Abstract Glucocorticoids (GCs) are well known to induce fat distribution, which is consistent with the central adiposity phenotype seen in Cushing’s syndrome. GCs have been proposed to be both adipogenic and lipolytic in action within adipose tissues. Different adipogenic and lipolytic effects between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are likely to play a role in GCs induced fat differential distribution. Wnt/β-catenin signaling pathway is one of the most important regulators in adipogenesis. Adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) are the major lipases contributing to lipolysis. In the present study, we measured fat depot masses and the expression of Wnt/β-catenin signaling pathway and lipolytic enzymes of female Sprague-Dawley rats treated with or without methylprednisolone. We assessed the roles of Wnt/β-catenin signaling pathway and lipolytic enzymes in fat differential distribution between SAT and VAT. Our data suggested that methylprednisolone could inhibit Wnt/β-catenin signaling pathway in SAT and VAT, increase the expression of ATGL and HSL in SAT, and decrease the expression of ATGL and HSL in VAT. The differential expression of lipolysis enzymes induced by methylprednisolone between SAT and VAT might play a crucial role in fat distribution. Those findings would offer novel insights into the mechanisms of GCs induced fat distribution.