Liver fat is associated with elevated FGF21 in youth with obesity but without MASLD

Authors: TAS, EMIR - University Of Pittsburgh; DIAZ, EVA - University Arkansas For Medical Sciences (UAMS); OU, XIAWEI - University Arkansas For Medical Sciences (UAMS); BØRSHEIM, ELISABET - University Arkansas For Medical Sciences (UAMS); ARSLANIAN, SILVA - University Of Pittsburgh

Submitted to: Pediatric Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2026
Publication Date: 2/10/2026
Citation: Tas, E., Diaz, E.C., Ou, X., Børsheim, E., Arslanian, S. 2026. Liver fat is associated with elevated FGF21 in youth with obesity but without MASLD. Pediatric Obesity. 21:Article e70092. https://doi.org/10.1111/ijpo.70092.
DOI: https://doi.org/10.1111/ijpo.70092

Interpretive Summary: Children and teens with obesity are at risk of developing fat buildup in the liver. Doctors usually diagnose a liver disease called metabolic dysfunction-associated steatotic liver disease (MASLD) when liver fat reaches 5% or more. Not much is known about what happens before it reaches that level. In this study, scientists looked at 58 adolescents with obesity whose liver fat was below 5%, meaning they did not have MASLD. The scientists wanted to see whether small increases in liver fat were already linked to early signs of metabolic stress. It was found that even modest increases in liver fat were linked to higher levels of a hormone called fibroblast growth factor-21 (FGF21). FGF21 is produced by the liver when it is under metabolic stress. Importantly, this relationship was seen even though the teens did not yet have liver disease. Other common markers of metabolic health (like insulin resistance, leptin, or adiponectin) were not clearly related to these small increases in liver fat. This suggests that FGF21 may be an early warning signal, similar to how slightly elevated blood sugar can signal “prediabetes.” Small increases in liver fat may represent a “pre-MASLD” stage, where the liver is beginning to experience stress before overt disease develops. In short, the findings suggest that the liver may start showing signs of stress earlier than previously recognized, and FGF21 could potentially help identify youth at risk before more serious liver disease develops.

Technical Abstract: Background: 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. Objectives: To examine the association between liver fat < 5% and metabolic markers in pubertal youth with obesity, with a focus on FGF21. Methods: 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). Results: 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 associ¬ated 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. Conclusions: 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.