Involvement of cholecystokinin 2 receptor in food intake regulation: hyperphagia and increased fat deposition in cholecystokinin 2 receptor-deficient mice.
The role of cholecystokinin (CCK) as a satiety factor has been extensively documented. Although most work implies that CCK1 receptor mediates the control of food intake, a contributing role for CCK2 receptor (CCK2R) in the CCK-induced satiety cannot be totally excluded. The hypothesis that CCK2R invalidation disrupts regulatory pathways with impact on feeding behavior was examined in CCK2R(-/-) mice. CCK2R(-/-) mice developed obesity that was associated with hyperphagia. Obesity was related with increased fat deposition resulting from adipocyte hypertrophy. Expression of several adipokines was dysregulated consistently with obesity. Moreover, obesity was associated with disturbed glucose homeostasis as revealed by increased fasting glycemia and insulinemia, impaired glucose tolerance, and hepatic insulin resistance in CCK2R(-/-) mice. In vitro analysis of isolated adipocytes metabolism was consistent with increased storage but preserved insulin sensitivity. Suppression of feeding and concomitant increased expression of hypothalamic proopiomelanocortin after intracerebroventricular injection of gastrin into control mice demonstrates that hypothalamic CCK2 receptors mediate inhibition of food intake. Comparative analysis of hypothalamic mediator gene expression in fed knockout and control mice demonstrated overexpression of ghrelin receptors in CCK2R(-/-) mice, indicating up-regulation of orexigenic pathways. This effect was also observed after body weight normalization, indicating a causative role in the development of hyperphagia and obesity of CCK2R(-/-) mice. Our results give evidence that CCK2 receptor activity plays a contributing regulatory role in the control of food intake.
Clerc
Pascal
P
Institut National de la Santé et de la Recherche Médicale Unit 531, Institut Fédératif de Recherche 31, Université de Toulouse 3, 31432 Toulouse Cedex 4, France.
Coll Constans
Maria Gràcia
MG
Lulka
Hubert
H
Broussaud
Stéphanie
S
Guigné
Charlotte
C
Leung-Theung-Long
Stéphane
S
Perrin
Christophe
C
Knauf
Claude
C
Carpéné
Christian
C
Pénicaud
Luc
L
Seva
Catherine
C
Burcelin
Rémy
R
Valet
Philippe
P
Fourmy
Daniel
D
Dufresne
Marlène
M
D050154:Adiposity; D000818:Animals; D001069:Appetite Regulation / Q000235:genetics*; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001835:Body Weight; D004734:Energy Metabolism; D005951:Glucose Tolerance Test; D006963:Hyperphagia / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009043:Motor Activity; D009765:Obesity / Q000235:genetics*; D043887:Receptor, Cholecystokinin B / Q000235:genetics* / Q000502:physiology*
D001786:Blood Glucose; D043887:Receptor, Cholecystokinin B