| A recently discovered peptide hormone, pituitary adenylate cyclase-activating polypeptide (PACAP) regulates several endocrine systems affecting essential physiological processes such as metabolism, growth, reproduction, and the stress response. PACAP acts as a hypophysiotropic factor, is a potent secretogogue of insulin, regulates production and release of catecholamines from the adrenal medulla and acts as a neuromodulator in the sympathetic and parasympathetic nervous system. The primary structure of PACAP has been highly conserved during the evolution of chordates suggesting it plays an important physiological role. The objective of my thesis was to identify PACAP's primary physiological function and to determine if it is essential for survival by generating a mouse line deficient in PACAP through targeted disruption of the PACAP gene locus.; Postnatal PACAP expression was examined to determine sites of peripheral PACAP production. In addition, several splice variants of the PACAP gene with alternate 5′untranslated regions were identified suggesting a complex system for regulating expression of the mouse PACAP gene.; A targeting vector that allows tissue specific or developmental stage specific knockout of the PACAP gene was constructed in the event that PACAP gene deletion resulted in embryonic lethality.; I conclude that PACAP null mice are unable to regulate lipid release from white adipose tissue stores, resulting in a flood of lipids to non-adipose tissues.; We have determined that the inability of the PACAP null pups to thermoregulate normally when exposed to a lower environmental temperature may be associated with decreased norepinephrine levels to the brown adipose tissue. PACAP may be important for the production and release of catecholamines in the adrenal gland or within the sympathetic nervous system in times of prolonged stress.; As one of two main stress response systems, the sympathetic nervous system elicits a vital coping mechanism in times of stress and PACAP's ability to regulate this system may explain why the primary structure of PACAP has remained so highly conserved. PACAP is a wide acting hormone and therefore the metabolic problems seen in the PACAP null mice may result from altered regulation of several endocrine systems at once. Targeted disruption of the PACAP gene in mouse has revealed a role for PACAP in the regulation of lipid metabolism and in the sympathetic control of thermoregulation. (Abstract shortened by UMI.)... |
