Conserved immunomodulatory transcriptional networks underlie antipsychotic-induced weight gain

Abstract

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.

Antipsychotic-induced weight gain and metabolic effects show diurnal dependence and are reversible with time restricted feeding

“…Our recent study identified that inflammation potentiates AP-induced hyperphagia and weight gain 33 . Since inflammation is regulated in part by the circadian clock 34 , we evaluated whether the timing of AP dosing affects inflammation in metabolically active tissues (hypothalamus, liver and gWAT).…”

“…Vehicle control pellets were then given to unfasted mice for an additional 3 consecutive days to overcome any novelty-associated behavior changes in feeding and locomotion. After training, mice consumed the pellet in less than ~15 min 33 allowing for precisely timed AP dosing. Dosing time was ~2 h after lights on between 8:00–8.30AM, (Zeitgeber time (ZT) 2) for the ‘AM’ group and between 5:30–6:00PM, ZT 11 for the ‘PM’ group.…”

Nuclear Receptor 5A2 Regulation of Agrp underlies Olanzapine-induced Hyperphagia

“…1B ) compared to vehicle treatment. While in general AP-drugs drive hyperphagia and weight gain, there is significant variation in the magnitude of these effects 79 . In our recent study, 29 we measured antipsychotic-induced weight gain (AIWG) in mice and stratified into subgroups that were highly prone to weight gain (gained 6.3g body weight) and weight gain resistant (gained 1.3g body weight) 29 .…”

Adverse effects of antipsychotic drugs on metabolism depend on drug dosing and feeding times

“…Our recent study identified that inflammation potentiates AP-induced hyperphagia and weight gain (20). Since inflammation is regulated in part by the circadian clock (21), we evaluated whether the timing of AP dosing affects inflammation in metabolically active tissues (hypothalamus, liver and gWAT).…”

“…Placebo control pellets were then given to unfasted mice for an additional 3 consecutive days to overcome any novelty-associated behavior changes in feeding and locomotion. After training, mice consumed the pellet in less than ∼15 mins (20) allowing for precisely timed AP dosing. Dosing time was approximately 2 h after lights on between 8:00-8.30AM, (Zeitgeber time (ZT) 2) for the ‘AM’ group and between 5:30-6:00PM, ZT 11 for the ‘PM’ group.…”