Yolk sac-mediated feto-maternal cholesterol transport is regulated by KLB-FGF15 axis contributing to fetal growth

Low birth weight causes adverse metabolic outcomes in later life. However, the molecular mechanisms of fetal growth restriction (FGR) remain elucidated. Here we show that feto-maternal cholesterol transport through the yolk sac is regulated by beta Klotho (KLB)-FGF15 axis and its defects provoke FGR in mice. Klb knockout (Klb-/-) embryos were morphologically normal but smaller than their control littermates in the post-implantation stages and kept lower body weight after birth. KLB deletion led to lipid shortage in embryos, while lipid accumulation in yolk sacs. Tracer experiments revealed that cholesterol supplies from maternal blood were decreased in Klb embryos. These phenotypes were consistent in Fgf15-/- embryos and yolk sacs, demonstrating that KLB regulates fetal growth and cholesterol homeostasis by mediating the FGF15 signal. Our results suggest that the yolk sac dysfunction causes early-onset FGR and determines the body size in postnatal life.