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Factors Contributing to Obesity in Bombesin Receptor Subtype-3-Deficient Mice

Department of Psychiatry and Behavioral Sciences (E.E.L., N.L.H., R.R.B., S.B., T.H.M.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; and National Institute of Neurological Disorders and Stroke (L.L.H., J.F.B.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ellen E. Ladenheim, Ph.D., Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Ross 618, 720 Rutland Avenue, Baltimore, Maryland 21205. E-mail: laden{at}jhmi.edu.

Mice with a targeted disruption of bombesin receptor subtype-3 (BRS-3 KO) develop hyperphagia, obesity, hypertension, and impaired glucose metabolism. However, the factors contributing to their phenotype have not been clearly established. To determine whether their obesity is a result of increased food intake or a defect in energy regulation, we matched the caloric intake of BRS-3 KO mice to wild-type (WT) ad libitum (ad lib)-fed controls over 21 wk. Although BRS-3 KO ad lib-fed mice were 29% heavier, the body weights of BRS-3 KO pair-fed mice did not differ from WT ad lib-fed mice. Pair-feeding BRS-3 KO mice normalized plasma insulin but failed to completely reverse increased adiposity and leptin levels. Hyperphagia in ad lib-fed KO mice was due to an increase in meal size without a compensatory decrease in meal frequency resulting in an increase in total daily food intake. An examination of neuropeptide Y, proopiomelanocortin, and agouti-related peptide gene expression in the arcuate nucleus revealed that BRS-3 KO mice have some deficits in their response to energy regulatory signals. An evaluation of the satiety effects of cholecystokinin, bombesin, and gastrin-releasing peptide found no differences in feeding suppression by these peptides. We conclude that hyperphagia is a major factor leading to increased body weight and hyperinsulinemia in BRS-3 KO mice. However, our finding that pair-feeding did not completely normalize fat distribution and plasma leptin levels suggests there is also a metabolic dysregulation that may contribute to, or sustain, their obese phenotype.