Liver Fat Is Associated With Elevated FGF21 in Youth With Obesity but Without MASLD

Youth with obesity are at risk for accumulating liver fat, even below the threshold for metabolic dysfunction-associated steatotic liver disease (MASLD), defined as ≥ 5% by MRI. While prior studies suggest that sub-threshold liver fat may carry metabolic risk, the role of fibroblast growth factor-21 (FGF21)-a liver-derived hormone responsive to metabolic stress-has not been well characterised in this context.

To examine the association between liver fat < 5% and metabolic markers in pubertal youth with obesity, with a focus on FGF21.

This secondary cross-sectional analysis included 58 pubertal adolescents with obesity (62% female; mean age 14.7 ± 1.7 years) and liver fat < 5% by MRI-proton density fat fraction (PDFF). Fasting glucose, insulin, lipids, leptin, adiponectin and FGF21 were measured. Insulin sensitivity was estimated by homeostatic model assessment of insulin resistance (HOMA-IR). Associations between PDFF and metabolic markers were analysed using Spearman correlations and multivariable regression, adjusted for age, sex, race, ethnicity and body mass index standard deviation score (BMI SDS).

The median PDFF was 2.68%. PDFF correlated positively with BMI SDS, waist circumference, glucose, triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C) and FGF21. In adjusted models, PDFF remained independently associated with FGF21 (Beta = 52 pg/mL per 1% increase; p = 0.02), even after log transformation. No associations were observed with HOMA-IR, leptin, or adiponectin.

Among pubertal youth with obesity and liver fat below the MASLD threshold, modest increases in PDFF were independently associated with higher FGF21. These findings support the potential utility of FGF21 as a biomarker of early hepatic-metabolic stress in the framework of 'pre-MASLD' state-similar to pre-diabetes before the development of overt steatosis.