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Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine (S.B., K.A.S., T.H.M.), Baltimore, Maryland 21205; and Molecular Pharmacology Research Center, Department of Medicine, Tufts-New England Medical Center (A.S.K.), Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Dr. S. Bi, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 618, Baltimore, Maryland 21205. E-mail: sbi{at}jhmi.edu.
Although cholecystokinin A (CCK-A) receptors (CCK-AR) mediate the feeding inhibitory actions of CCK in both rats and mice, the absence of CCK-AR results in species-specific phenotypes. The lack of CCK-AR in Otsuka Long-Evans Tokushima fatty (OLETF) rats results in hyperphagia and obesity. We have suggested that demonstrated increases in meal size and elevated levels of dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) gene expression may contribute to this phenotype. In contrast to OLETF rats, CCK-AR–/– mice have normal total daily food intake and do not develop obesity. To assess the basis underlying the different phenotypes in rats and mice lacking CCK-AR, we characterized meal patterns in CCK-AR–/– mice and determined whether CCK-AR–/– mice exhibited an alteration in DMH NPY gene expression. We demonstrate that although CCK-AR–/– mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels. In fact, intact mice have no CCK-AR in the DMH. Furthermore, in intact rats, NPY and CCK-AR are colocalized in DMH neurons, and parenchymal injection of CCK into the DMH reduces food intake and down-regulates DMH NPY mRNA expression. These results suggest that although CCK-AR plays a role in the mediation of CCK actions in the control of meal size in both rats and mice, CCK-AR seems to contribute to modulating DMH NPY levels only in rats. The deficit in CCK’s action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats.
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