Neuroendocrine regulation of energy metabolism: role of pituitary adenylate cyclase-activating polypeptide (PACAP) in the thermoregulatory cascade

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Energy balance is achieved by matching the amount of energy consumed, with the amount of energy expended. In the past 25 years, knowledge of neuronal pathways regulating energy balance has advanced substantially, driven by a desire to understand the complex physiology regulating metabolism. Neuronal pathways utilize chemical messengers called hormones (or neuropeptides) that communicate within the brain, and between the brain and the peripheral organs, to regulate how much energy is consumed and expended. The specific pathways that control appetite are well characterized; however, the pathways involved in regulating energy expenditure (basal metabolic rate, thermogenesis and physical activity) are still being realized. Some well-known hormones that influence energy balance include thyroid hormones, leptin and cortisol. There are many other hormones, however, whose actions or interactions in energy balance are not yet clear - basic knowledge of which is critical to a comprehensive understanding of energy balance in animal physiology. In my lab, we study a hormone called pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is an ancient neuropeptide found in all vertebrates. It plays a critical role in coordinating the body's response to stress, activating or inhibiting pathways to restore balance when physiological processes have been tipped out-of-balance by stressors such as danger, starvation, injury/infection or cold. My research has identified a role for PACAP in restoring energy balance in response to cold stress by regulating thermogenesis. Thermogenesis is an energy burning pathway that is turned on in response to cold exposure and overfeeding. Shivering thermogenesis occurs in skeletal muscle in response to acute cold. In long-term cold exposure, a process called adaptive thermogenesis is turned on in a specialized type of adipose tissue, brown fat. In addition to human infants and rodents, brown fat is present in all mammals, including adult humans, and plays a significant role in maintaining energy balance throughout life. This proposal aims to characterize how PACAP and its receptors regulate thermogenesis through actions in the brain, in the "fight or flight" pathways of the sympathetic nervous system (SNS) and in brown fat in response to cold stress, exploring how PACAP acts at each level of the thermoregulatory cascade (brain-SNS-brown fat) to re-balance energy metabolism in times of thermogenic stress. Knowledge generated will elucidate how PACAP initiates and modulates the physiological response to cold stress, illuminating unknown aspects thermogenic and endocrine physiology. These foundational building blocks of physiological knowledge can be applied to diverse areas of scientific study including biological studies related to changes in body temperature such as hibernation and fever, therapeutic targeting of hormone receptors and human/animal pathophysiology of energy metabolism.