospective Investigation of the Vasculature in Uppsala Seniors study: 946 men and women aged 70). In both cohorts, FGF23 associated negatively with high-density lipoprotein and apolipoprotein A1 (7% to 21% decrease per 1-SD increase in log FGF23; P<0.01) and positively with triglycerides (11% to 14% per 1-SD increase in log FGF23; P<0.01). A 1-SD increase in log FGF23 was associated with a 7% to 20% increase in BMI, waist circumference, and waist-to-hip ratio and a 7% to 18% increase in trunk and total body fat mass (P<0.01) as determined by whole-body dual x-ray absorptiometry. FGF23 levels were higher in subjects with the metabolic syndrome compared with those without (46.4 versus 41.2 pg/mL; P<0.05) and associated with an increased risk of having the metabolic syndrome (OR per 1-SD increase in log FGF23, 1.21; 95% CI, 1.04 to 1.40; P<0.05). Conclusion—We report for the first time on associations between circulating FGF23, fat mass, and adverse lipid metabolism resembling the metabolic syndrome, potentially representing a novel pathway(s) linking high FGF23 to an increased cardiovascular risk.

[1]  T. Maeda,et al.  Leptin stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1α,25‐dihydroxyvitamin D3 synthesis in leptin‐deficient ob/ob Mice , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[2]  L. Schurgers,et al.  The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study , 2010, Annals of Internal Medicine.

[3]  H. Melhus,et al.  Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. , 2009, Atherosclerosis.

[4]  E. Hagström,et al.  Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community‐based cohort of men and women , 2009, Clinical endocrinology.

[5]  L. Lind,et al.  Relationship between circulating FGF23 and total body atherosclerosis in the community. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[6]  M. Matoulek,et al.  Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor‐21 in patients with type 2 diabetes and obesity , 2009, Clinical endocrinology.

[7]  C. Chazot,et al.  High levels of serum fibroblast growth factor (FGF)-23 are associated with increased mortality in long haemodialysis patients. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  L. Lind,et al.  Circulating fibroblast growth factor-23 is associated with vascular dysfunction in the community. , 2009, Atherosclerosis.

[9]  Thomas J. Wang,et al.  Fibroblast Growth Factor 23 and Left Ventricular Hypertrophy in Chronic Kidney Disease , 2009, Circulation.

[10]  D. Goldsmith,et al.  Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. , 2009, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[11]  Y. J. Foss.  Vitamin D deficiency is the cause of common obesity. , 2009, Medical hypotheses.

[12]  Mai-Szu Wu,et al.  Fibroblast Growth Factor 23: A Possible Cause of Left Ventricular Hypertrophy in Hemodialysis Patients , 2009, The American journal of the medical sciences.

[13]  Jason K. Kim,et al.  Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice , 2009, Diabetes.

[14]  S. Mundra,et al.  Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis , 2009 .

[15]  D. Mellström,et al.  Relation between fibroblast growth factor-23, body weight and bone mineral density in elderly men , 2009, Osteoporosis International.

[16]  D. Moller,et al.  Fibroblast growth factor 21 corrects obesity in mice. , 2008, Endocrinology.

[17]  G. Karsenty,et al.  Reciprocal regulation of bone and energy metabolism. , 2008, Journal of musculoskeletal & neuronal interactions.

[18]  Z. Massy,et al.  Vitamin D levels and early mortality among incident hemodialysis patients. , 2008, Kidney international.

[19]  N. Powe,et al.  Impact of activated vitamin D and race on survival among hemodialysis patients. , 2008, Journal of the American Society of Nephrology : JASN.

[20]  Feng Liu,et al.  Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans , 2008, Diabetes.

[21]  T. Kadowaki,et al.  The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS , 2008, FEBS letters.

[22]  N. Itoh,et al.  Functional evolutionary history of the mouse Fgf gene family , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[23]  G. Boden,et al.  Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. , 2007, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[24]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[25]  B. Goldstein,et al.  Adiponectin suppresses IκB kinase activation induced by tumor necrosis factor-α or high glucose in endothelial cells: role of cAMP and AMP kinase signaling , 2007 .

[26]  M. Stridsberg,et al.  Regulation of fibroblast growth factor-23 in chronic kidney disease. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[27]  G. Åkerström,et al.  Fibroblast growth factor-23 regulates parathyroid hormone and 1alpha-hydroxylase expression in cultured bovine parathyroid cells. , 2007, The Journal of endocrinology.

[28]  C. Blackmore,et al.  Liver-specific Activities of FGF19 Require Klotho beta* , 2007, Journal of Biological Chemistry.

[29]  S. Kliewer,et al.  Tissue-specific Expression of βKlotho and Fibroblast Growth Factor (FGF) Receptor Isoforms Determines Metabolic Activity of FGF19 and FGF21* , 2007, Journal of Biological Chemistry.

[30]  M. McKee,et al.  Endocrine Regulation of Energy Metabolism by the Skeleton , 2007, Cell.

[31]  Jason R. Stubbs,et al.  Role of hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and mortality in fibroblastic growth factor 23 null mice. , 2007, Journal of the American Society of Nephrology : JASN.

[32]  K. Rosenblatt,et al.  βKlotho is required for metabolic activity of fibroblast growth factor 21 , 2007, Proceedings of the National Academy of Sciences.

[33]  B. Lanske,et al.  Ablation of vitamin D signaling rescues bone, mineral, and glucose homeostasis in Fgf-23 deficient mice. , 2007, Matrix biology : journal of the International Society for Matrix Biology.

[34]  L. Hansson,et al.  Evaluation of Gentian cystatin C reagent on Abbott Ci8200 and calculation of glomerular filtration rate expressed in mL/min/1.73 m2 from the cystatin C values in mg/L , 2007, Scandinavian journal of clinical and laboratory investigation.

[35]  K. Okawa,et al.  Klotho converts canonical FGF receptor into a specific receptor for FGF23 , 2006, Nature.

[36]  M. Razzaque,et al.  Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. , 2006, American Journal of Pathology.

[37]  M. Econs,et al.  Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia. , 2006, The Journal of clinical endocrinology and metabolism.

[38]  S. Kihara,et al.  Adiponectin Replenishment Ameliorates Obesity-Related Hypertension , 2006, Hypertension.

[39]  Jason R. Stubbs,et al.  Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. , 2006, Journal of the American Society of Nephrology : JASN.

[40]  O. Johnell,et al.  Free Testosterone is an Independent Predictor of BMD and Prevalent Fractures in Elderly Men: MrOS Sweden , 2006, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  K. Rosenblatt,et al.  Regulation of Fibroblast Growth Factor-23 Signaling by Klotho* , 2006, Journal of Biological Chemistry.

[42]  M. Joffe,et al.  Revisiting survival differences by race and ethnicity among hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study. , 2006, Journal of the American Society of Nephrology : JASN.

[43]  Lars Lind,et al.  A Comparison of Three Different Methods to Evaluate Endothelium-Dependent Vasodilation in the Elderly: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[44]  M. Wolf,et al.  Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. , 2005, Journal of the American Society of Nephrology : JASN.

[45]  J. Gromada,et al.  FGF-21 as a novel metabolic regulator. , 2005, The Journal of clinical investigation.

[46]  N. Itoh,et al.  Evolution of the Fgf and Fgfr gene families. , 2004, Trends in genetics : TIG.

[47]  G. Chertow,et al.  Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. , 2004, Journal of the American Society of Nephrology : JASN.

[48]  C. Ohlsson,et al.  Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. , 2004, Endocrinology.

[49]  R. Soriano,et al.  Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes. , 2004, Endocrinology.

[50]  Y. Takeuchi,et al.  Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. , 2004, The Journal of clinical investigation.

[51]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[52]  H. Jüppner,et al.  Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. , 2003, Kidney international.

[53]  Margit S Rezabek,et al.  Meta-analysis of the effect of sevelamer on phosphorus, calcium, PTH, and serum lipids in dialysis patients. , 2003, Advances in renal replacement therapy.

[54]  M. Rocco,et al.  Survival advantage for adult Hispanic hemodialysis patients? Findings from the end-stage renal disease clinical performance measures project. , 2003, Journal of the American Society of Nephrology : JASN.

[55]  Y. Takeuchi,et al.  Increased circulatory level of biologically active full-length FGF-23 in patients with hypophosphatemic rickets/osteomalacia. , 2002, The Journal of clinical endocrinology and metabolism.

[56]  D. French,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity , 2022 .

[57]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[58]  J. Mckenney,et al.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). , 2001, JAMA.