Disruption of the pituitary adenylate cyclase-activating polypeptide (PACAP) gene in mice has demonstrated a role for this highly conserved neuropeptide in the regulation of me- tabolism and temperature control. Localization of PACAP neurons within hypothalamic nuclei that regulate appetite suggest PACAP may affect feeding and thus energy balance. We used PACAP-null mice to address this question, examining both food intake and energy expenditure. PACAP-null mice were leaner than wild-type littermates due to decreased ad- iposity and displayed increased insulin sensitivity. The lean phenotype in the PACAP-null mice was completely eliminated if animals were fed a high-fat diet or housed near thermo- neutrality (28 C). Further metabolic analyses of PACAP-null mice housed at 21 C indicated that the reduced body weight could not be explained by decreased food intake, increased metabolic rate, or increased locomotor activity. The thyroid hormone axis of PACAP-null mice was affected, because mRNA levels of hypothalamic TRH and brown adipose tissue type 2 deiodinase were reduced in PACAP-null mice housed at room temperature, and brain deiodinase activity was lower in PACAP-null mice after an acute cold challenge compared with wild-type controls. These results demonstrate that PACAP is not required for the regulation of food intake yet is necessary to maintain normal energy homeostasis, likely playing a role in central cold-sensing mechanisms.

Feeding and Metabolism in Mice Lacking Pituitary Adenylate Cyclase-Activating Polypeptide.

Bruce A. Adams, Sarah L. Gray, Emma R. Isaac, Antonio C. Bianco, Antonio J. Vidal-Puig, and Nancy M. Sherwood. Molecular Endocrinology. May 8, 2008. doi: 10.1210/en.2007-0515

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