Chronic mifepristone administration induces obese sarcopenia, hepatic steatosis and insulin resistance in androgen-deprived male mice.

Both glucocorticoids receptor (GR) and peroxisome proliferator-activated receptor-γ (PPARγ) are critical metabolic checkpoints in endocrine control of whole-body energy homeostasis. Mifepristone, which serves as a non-selective antagonist for GR, androgen receptor (AR) and progesterone receptor (PR), but an agonist for PPARγ, has been clinically approved for the treatment of Cushing's syndrome and as an anti-contraceptive agent. However, the side effects of its chronic administration on metabolism via GR and/or PPARγ are largely unknown. Adult male mice were underwent bilateral orchiectomy to remove metabolic interference derived from sex steroid hormones, and then intraperitoneally administered of mifepristone at a dose of 30 mg/kg every other day for consecutive 28 days. Biochemical, histological and RNA-seq analyses were performed on critical metabolic organs. Resultantly, compared to the vehicle-treated controls, chronic mifepristone administration induced obese sarcopenia, hepatic steatosis and insulin resistance, accelerated thymus aging, but prevented bone loss in male mice. Mechanically, transcriptomic profiling analysis indicates that chronic mifepristone administration drives obesity, hepatic steatosis and insulin resistance via activating PPARγ signaling, but induces sarcopenia and prevents bone loss by antagonizing GR signaling. Further in vitro cell culture studies confirmed that mifepristone addition promotes preadipocyte differentiation and hepatocellular lipid accumulation via stimulating PPARγ-dependent de novo lipogenesis. Collectively, these results reveal multifaceted tissue-specific metabolic disorders of chronic mifepristone exposure, providing critical implications for understanding the clinical risks of chronic mifepristone use.