Factors contributing to obesity in bombesin receptor subtype-3-deficient mice.
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.
Ladenheim
Ellen E
EE
Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, Maryland 21205, USA. laden@jhmi.edu
Hamilton
Nahketah L
NL
Behles
Robert R
RR
Bi
Sheng
S
Hampton
Lori L
LL
Battey
James F
JF
Moran
Timothy H
TH
D050154:Adiposity / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001839:Bombesin / Q000494:pharmacology; D002766:Cholecystokinin / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006946:Hyperinsulinism / Q000209:etiology; D006963:Hyperphagia / Q000150:complications* / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology* / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000378:metabolism*; D012527:Satiation / Q000502:physiology; D015430:Weight Gain
D007328:Insulin; D020738:Leptin; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; D019886:Gastrin-Releasing Peptide; D002766:Cholecystokinin; D005947:Glucose; D001839:Bombesin