Hepatic Stearoyl-CoA desaturase deficiency-mediated induction of the insulin-like growth factor-binding protein 1 requires FGF21.

Stearoyl-CoA desaturase-1 (SCD1) catalyzes the rate-limiting step in the biosynthesis of monounsaturated acids and is a key regulator of systemic glucose metabolism. Hepatic deletion of Scd1protects mice from high-carbohydrate diet (HCD)-induced hepatic steatosis and adiposity in part by suppressing hepatic lipogenesis, increasing adipose tissue lipogenesis, and increasing systemic glucose uptake. However, the mechanism leading to these phenotypes is unclear. Given that high carbohydrate diets can lead to chronic metabolic diseases such as obesity, diabetes, and hepatic steatosis, it is critical to understand how SCD1 deficiency alters metabolic pathways to produce metabolically beneficial phenotypes. Here we show that hepatic SCD1 deficiency enhances tissue glucose uptake and is correlated with dramatic increases in the expression and plasma levels of the fibroblast growth factor 21 (FGF21), and Insulin growth factor binding protein-1 (IGFBP1), both liver derived insulin-sensitizing hormones that are known to regulate whole body lipid and glucose homeostasis. Feeding both male and female LKO mice with triolein, but not tristearin, supplemented HCD reduced Fgf21 and Igfbp1 expression and restored plasma glucose levels. Inhibition of SCD activity in primary hepatocytes induced the expression of Fgf21 and Igfbp1 which was repressed by treatment with oleate but not stearate. Moreover, we show that the hepatic stearoyl-CoA desaturase deficiency-mediated induction of the Igfbp1 is through the oleate-FGF21 axis.