Clinical Endocrinology (2015) 82, 550–556

doi: 10.1111/cen.12552

ORIGINAL ARTICLE

Fibroblast growth factor-21, body composition, and insulin resistance in pre-pubertal and early pubertal males and females rrez‡ Lynae J. Hanks*, Krista Casazza†, Ambika P. Ashraf*, Stephenie Wallace* and Orlando M. Gutie *Children’s Hospital of Alabama, University of Alabama at Birmingham (UAB), †Department of Nutrition Sciences, UAB and ‡Department of Medicine, UAB, Birmingham, AL, USA

Summary Objective 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. Design Cross-sectional. Patients Children ages 7–12 years (n = 69, 38% male, 48% non-Hispanic black, 45% obese). Measurements Fasting FGF-21, glucose and insulin measures were obtained. An estimate of insulin resistance was derived using the homoeostatic model assessment of insulin resistance (HOMA-IR). Body composition (BMC, lean mass and fat mass) was assessed by DXA. Multivariate regression analysis was used to evaluate the influence of FGF-21 on BMC, lean mass and HOMA-IR as dependent variables. Obesity status was established based on BMI z-score. Results FGF-21 concentrations did not differ by obesity status or by sex. There was an inverse association between FGF-21 and BMC among nonobese individuals (P = 001) and an inverse association between FGF-21 and lean mass among females (P = 002), which were both independent of fat mass. FGF-21 was inversely associated with HOMA-IR in males, but not females (P = 004). Conclusions The existence of relationships of FGF-21 with musculoskeletal parameters and insulin resistance raises the

Correspondence: Lynae J. Hanks, University of Alabama at Birmingham, CPPII M30, 1601 4th Ave S, Birmingham, AL 35233, USA. Tel.: 205-996-9657; Fax: 205-934-7050; E-mail: [email protected] Clinical trial registration number: NCT02040740 & NCT01410643

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possibility of crosstalk between these systems. These findings suggest that circulating FGF-21 may differ in its association with bone, lean mass and insulin resistance depending on sex and weight status. (Received 31 January 2014; returned for revision 10 April 2014; finally revised 26 May 2014; accepted 7 July 2014)

Introduction Adverse health outcomes associated with insulin-resistant states (e.g. prediabetes, type 2 diabetes) are well-described and coincide with the paediatric obesity epidemic.1,2,3 Numerous studies have established that endocrine factors secreted by adipose tissue (adipokines) influence insulin resistance within the paediatric population.4,5,6 However, the extent to which secretory factors emanating from muscle, the body’s largest glucose-utilising tissue, may also exert effects on communicative networks between the musculoskeletal system and insulin dynamics is poorly understood. Fibroblast growth factor-21 (FGF-21) is a hormone that may partly mediate the ability of skeletal muscle to maintain glucose homoeostasis. Although primarily secreted by the liver and adipose tissue, FGF-21 has recently been identified as myokine exerting7 important systemic actions including facilitating metabolic adaptation in the fasted state8,9,10 and regulating glucose uptake,11,12,13 Higher circulating FGF-21 levels in humans have been observed among insulin-resistant and obese individuals relative to their insulin-sensitive and normal weight peers.11,14,15 In addition to having a role in glucose homoeostasis, fuel utilisation pathways converge with anabolic growth processes suggesting FGF-21 may be important for developmental aspects of the musculoskeletal system (e.g. myogenesis, thermogenesis, osteogenesis).16,17 Metabolic insulin responses undergo substantial changes during puberty, particularly among girls. Most notably, the increase in oestradiol from the ovaries increases lipid mobilisation, drives fat deposition and coincides with a heightened state of insulin resistance, manifesting by the second Tanner stage. In males, the hormonal changes are more sequential, and the insulin-resistant state is shorter and less pronounced. These changes may play an © 2014 John Wiley & Sons Ltd

FGF-21, body composition, and insulin resistance 551 important role in coordinating musculoskeletal adaptations associated with the rapid period of growth in puberty. Therefore, evaluating the relationships between FGF-21, body composition and insulin resistance during pre-/early puberty is warranted. Our overarching hypothesis is that elevated FGF-21 concentrations among insulin-resistant and obese children can adversely affect musculoskeletal development. Early pubertal children are an ideal model to test this hypothesis, as this represents a stage characterised by substantial metabolic changes in preparation for rapid linear growth. Further, as influential factors in rate and/or pattern of growth, weight status and sex may impact FGF-21 actions. The objectives of this study were to 1) characterise the relationship between FGF-21 levels in circulation with quantitative aspects of the musculoskeletal system (i.e. bone mineral content and lean mass) and insulin resistance in prepubertal and early pubertal children and 2) investigate differences by obesity status and sex.

Materials and methods Participants included a convenience sample of prepubertal and early pubertal children aged 7–12 years who participated in a variety of research protocols within the Department of Nutrition Sciences at the University of Alabama at Birmingham (UAB) from 2011 to 2013 and had stored blood samples for measurement of FGF-21. Samples were derived from a dietary weight loss intervention [described in Casazza et al18] and from two observational studies investigating body composition and metabolic health in boys (NCT02040740) and girls (NCT01410643). All data used in the analysis were derived from the baseline assessment if enrolled in a study with multiple collection points, and blood draw protocols were the same across all studies. Participants were recruited using newspaper advertisements, posted flyers, various community partnerships, by word-of-mouth and through local radio advertisements. Exclusion criteria were medical diagnoses and/or current use of medications known to affect body composition, lipid or glucose metabolism, or blood pressure (e.g. diabetes; impaired fasting glucose; use of thyroid medication, diuretics, beta blockers and thiazolidinediones.); an allergy to EMLA cream, which was used for topical anaesthesia prior to venipuncture in study participants; and history of an eating disorder(s). The nature of the studies was carefully explained to each participant and guardian(s), and informed assent and consent, respectively, were obtained. All research protocols were approved by the Institutional Review Board for Human Subjects at UAB. All measurements were performed at the Clinical Research Unit (CRU) and the Department of Nutrition Sciences at UAB. Blood/serum analyses Blood was drawn after an overnight fast to obtain glucose, insulin and FGF-21. Serum concentrations of FGF-21 were measured using a commercially available enzyme linked immunoassay (Millipore Corporation, Billerica, MA, USA). All samples were processed immediately upon completion of blood draw to © 2014 John Wiley & Sons Ltd Clinical Endocrinology (2015), 82, 550–556

extract serum samples and subsequently stored at 80 degrees until measurement of the analytes of interest in batched assays in accordance with assay specifications. The inter- and intraassay coefficients of variation (CV) were < 10%. Glucose was measured in 3 ll sera with the glucose oxidase method using a SIRRUS analyser (interassay CV 256%). Insulin was analysed using a TOSOH AIA-600 II Automated Immunoassay Analyzer (TOSOH Bioscience, South San Francisco, CA, USA). Minimum assay sensitivity was 05 uU/ml, mean intra-assay CV was 469%, and interassay CV was 60%. Insulin resistance was calculated using the homoeostasis model assessment of insulin resistance (HOMA-IR), based on fasting insulin and glucose concentrations.9 Height, weight, BMI z-score Height (Heightronic 235; Measurement Concepts, Snoqualmie, WA, USA) and weight (Scale-tronix 6702W; Scale-tronix, Carol Stream, IL, USA) were measured in minimal clothing without shoes. BMI z-score was calculated using age- and sex-specific CDC growth charts.11 Body composition Whole-body DXA scanning was used to assess fat mass, lean soft tissue mass, bone mineral content (BMC) and bone mineral density (BMD) using an iDXA instrument (GE-Lunar, Madison, WI, USA) with paediatric software. Pubertal status Pubertal stage was determined by direct observation according to the staging based on the criteria of Marshall and Tanner.19,20 One composite number was assigned for Tanner staging, representing the higher of the two values defined by breast/testes development and/or pubic hair. Statistics Descriptive statistics (mean  standard error) were determined for the overall sample and for stratified groups according to obesity status (z-score

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 vi...
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