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.