Chronic overconsumption of high-carbohydrate diet leads to steatosis and its associated metabolic disorder, and eventually non-alcoholic fatty liver disease. Carbohydrate responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein we report reduced reticulon-4 (Nogo) expression protected mice against high-carbohydrate diet-induced metabolic disorders by regulating ChREBP and insulin activity.Nogo deficient (Nogo-/-) and littermate control (WT) mice were used to determine high-glucose or fructose diet (HGD/HFrD)-induced hepatic metabolic disorders and the underlying mechanisms. The effects of Nogo si-RNA on HFrD-induced metabolic disorders in C57BL/6J mice were investigated.HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce expression of ChREBP and lipogenic molecules, activated AMPKα, PPARα and FGF21, and reduced ER stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation.Our study identified Nogo as an important mediator for insulin sensitivity and ChREBP activity. Reduction of Nogo expression can be a potential strategy for treatment of high-carbohydrate diet-induced metabolic complications.