REGULATION OF LIPID OXIDATION DURING THERMOGENESIS AT HIGH ALTITUDE IN DEER MICE

Abstract

Organisms are constantly balancing energy demand with an adequate supply of oxygen and substrates to sustain metabolic activity. Thermogenesis is an important metabolic process by which endotherms predominately burn lipids to regulate and maintain their body temperatures by balancing heat loss with heat production. Due to their high rates of heat loss, small winter-active mammals, like the North American deer mouse (Peromyscus maniculatus), are constantly challenged with thermogenesis. Deer mice are also native to high-altitude environments, conditions that further complicate the process of thermogenesis due to the inherent reduced oxygen availability. How metabolic substrates are used for fuelling and sustaining thermogenesis at high altitude remains unclear. The goal of my thesis was to examine how lipid metabolism has evolved to sustain heat production in animals living in high-altitude environments. This was achieved by using deer mice native to high- and low-altitudes acclimated to either standard lab conditions or simulated high altitude (cold hypoxia). I demonstrate that during thermogenic capacity (cold-induced V̇O2max), high-altitude deer mice have higher thermogenic lipid oxidation rates compared to their lowland counterparts, which is further increased after cold hypoxia acclimation. Interestingly, these high rates of lipid oxidation were associated with higher circulatory delivery rates of fatty acids and triglycerides to thermo-effector tissues. Specifically, I show that after a bout of cold-induced V̇O2max, fatty acid uptake occurs primarily in the skeletal muscle in control acclimated high-altitude deer mice, and then shifts to brown adipose tissue following acclimation to high altitude conditions. These findings clearly show that in high-altitude deer mice, maximal thermogenesis is reliant on elevated delivery of circulatory lipids to muscle and brown adipose tissue. This research further sheds light on the mechanistic underpinnings responsible for enhanced thermogenic capacity of high-altitude deer mice and capacity for the highest lipid oxidation rates observed in any mammal.