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Leptin Deficiency Induced by Fasting Impairs the Satiety Response to Cholecystokinin¹

Program in Nutritional Sciences (J.E.M.) and Department of Medicine (D.K.S., M.W.S.), University of Washington, Seattle, Washington 98195; and Department of Nutrition (P.J.H.), University of California at Davis, Davis, California 95616

Address all correspondence and requests for reprints to: Michael W. Schwartz, M.D., Division of Metabolism, Endocrinology and Nutrition, University of Washington and Harborview Medical Center (359757), 325 Ninth Avenue, Seattle, Washington 98104-2499. E-mail: mschwart{at}u.washington.edu

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.

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