Associations of Fibroblast Growth Factor-23 with Markers of Inflammation, Insulin Resistance and Obesity in Adults

Abstract

IntroductionElevated fibroblast growth factor-23 (FGF23) is an established marker of cardiovascular disease. The underlying reason(s) for the rise accompanying cardiovascular health decline are unclear. Prior studies have shown that FGF23 concentrations are associated with markers of inflammation and insulin resistance but they have been limited by a focus on persons with chronic kidney disease (CKD) and lack of race and sex diversity. The objective of this study was to examine the associations of FGF23 and markers of inflammation, insulin resistance, and anthropometrics in a large cohort of community-dwelling adults.MethodsAssociations of FGF23 with markers of inflammation [interleukin-6 (IL-6), IL-10, high sensitivity-CRP (hsCRP)], insulin utilization [resistin, adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR)] and anthropometrics [BMI and waist circumference (WC)] were examined cross-sectionally in a 1,040 participants randomly selected from the Reason for Geographic and Racial Differences in Stroke (REGARDS) Study, a national study of black and white adults ≥45 years. Effect modification by race and CKD status was tested, and stratified models were analyzed accordingly.ResultsMedian FGF23 concentration was 69.6 RU/ml (IQR: 53.2, 102.7). Higher quartiles of FGF23 were associated with higher mean concentrations of IL-6, IL-10, hsCRP and resistin (P trend<0.001 for all). There were no significant differences in HOMA-IR, adiponectin concentrations, BMI, or WC across FGF23 quartiles in the crude analyses. CKD significantly modified the relationships between FGF23 and inflammatory markers, HOMA-IR, BMI and WC (P ≤ 0.01 for all). In linear regression models adjusted for sociodemographic and clinical variables, FGF23 was positively associated with IL-6, hsCRP, IL-10, HOMA-IR, BMI and WC in individuals without CKD, but not among individuals with CKD. Additionally, FGF23 was positively associated with resistin irrespective of CKD status.ConclusionsElevated FGF23 concentrations may be considered a biomarker for decline in metabolic function among individuals with normal kidney function.

Fibroblast growth factor 23 as novel biomarker for early risk stratification after ST-elevation myocardial infarction

“…Besides higher FGF-23 concentrations, women were significantly older in our cohort; however, age and FGF-23 did not show any significant relation, therefore, a confounding influence of age on the relation between gender and FGF-23 seems implausible. Furthermore, diabetes mellitus was significantly associated with FGF-23, which is in agreement with earlier studies reporting a pathophysiological interplay between insulin metabolism and FGF-23, particularly in patients without CKD 26. Since our population showed a low CKD prevalence and no other parameter than FGF-23 (from table 1) was significantly related to diabetic status, this pathophysiological mechanism is considered as the most probable reason for the increased FGF-23 concentrations in diabetics.…”

Associations of Fibroblast Growth Factor 23 with Markers of Inflammation and Leukocyte Transmigration in Chronic Kidney Disease

“…Associations of fibrinogen, TNF-α and IL-6 with FGF23 levels were described in the Chronic Renal Insufficiency cohort, of 3,879 patients; however, the findings were independent of the renal function [18]. Correlations were found between FGF23 and IL-6 as well as VCAM in a non-CKD cohort [7] and a sub-study of the REGARDS cohort with 1,040 patients found positive correlations between FGF23 and IL-10 and CRP in individuals with intact kidney function, but not in the participants with CKD [17]. Hence, several FGF23 association studies have delivered information on the relationship to inflammation, but none of these have analyzed multiple soluble markers and effector cells simultaneously.…”

“…It is intriguing to speculate that FGF23 might contribute to the primed state of leukocytes in CKD that alters the response pattern of activated cells; however, this could not be confirmed after adjustment of GFR concerning monocytes in the present study, and a possible explanation is that we lacked the study power to do so. FGF23 linkage to inflammatory markers has been described in multiple studies in both CKD and non CKD cohorts [9,[17][18][19][20]. Results have been inconsistent perhaps due to diverging demographic profiles or methodological constraints.…”

“…FGF23 acts through triggering genes, which encode cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) [15,16] and associations of FGF23 levels with pro-inflammatory markers have been described in both CKD and non-CKD cohorts. This highlights the role of FGF23 as an inflammatory mediator, presumably acting through cytokine upregulation [9,[17][18][19][20][21]. Interestingly, a recent study described that FGF23 exposure inhibits neutrophil recruitment through interference of integrin expression, compromising host defense in CKD [22].…”

Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice

“…Increased serum FGF23 levels are independently associated with cardiovascular morbidity and mortality among patients who are beginning hemodialysis treatment 3,4 . Furthermore, several clinical studies have shown a strong correlation between elevated FGF23 levels and serum levels of C-reactive protein (CRP), Interleukin-6 (IL-6) and Tumor Necrosis Factor α (TNFα) 5,6 . Moreover, in an experimental study, we have recently demonstrated that FGF23 can directly target hepatocytes and cause an inflammatory response by increasing CRP and IL-6 production in the liver 7 .…”