The brain-gut
peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous
peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop
non-insulin dependent diabetes mellitus (
NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young
as 2 days of age. OLETF
obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes
body weight, body fat and elevated
insulin and
glucose levels. Hypothalamic arcuate nucleus
peptide mRNA expression in OLETF rats is appropriate to their
obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (
DMH)
neuropeptide Y (NPY)
mRNA expression. Elevated
DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the
DMH and local CCK administration reduces food intake and decreases
DMH NPY
mRNA expression. We have proposed that the absence of
DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall
hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and
body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not
gain weight to the same degree as sedentary OLETF rats and do not develop
NIDDM. Exercise also prevents elevated levels of
DMH NPY
mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on
DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.