Lynae J. Hanks

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

Introduction Elevated 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. Methods Associations 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. Results Median 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. Conclusions Elevated FGF23 concentrations may be considered a biomarker for decline in metabolic function among individuals with normal kidney function.

Obesity, metabolic health, and the risk of end-stage renal disease.

Obesity is associated with chronic kidney disease progression. Whether metabolic risk factors modify this association is unclear. Here we examined associations of body mass index (BMI) and metabolic health with risk of end-stage renal disease (ESRD) in the Reason for Geographic and Racial Differences in Stroke (REGARDS) study. Among 21,840 participants eligible for analysis, 247 developed ESRD (mean follow-up of 6.3 years). Metabolic health significantly modified the association of BMI with ESRD. In models stratified by presence or absence of metabolic syndrome and adjusted for demographic, lifestyle and clinical factors, higher BMI was associated with lower risk of ESRD in those without (hazard ratio per 5 kg/m2 increase in BMI 0.70, 95%CI 0.52,0.95), but not those with (hazard ratio, 1.06) metabolic syndrome. In models stratified by weight and metabolic health, compared to normal weight (BMI 18.5–24.9 kg/m2) participants without metabolic syndrome the overweight individuals (BMI 25–29.9) and obese individuals (BMI of 30 or more) with metabolic syndrome had greater risk of ESRD (hazard ratios of 2.03 and 2.29, respectively), whereas obesity without the metabolic syndrome was associated with lower risk of ESRD (hazard ratio 0.47). Thus, higher BMI is associated with lower ESRD risk in those without but not those with metabolic syndrome.

Short-term physical activity intervention decreases femoral bone marrow adipose tissue in young children: a pilot study.

Mechanical stimulation is necessary for maximization of geometrical properties of bone mineralization contributing to long-term strength. The amount of mineralization in bones has been reciprocally related to volume of bone marrow adipose tissue and this relationship is suggested to be an independent predictor of fracture. Physical activity represents an extrinsic factor that impacts both mineralization and marrow volume exerting permissive capacity of the growing skeleton to achieve its full genetic potential. Because geometry- and shape-determining processes primarily manifest during the linear growth period, the accelerated structural changes accompanying early childhood (ages 3 to 6 y) may have profound impact on lifelong bone health. The objective of this pilot study was to determine if a short-term physical activity intervention in young children would result in augmentation of geometric properties of bone. Three days per week the intervention group (n=10) participated in 30 min of moderate intensity physical activity, such as jumping, hopping and running, and stretching activities, whereas controls (n=10) underwent usual activities during the 10-week intervention period. Femoral bone marrow adipose tissue volume and total body composition were assessed by magnetic resonance imaging and dual-energy X-ray absorptiometry, respectively, at baseline and after 10 weeks. Although after 10-weeks, intergroup differences were not observed, a significant decrease in femoral marrow adipose tissue volume was observed in those participating in physical activity intervention. Our findings suggest that physical activity may improve bone quality via antagonistic effects on femoral bone marrow adipose tissue and possibly long-term agonistic effects on bone mineralization.

The relationships among total body fat, bone mineral content and bone marrow adipose tissue in early-pubertal girls.

Investigation of the physiologic relevance of bone marrow adipose tissue (BMAT) during growth may promote understanding of the bone-fat axis and confluence with metabolic factors. The objective of this pilot investigation was two-fold: (1) to evaluate the relationships among total body fat, bone mineral content (BMC) and femoral BMAT during childhood and underlying metabolic determinants and (2) to determine if the relationships differ by race. Participants included white and non-Hispanic black girls (n=59) ages 4–10 years. Femoral BMAT volume was measured by magnetic resonance imaging, BMC and body fat by dual-energy X-ray absorptiometry. Metabolic parameters were assessed in the fasted state. Total fat and BMC were positively associated with BMAT; however, simultaneous inclusion of BMC and body fat in the statistical model attenuated the association between BMC and BMAT. Differences in BMAT volume were observed, non-Hispanic black girls exhibiting marginally greater BMAT at age eight (P=0.05) and white girls exhibiting greater BMAT at age ten (P<0.001). Metabolic parameters conferred differential impact by race, such that, a positive association for BMAT and leptin (P=0.02) and adiponectin (P=0.002) in white girls while BMAT and insulin were inversely related in non-Hispanic black girls (P=0.008). Our findings revealed a positive relationship between BMAT, body fat and BMC, although body fat, respective to leptin, contributed partly to the relationship between BMAT and BMC. Despite large differences in total fat between non-Hispanic black and white, the relationship between BMAT and BMC was similar to white girls. However, this relationship appeared to be impacted through different mechanisms according to race.

Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals

Background Circulating FGF21 levels are commonly elevated in disease states. There is limited information regarding concentrations of circulating FGF21 in the absence of disease, as well as age-related differences in body composition that may contribute to FGF21 regulation across groups. Objective The objectives of this study were to assess FGF21 levels across age groups (childhood to elder adulthood), and investigate whether body composition indices are associated with age-related differences in circulating FGF21. Materials and methods We cross-sectionally analyzed serum concentrations of FGF21 in 184 healthy subjects aged 5–80 y (45% male). Multiple linear regression was performed to assess the independent association of categorical age (children: 5–12 y, young adults: 20–29 y, adults: 30–50 y, older adults: 55–64 y, elder adults: 65–80 y) with FGF21 concentration taking into account DXA-measured body composition indices [bone mineral density (BMD) and percent lean, trunk, and fat mass]. We also stratified analysis by tertile of FGF21. Results Incremental increases in FGF21 levels were observed across age groups (youngest to highest). Age group was positively associated with FGF21 level independent of body composition indices (age group variable: β = 0.25, 0.24, 0.24, 0.23, all P < 0.0001, controlling for percent lean, BMD, percent fat, and percent trunk fat, respectively). By FGF21 tertile, age group was associated with FGF21 in the lowest tertile only (β = 13.1, 0.19, 0.18, all P ≤ 0.01, accounting for percent lean, fat and trunk fat, respectively), but not when accounting for BMD. Conclusions Our findings in a healthy population display an age-related increase in serum FGF21, highlighting a potential age effect in response to metabolic demand over the lifecourse. FGF21 levels increase with age independently of body composition. At lower levels of FGF21, BMD, but not other body composition parameters, attenuates the association between FGF21 level and age, suggesting the metabolic demand of the skeleton may provide a link between FGF21 and energy metabolism.

Role of Various Cytokines and Growth Factors in Pubertal Development

Historical data suggest that body composition is intricately involved in pubertal development. Progression through puberty is dependent on the interaction between the growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis, reproductive and metabolic hormones as well as pro- and anti-inflammatory cytokines which induce alterations in feedback mechanisms and therefore mediate body composition and growth. Simultaneous increases in GH and IGF-1, and the concomitant changes in the hormonal milieu (i.e. reproductive hormones, testosterone and estrogen, and insulin)are the major contributors to anabolic effects seen throughout the pubertal transition, and are affected by various factors including (but not limited to) energy status and body composition. Orexigenic agents (i.e. ghrelin and leptin) also play a role at the level of the hypothalamus affecting not only energy intake, but also pubertal onset and progression. Effects of cytokines, many of which may be considered catabolic, extend beyond their traditionally viewed role involving the immune system, accompanying reproductive maturity further regulating aspects of energy and bone metabolism. As such, the signal(s) initiating the hypothalamic response that triggers puberty is likely reliant on a number of neural, metabolic and endocrine networks, all of which are at least partially influenced by pubertal growth factors, and act independently, antagonistically and/or synergistically to regulate anabolic pathways, therefore modifying body composition trajectory and growth during adolescence.

Fibroblast growth factor‐21, body composition, and insulin resistance in pre‐pubertal and early pubertal males and females

Accumulating evidence derived primarily from animal models suggests that fibroblast growth factor‐21 (FGF‐21) may affect the musculoskeletal system via effects on the capacity of tissues to respond to insulin. A proportion of musculoskeletal properties and underpinnings of promoting/preventing insulin resistance are established early in the pubertal transition. Thus, the objective of this study was to test the hypothesis that insulin resistance and/or obesity will promote greater FGF‐21 concentration which will be inversely associated with musculoskeletal parameters [lean mass and bone mineral content (BMC)] in pre‐/early pubertal children. Given the sexual dimorphic nature of musculoskeletal development of fat mass accrual, differences by obesity status and sex were also investigated.

Reduced carbohydrate diet to improve metabolic outcomes and decrease adiposity in obese peripubertal African American girls.

Objective: Obesity prevalence among African American (AA) girls is higher than that in other groups. Because typical energy-restriction obesity treatment strategies have had limited success, alterations in macronutrient composition may effectively improve metabolic outcomes in this population and affect future body composition trajectories. The objective was to evaluate the efficacy of a moderately restricted carbohydrate (CHO) versus a standard CHO diet on weight/fat loss and metabolic parameters in overweight/obese AA girls ages 9 to 14 years. Methods: A total of 26 AA girls (ranging from 92nd body mass index percentile and above) were assigned to either a reduced- (SPEC: 42% energy from CHO, n = 12) or a standard- (STAN: 55% of energy from CHO, n = 14) CHO diet (protein held constant) for 16 weeks. All of the meals were provided and clinically tailored to meet the estimated energy requirements (resting energy expenditure × 1.2 in eucaloric phase and resting energy expenditure × 1.2 − 1000 kcal in energy deficit phase). The first 5 weeks encompassed a eucaloric phase evaluating metabolic changes in the absence of weight change. The subsequent 11 weeks were hypocaloric (1000 kcal/day deficit) to promote weight/fat loss. Meal tests were performed during the eucaloric phase for metabolic analyses. Dual-energy x-ray absorptiometry was used to evaluate body composition. Results: Both groups experienced reductions in weight/adiposity, but the difference did not reach significance. The solid meal test indicated improved glucose/insulin homeostasis on the SPEC diet up to 3 hours postingestion. In addition, significantly lower triglycerides (P < 0.001) were observed on the SPEC diet. Conclusions: Dietary CHO reduction favorably influences metabolic parameters but did not result in greater weight/fat loss relative to a standard diet in obese AA girls. Future research is needed to determine long-term effectiveness of a reduced CHO diet on glucose and insulin homeostasis and how it may apply to weight maintenance/fat loss during development alone and/or in combination with additional weight loss/metabolic improvement strategies.

Metabolic Subtypes and Risk of Mortality in Normal Weight, Overweight, and Obese Individuals with CKD

BACKGROUND AND OBJECTIVES Higher body mass index (BMI) is paradoxically associated with lower mortality in persons with CKD, but whether cardiometabolic abnormalities modulate this association is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Participants with CKD from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=4374) were analyzed. The harmonized criteria for metabolic syndrome were used to define metabolic health, and participants were categorized into one of six mutually exclusive categories defined by combined measures of metabolic health (metabolically healthy, <3 criteria for metabolic syndrome; metabolically unhealthy, ≥3 criteria) and weight status (normal weight, BMI 18.5-24.9 kg/m(2); overweight, BMI 25-29.9 kg/m(2); obese, BMI ≥30 kg/m(2)). Cox models were used to estimate the hazard ratio (HR) of death as a function of each category. RESULTS A total of 683 deaths were observed over a mean 4.5 years of follow-up. In analyses adjusted for age, race, sex, and geographic region of residence, compared with metabolically healthy normal weight persons, the HRs of mortality in metabolically healthy overweight and obese persons were 0.68 (95% confidence interval [95% CI], 0.53 to 0.87) and 0.71 (95% CI, 0.51 to 0.98), respectively, whereas there were no statistically significant differences in survival among metabolically unhealthy overweight or obese individuals. After further adjustment for lifestyle, clinical and laboratory factors including markers of kidney function, the HR of mortality remained lower in metabolically healthy overweight individuals compared with metabolically healthy normal weight individuals (HR, 0.74; 95% CI, 0.57 to 0.96). CONCLUSIONS Metabolic abnormalities may attenuate the magnitude and strength of survival benefits associated with higher BMI in individuals with CKD.

Associations between Vascular Health Indices and Serum Total, Free and Bioavailable 25-Hydroxyvitamin D in Adolescents

Objective The role of vitamin D in cardiovascular health remains debated as results have been inconsistent. Previous studies have not considered the bioavailability of 25-hydroxy vitamin D [25(OH)D]. Objectives of our study were to investigate the association between serum concentrations of total, free and bioavailable 25(OH)D and independent predictors of cardiovascular risk such as flow mediated dilatation (FMD) and augmentation index (AIx). Design This cross-sectional study included 47 post-menarchal, adolescent females [31 African American (AA) and 16 European American (EA)]. Methods AIx was standardized to a heart rate of 75 beats/min (AIx75). Free and bioavailable 25(OH)D concentrations were calculated from standard formulas. Results and Conclusions Mean age of the participants was 15.8±1.4 years and mean body mass index was 23.1±4.0 kg/m2. Serum total 25(OH)D was not associated with FMD, but was positively associated with AIx75 in the adjusted model (rho = 0.4, P = 0.03). AIx75 was positively associated with bioavailable 25(OH)D (rho = 0.4, P = 0.004) and free 25(OH)D (rho = 0.4, P = 0.009) and the associations persisted after adjusting for covariates. In race-specific analyses, total, free and bioavailable 25(OH)D were strongly positively associated with AIx75 in AA (rho = 0.5, 0.4, 0.4, respectively), which persisted even after adjusting for covariates. Whereas in EA there was an inverse association between total 25(OH)D and AIx75 in EA (rho = −0.6), which attenuated after adjusting for covariates. Conclusion Circulating total, free and bioavailable 25(OH)D were associated with arterial stiffness in adolescent girls, and these associations were race dependent. Notwithstanding, the implications of associations between vascular function indices and 25(OH)D remains unclear.