Liver FGF21 mediates sex-specific adaptation to juvenile protein malnutrition

Dietary protein sufficiency during childhood is essential for healthy growth and tissue development. Chronic protein deficiency leads to stunting, height-for-age more than two standard deviations below the median, and affects 149 million children under five ( https://www.who.int/publications/i/item/9789240073791 ). Linear growth is governed by the somatotropic axis, wherein pituitary growth hormone (GH) stimulates hepatic insulin-like growth factor 1 (IGF-1) to promote bone elongation ¹ . Although boys are consistently more stunted than girls across populations (ranging from 18% to 45%) ^2,3 , mechanisms underlying this apparent resilience remain unclear. Rodent studies suggest that the protein-to-carbohydrate ratio modulates life-history traits such as metabolism, lifespan, and reproduction, with evidence of sex-dependent sensitivity ^4,5 . Whether such dimorphism reflects coordinated developmental adaptations in response to protein scarcity, particularly in females, has not been fully explored.

Here, we show that juvenile dietary protein restriction causes sexually dimorphic adaptations with pronounced stunting in males and delayed reproductive maturation in females. Using liver-specific deletion, we identify fibroblast growth factor 21 (FGF21) as a sex-specific hepatic regulator of female somatic growth and reproductive development, revealing a dimorphic endocrine adaptation to early-life protein scarcity. Our findings position FGF21 as a critical physiological checkpoint coordinating growth and reproductive timing in response to nutritional stress.