Leptin Deficiency Induced by Fasting Impairs the Satiety Response to Cholecystokinin**This work was supported by grants from the NIH (DK-12829, DK-52989, and NS-32272) and by the Royalty Research Fund, the Diabetes Endocrinology Research Center, and the Clinical Nutrition Research Unit of the University of Washington.

Abstract

Abstract Leptin administration potentiates the satiety response to signals such as cholecystokinin (CCK), that are released from the gut during a meal. To investigate the physiological relevance of this observation, we hypothesized that leptin deficiency, induced by fasting, attenuates the satiety response to CCK. To test this hypothesis, 48-h-fasted or fed rats were injected with ip saline or CCK. Fasting blunted the satiety response to 3.0 μg/kg CCK, such that 30-min food intake was suppressed by 65.1% (relative to saline-treated controls) in fasted rats vs. 85.9% in the fed state (P< 0.05). In a subsequent experiment, rats were divided into three groups: 1) vehicle/fed; 2) vehicle/fasted; and 3) leptin-replaced/fasted; and each group received 3.0 μg/kg ip CCK. As expected, the satiety response to CCK was attenuated by fasting in vehicle-treated rats (30-min food intake: vehicle/fed, 0.3 ± 0.1 g; vehicle/fasted, 1.7 ± 0.4 g; P < 0.01), and this effect was prevented by leptin replacement (0.7 ± 0.2 g, P < 0.05 vs. vehicle/fasted; P = not significant vs. vehicle/fed). To investigate whether elevated neuropeptide Y (NPY) signaling plays a role in the effect of leptin deficiency to impair the response to CCK, we measured the response to 3.0 μg/kg ip CCK after treatment with 7.5 μg intracerebroventricular NPY. We found that both CCK-induced satiety and its ability to increase c-Fos-like-immunoreactivity in key brainstem-feeding centers were attenuated by NPY pretreatment. We conclude that an attenuated response to meal-related satiety signals is triggered by leptin deficiency and may contribute to increased food intake.