Tricyclic antipsychotics promote adipogenic gene expression to potentiate preadipocyte differentiation in vitro

Antipsychotic-induced weight gain is a well-established but poorly understood clinical phenomenon. New mechanistic insights into how antipsychotics modulate adipose physiology are sorely needed, in hopes of either devising a therapeutic intervention to ameliorate weight gain or contributing to improved design of future agents. In this study, we have hypothesized that the weight gain-associated tricyclic antipsychotics clozapine and chlorpromazine directly impact adipose tissue by potentiating adipogenic differentiation of preadipocytes. Utilizing a well-established in vitro model system (3T3-L1 preadipocyte cell line), we demonstrate that, when applied specifically during induction of adipogenic differentiation, both clozapine and chlorpromazine significantly potentiate in vitro adipogenesis, observed as morphological changes and increased intracellular lipid accumulation. These persistent effects, observed at endpoints well after the end of antipsychotic exposure, are accompanied by increased transcript- and protein-level expression of the mature adipocyte marker perilipin-1, as indicated by RT-qPCR and Western blotting, but not by further upregulation of pro-adipogenic transcription factors versus positive controls. Our findings point to a possible physiological mechanism of antipsychotic-induced hyperplasia, with potentiated expression of mature adipocyte markers enhancing the differentiation and maturation of preadipocytes.