Glucocorticoids (GCs) are widely used in the treatment of acute inflammatory, allergic, immunologic, and malignant disorders. However, long-term GC therapy is associated with many metabolic side effects, including hepatic steatosis. The molecular basis of GC-dependent development of fatty liver is poorly understood. Wan, Shan, et al. show that treatment with dexamethasone (DEX), a synthetic analog of GCs, results in triglyceride accumulation in the livers of healthy mice, but not in cultured hepatocytes. They further show that DEX can upregulate the expression levels of the adipokine Periostin in white adipose tissue, which in turn contributes to liver steatosis and hyperglycemia.