Background

Energy expended during activity is the second largest contributor to our total daily energy expenditure. Uncovering ways to increase energy expenditure during activity could yield new treatments for obesity. Steroidogenic Factor-1 (SF1) cells in the ventromedial hypothalamus (VMH) regulate body weight by modulating peripheral metabolism and sympathetic nervous system (SNS) activity. Interestingly, VMH SF1 cells are also critical mediators of behavioral responses to predator threat. Previously, we’ve shown that predator odor (PO) exposure to rats causes a rapid and robust increase in skeletal muscle thermogenesis that is associated with increased physical activity, energy expenditure, and weight loss. VMH SF1 cells are a likely mediator of these PO-induced metabolic responses, but the causal links remain unexplored. We utilized the SF1-specific chemogenetic tool we created to explore the dual-processing role of VMH SF1 cells.

Methods

Via stereotaxic surgery, Sprague Dawley rats received our AAV8-SF1-HM4D(Gi)-mCherry. Temperature transponders were implanted in the gastroc muscles. One hour after intraperitoneal injections of the DREADD activator, clozapine-N-oxide, or saline vehicle, rats were exposed to a small piece of towel covered in ferret odor while treadmill walking to control for physical activity. Temperature was recorded at multiple time points for 35 minutes.

Results

A significant 3-way interaction suggests that DREADD inhibition of VMH SF-1 cells significantly suppressed muscle thermogenesis following predator odor exposure even when controlling for physical activity. This implicates VMH SF1 cell activity in the ability of PO to enhance skeletal muscle activity thermogenesis.

Conclusions

Our data support the role of VMH SF1 cells in regulating the skeletal muscle thermogenic response to predator threat. This reveals a novel pathway that has potential to be exploited for treating obesity.