Targeted disruption of the pituitary adenylate cyclase-activating polypeptide gene results in early postnatal death associated with dysfunction of lipid and carbohydrate metabolism

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a hormone bel onging to the glucagon superfamily of hormones. These hormones are known to play important roles in metabolism and growth. PACAP is a neuropeptide tha t causes accumulation of cAMP in a number of tissues and affects the secret ion of other hormones, vasodilation, neural and immune functions, as well a s the cell cycle. To determine whether PACAP is essential for survival and to evaluate its function(s), we have generated mice lacking the PACAP gene via homologous recombination. We found that most PACAP null mice died in th e second postnatal week in a wasted state with microvesicular fat accumulat ion in liver, skeletal muscle, and heart. Gas chromatography-mass spectrome try showed that fatty acid beta -oxidation in liver mitochondria of PACAP(- /-) mice was not blocked based on the distribution of 3-hydroxy-fatty acids (C6-16) in the plasma. Instead, increased metabolic flux through the beta -oxidation pathway was suggested by the presence of ketosis. Also, serum tr iglycerides and cholesterol were significantly higher (2- to 3-fold) in PAC AP null mice than littermates. In the fed state, both serum insulin and blo od glucose were normal in 5-d-old null mice compared with their littermates . In contrast, fasted PACAP null pups had a significant increase in insulin , but a decrease in blood glucose compared with littermates. Glycogen in th e liver was reduced. These results suggest PACAP is a critical hormonal reg ulator of lipid and carbohydrate metabolism.