Metabolism describes the sum of biochemical reactions that take place within a living organism which provide energy for vital processes; this can be studied at the whole-body, organ specific, or cellular level. Energy availability, which is determined by the difference between energy intake and exercise energy expenditure, is affected by selected environmental and energetic stresses (e.g., high-altitude, exercise, diet/nutrition). Systemic energy deficits have implications for the regulation of organ-specific metabolism. This thesis provides novel insights for integrative brain, skeletal muscle, and systemic substrate oxidation and relative fuel utilization in the context of environmental and energetic stress (e.g., high-altitude, exercise, nutritional caloric deficits). Experiments included: metabolism in the brain in response to CO2; the brain’s inflammatory response to maximal exercise following 6-8 days of acclimatization at 3,800 m; and a diet intervention in females involving 14-days of effectively 50% caloric restriction while maintaining 8 hours of endurance training per week.