Nonlinear relationship between body fat percentage and NAFLD mediated by METS-IR: threshold effects and subgroup differences

The mechanism linking body fat percentage (BFR) and non-alcoholic fatty liver disease (NAFLD) remains unclear. This study investigated whether the metabolic score for insulin resistance (METS-IR) mediates this relationship and examined threshold effects and population heterogeneity. In this cross-sectional study of 6281 participants from the 2011-2018 National Health and Nutrition Examination Survey (NHANES), logistic regression with restricted cubic splines was used to evaluate the BFR-NAFLD association and identify a threshold. A causal mediation analysis quantified the proportion of the BFR-NAFLD association mediated by METS-IR, and subgroup analyses examined differences by sex, race, and income. BFR was positively associated with NAFLD (OR per 1% increase = 1.12, 95% CI 1.06-1.20), with a threshold at 25.103% BFR; below this point, NAFLD risk rose sharply (OR = 1.61) and above it the association plateaued (OR = 1.09). METS-IR mediated 84.7% (95% CI 80.5-90%) of the BFR-NAFLD association and exhibited an inflection at 36.066 (OR = 1.72 below vs. 1.47 above this value). The BFR-NAFLD association was stronger in men (OR = 1.32), non-Hispanic Blacks (OR = 1.15), and low-income individuals (OR = 1.13) (P for interaction < 0.05). METS-IR mediates most of the relationship between body fat and NAFLD, with a clear threshold effect observed. Early intervention targeting insulin resistance may curb NAFLD progression, especially in individuals with BFR below 25%. These findings provide epidemiological evidence for the metabolic mechanism of NAFLD and inform precision prevention strategies.