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Obesity and overweight rates continue to increase in the U.S. and throughout the world, with nearly 70% of Americans affected. Identifying ways to increase energy expenditure is critical for treating the energy imbalance that promotes obesity. Skeletal muscle is a promising target for enhancing energy expenditure because it accounts for 40% of total human body mass and has a high capacity for oxygen uptake, glucose disposal, and fatty acid oxidation. We have previously shown that exposure to predator odor (PO) induces skeletal muscle thermogenesis and results in increased physical activity, energy expenditure, and weight loss in rodents. This effect is rapid and robust, with a 1-2°C within the first 2-5 minutes of exposure and remaining for 2 hours or longer. To explore the peripheral nervous pathway mediating this effect, I performed surgical denervation of the lumbar sympathetic nerve, which innervates the gastrocnemius muscle, and administered a peripherally acting beta-1 and beta-2 adrenergic antagonist. I found that PO-induced thermogenesis is likely mediated through central activation of the sympathetic nervous system and subsequent activation of muscle beta-2 adrenergic receptors by sympathetic drive. I also explored the influence of brown adipose tissue (BAT) on muscle thermogenesis by surgically excising the interscapular BAT depot and found that PO-induced muscle thermogenesis is not detectably influenced by interscapular BAT. I also determined that PO-induced muscle thermogenesis is not detectably altered by estrous cycling in female rats by measuring thermogenesis during proestrus and diestrus phases of the cycle, when circulating estradiol is highest and lowest, respectively. Taken together, these findings increase our understanding of the neural pathways mediating PO-induced muscle thermogenesis, specifically supporting the primary role of the sympathetic nervous system. By determining the mechanisms mediating this process in the brain and at the level of the myocyte, we can continue to advance our understanding of muscle thermogenesis and its potential as a target for enhancing energy expenditure as a therapy for obesity.