The equilibrium between energy consumption and energy production defines the metabolic rate of an organism. This homeostatic balance is tightly regulated by a variety of sophisticated processes that occur within and between cells and tissues. These processes also allow animals to tolerate some deviation from baseline by recruiting adaptive mechanisms to bring cells and organisms back to homeostasis. Temporary changes in the organism’s environment, such as alterations in ambient temperature, oxygen levels and infections are examples of conditions where animals must have a healthful adaptive metabolic response, allowing them to sustain the duration of the stress. However, in conditions of chronic disease or long-term stress, these adaptive mechanisms can no longer be protective and may even contribute to the damage incurred by the animal. Therefore, metabolism can either be healthful and adaptive to stressors, or stressors can induce pathogenic metabolic changes in an organism. In this body of work, I explore this bidirectional relationship between external stresses and organismal metabolism. In chapter 2, I investigate the contribution of hypermetabolism (energy production > energy consumption) in a mouse model of the disease amyotrophic lateral sclerosis (ALS). While hypermetabolism is a feature of ALS, it is not known if it contributes to disease pathogenesis. In a mouse model of ALS, I genetically induce hypometabolism to determine if this change alters disease progression. In chapter 3, I study the role of neuropeptides in regulating hypometabolic tolerance to extreme oxygen deprivation. Here, I employ C. elegans, a genetically tractable soil-dwelling nematode, as a model. Worms can tolerate long durations of anoxia by lowering their metabolic rate, and loss of neuropeptide signaling can further increase its ability to tolerate this stress. I investigate various aspects of neuropeptide regulation of this phenotype. Together, these projects demonstrate the role of metabolism in health, disease and stress, and suggest that inter-cellular and inter-tissue communication is a critical aspect of metabolic homeostasis.