These findings suggest that increases in plasma FGF21 levels and expression of hepatic FGF21 precede hyperinsulinemia, hyperglycemia, and body weight gain in mice fed a high-fat diet, and that increased expression of hepatic htr2a and Sdf2l1 is associated with insulin resistance in mice fed a high-fat diet. This evidence concerns the gene FGF21 and hyperinsulinism.