Leptin, troglitazone, and high fat feeding profoundly influence the lipid content of various tissues. To determine if they affect the expression of stearoyl CoA desaturase (SCD)-1 and -2, their mRNA was measured in livers of normal, hyperleptinemic, troglitazone-treated, and fat-fed rats. Hyperleptinemia, which reduces tissue TG by downregulating lipogenic enzymes and upregulating fatty acid oxidation, lowered SCD-1 96% below controls and reduced SCD-2 slightly. By contrast, hepatic SCD-1 mRNA of leptin-resistant fa/fa rats was five times wild-type controls, but SCD-2 mRNA was 66% lower. High fat feeding lowered SCD-1 by 80%, possibly by inducing hyperleptinemia. Troglitazone treatment, which reduces nonadipose tissue TG of fa/fa rats without downregulating lipogenic enzymes, raised SCD-2 13-fold but lowered SCD-1 by 25%. The findings suggest that leptin controls SCD-1 expression and that troglitazone's antilipotoxic action may involve SCD-2 upregulation.