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

Department of Biology (B.A.A., E.R.I., N.M.S.), University of Victoria, Victoria, British Columbia, Canada V8W 3N5; Diabetes Center (B.A.A.), University of California San Francisco, San Francisco, California, 94143; Department of Clinical Biochemistry (S.L.G., A.J.V.-P.), University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom; and Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital (A.C.B.), Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Nancy M. Sherwood, Department of Biology, University of Victoria, PO Box 3020 Stn CSC, Victoria, British Columbia, Canada V8W 3N5. E-mail: nsherwoo{at}uvic.ca.

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 metabolism 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 adiposity 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 thermoneutrality (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.