Although overall mortality rate of prostate cancer (PCa) declines in recent years, castration-resistant prostate cancer (CRPC) remains incurable. Clinical evidence indicates that CRPC recurred from hormonal therapy exhibits neuroendocrine differentiated (NED) phenotypes, which could contribute to therapeutic resistance and poor survival. Understanding the onset of NED could lead us to develop new therapeutic strategies for CRPC. Although PCa is known as a lipid-enriched tumor, its role in CRPC development is not fully understood. In this study, we demonstrated that IL-6 or androgen deprivation therapy (ADT)-induced lipid accumulation is associated with NED phenotypes. IL-6 or ADT can induce NED in PCa cells via peroxisome proliferator-activated receptor γ (PPARγ, a major lipogenic transcription factor) and adipocyte differentiation-related protein (ADRP, a major component of adiposome). In addition, ADRP protein can be detected in exosomes released from these cells and these exosomes are capable of inducing NED of PCa cells in a paracrine fashion. Understanding the role of PPARγ/ADRP in NED could provide new target(s) for CRPC therapy.