Abstract
Neuropeptide Y (NPY) and galanin have both been implicated in the regulation of body weight, yet mice bearing deletions of either of these molecules have unremarkable metabolic phenotypes. To investigate whether galanin and NPY might compensate for one another, we produced mutants lacking both neuropeptides (GAL−/−/NPY−/−). We found that male GAL−/−/NPY−/− mice ate significantly more and were much heavier (30%) than wild-type (WT) controls. GAL−/−/NPY−/− mice responded to a high-fat diet by gaining more weight than WT mice gain, and they were unable to regulate their weight normally after a change in diet. GAL−/−/NPY−/− mice had elevated levels of leptin, insulin, and glucose, and they lost more weight than WT mice during chronic leptin treatment. Galanin mRNA was increased in the hypothalamus of NPY−/− mice, providing evidence of compensatory regulation in single mutants. The disruption of energy balance observed in GAL−/−/NPY−/− double knockouts is not found in the phenotype of single knockouts of either molecule. The unexpected obesity phenotype may result from the dysregulation of the leptin and insulin systems that normally keep body weight within the homeostatic range.
This work was supported by grants from the USPHS/NIH (R01 HD27142, R01 DK61517, AG05136, and the Specialized Cooperative Centers Program for Reproduction Research/U5412629) and the NSF (IBN-9720143/0110686).
We thank Tom Teal and Jennifer Holloman for their technical assistance, Stephanie Krasnow, Matt Cunningham, and Greg Fraley for comments on the manuscript, and Richard Palmiter for providing NPY−/− mice and advice on experimental design. We thank Brigitte Mann at Northwestern University, Evanston, Ill., Gloria Tannenbaum at McGill University, Montreal, Quebec, Canada, and William Bremner and the Diabetes Research Center at the University of Washington for performing hormone assays.