We report the following novel findings: (1) Sort1 deficiency reduces body and WAT weight, adipocyte lipid droplet size, and increases BAT function in HF/HC-fed female Ldlr−/− mice, (2) Sort1 deficiency increases FGF21 and Adiponectin in HF/HC-fed female Ldlr−/− mice, (3) Sort1 deficiency decreases Npc1l1 mRNA levels and cholesterol absorption in female Ldlr−/− mice and human Caco-2 cells, and 4) Sort1 deficiency decreases Klf4 mRNA and LXR-mediated transcription in female Ldlr−/− mice and human cell lines. The gene discussed is FGF21; the disease is hydrops fetalis.