Liver fat but not other adiposity measures influence circulating FGF21 levels in healthy young adult twins.

CONTEXT: Emerging as an important metabolic regulator, fibroblast growth factor 21 (FGF21) has gained considerable interest in diabetes and obesity research. The circulating FGF21 concentration is fairly low in normal individuals, but elevated hormone levels may associate with obesity. The determining factors of FGF21 levels in humans are not clear.

OBJECTIVE: Our objective was to study the influence of genetic and acquired components to serum FGF21 variability in healthy young adult twins.

DESIGN AND PARTICIPANTS: Fasting serum FGF21, lipids, body fat, and oral glucose tolerance test were investigated in 46 monozygotic (MZ) and 75 dizygotic twin pairs aged 22.8-33.1 yr. Subcutaneous, intraabdominal, and liver fat content were measured by magnetic resonance imaging/spectroscopy in a subsample of 24 MZ pairs.

RESULTS: Genetic factors contributed moderately (heritability 40%) to circulating serum FGF21 levels. Subjects with high FGF21 concentrations (≥ 250 pg/ml, n = 30) had higher fasting triglycerides, insulin, homeostasis model assessment index, and area under the curve glucose and lower high-density lipoprotein cholesterol but similar measures of overall adiposity (body mass index, body fat percent) than subjects with lower FGF21 (<100 pg/ml, n = 148). Importantly, in the MZ subsample, higher liver fat but not sc or intraabdominal fat content was found in subjects with high FGF21. Furthermore, in analyses controlling for genetic/familial effects in twin pairs, within-pair differences in liver fat (MZ) and triglycerides (dizygotic pairs) were the major acquired factors that correlated with differences in FGF21 concentrations.

CONCLUSIONS: Genetic factors influence serum FGF21 levels. Of the acquired components, high liver fat and triglycerides rather than overall adiposity associate with high FGF21 levels.