Identification of an alternative ligand-binding pocket in peroxisome proliferator-activated receptor gamma and its correlated selective agonist for promoting beige adipocyte differentiation

The pharmacological activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is a convenient and promising strategy for promoting beige adipocyte biogenesis to combat obesity-related metabolic disorders. However, thiazolidinediones (TZDs), the full agonists of PPAR gamma exhibit severe side effects in animal models and in clinical settings. Therefore, the development of efficient and safe PPAR gamma modulators for the treatment of metabolic diseases is emerging. In this study, using comprehensive methods, we report a previously unidentified ligand-binding pocket (LBP) in PPAR gamma and link it to beige adipocyte differentiation. Further virtual screening of 4097 natural compounds based on this novel LBP revealed that saikosaponin A (NJT-2), a terpenoid compound, can bind to PPAR gamma to induce coactivator recruitment and effectively activate PPAR gamma-mediated transcription of the beige adipocyte program. In a mouse model, NJT-2 administration efficiently promoted beige adipocyte biogenesis and improved obesity-associated metabolic dysfunction, with significantly fewer adverse effects than those observed with TZD. Our results not only provide an advanced molecular insight into the structural ligand-binding details in PPAR gamma, but also develop a linked selective and safe agonist for obesity treatment. Identification of an alternative ligand-binding pocket in proliferator-activated receptor gamma (PPAR gamma), and screening out NJT-2, a natural compound derived from Bupleurum chinense DC, binds in this pocket, induces the coactivator recruitment, guides the PPAR gamma binding to the promotors of beige adipocyte-related genes, thus enhances white adipose tissue browning and improves the metabolic disorders without the similar adverse effects observed with thiazolidinediones. image