RNA-sequencing Reveals Altered Gene Expression in the Ventromedial Hypothalamus Following Predator Odor Exposure

Abstract

Background Physical activity is the second largest contributor to our total daily energy expenditure (EE). Uncovering ways to increase EE during activity could yield new approaches to treat obesity. The ventromedial hypothalamus (VMH) regulates body weight by modulating muscle metabolism and sympathetic nervous system (SNS) activity. The VMH also mediates behavioral responses to predator threat. While the VMH is a potential mediator of metabolic responses to predator threat, the mechanisms are unknown. Methods and Results Exposing rats to predator odor (PO) exposure causes a rapid increase in skeletal muscle thermogenesis that peaks between 20-30 min and dissipates to baseline by 4 hr. This thermogenic response is associated with weight loss and increased EE even when controlling for physical activity. To probe potential targets of PO-induced metabolic responses in the VMH, we first performed qPCR for genes known to be involved in brain regulation of muscle metabolism using VMH samples from rats exposed to PO or control odor for either 30 min or 4 hr. Next, to uncover novel, relevant genes, we performed RNA-sequencing on VMH samples of rats exposed to either PO or control odor for 20 min. qPCR results show that after 4 hr of PO exposure, Bdnf and Sirt1 expression were increased. RNA-sequencing analyses further identified 245 differentially expressed genes (DEGs) that showed at least 1.5-fold change in expression due to PO exposure. Functional and Gene Ontology annotation showed that pathways related to immune response, oxidative stress, and synaptic plasticity were overrepresented among these DEGs. Discussion Taken together, these findings suggest that acute PO exposure induces both rapid and delayed changes in VMH gene expression that likely have downstream metabolic consequences.