Although antipsychotics, such as olanzapine, are effective in the management of psychiatric conditions, some patients experience excessive antipsychotic-induced weight gain (AIWG). To illuminate pathways underlying AIWG, we compared baseline blood gene expression profiles in two cohorts of mice that were either prone (AIWG-P) or resistant (AIWG-R) to weight gain in response to olanzapine treatment for two weeks. We found that transcripts elevated in AIWG-P mice relative to AIWG-R are enriched for high-confidence transcriptional targets of numerous inflammatory and immunomodulatory signaling nodes. Moreover, these nodes are themselves enriched for genes whose disruption in mice is associated with reduced body fat mass and slow postnatal weight gain. In addition, we identified gene expression profiles in common between our mouse AIWG-P gene set and an existing human AIWG-P gene set whose regulation by immunomodulatory transcription factors is highly conserved between species. Finally, we identified striking convergence between mouse AIWG-P transcriptional regulatory networks and those associated with body weight and body mass index in humans. We propose that immunomodulatory transcriptional networks drive AIWG, and that these networks have broader conserved roles in whole body-metabolism.
© 2021. The Author(s).