Leptin amplifies the feeding inhibition and neural activation arising from a gastric nutrient preload
Introduction
Leptin, the protein product of the ob gene, plays an important role in energy balance. Leptin is secreted from white adipose tissues, and its levels in circulation are correlated with the overall fat mass [12]. The absence of leptin, as in the ob/ob mouse [30], or the absence of functional leptin receptors, as in the db/db mouse or Zucker rat [4], results in hyperphagia and obesity. Exogenous administration of leptin normalizes food intake and body weight in the ob/ob mouse [3]. As well, leptin reduces food intake in normal animals [3]. The site of action of leptin in feeding is within the hypothalamus, and actions of NPY and central melanocortins in the mediation of these effects have been documented [21], [22], [23].
Leptin reduces food intake by specifically affecting meal size. Administration of a form of leptin modified to increase its duration of action results in decreases in food intake and body weight in both male and female rats [5], [9], [11]. The reduction in food intake is completely accounted for by a decrease in meal size. No change in meal number is observed during the leptin administration period.
Actions of leptin on meal size have led to the view that leptin's effects on food intake are due to its ability to modify the efficacy of within-meal satiety signals. Consistent with this view, leptin increases the feeding inhibitory actions of exogenously administered CCK [2], [6], [14], [15], [16], and leptin/CCK combinations result in an increase in the number of c-Fos positive cells within the nucleus of the solitary tract (NTS) beyond that produced by either stimulus alone or their arithmetic combination [6], [28].
The aim of the present study was to extend our understanding of the potential role of leptin in modifying within-meal satiety signals. Gastric nutrient preloads can result in decreases in subsequent scheduled food intake when they are of sufficient size and are administered in close temporal proximity to the scheduled meal. We addressed the issue of whether a dose of leptin, that by itself did not affect meal size, would increase the feeding inhibitory actions of a gastric nutrient preload, and if so, whether patterns of c-Fos activation would reflect such a synergistic interaction either at the level of the dorsal hindbrain or within the hypothalamus.
Section snippets
Method
Male Sprague–Dawley rats, weighing between 250 and 300 g, were housed in individual hanging wire mesh cages and maintained on a 12:12 h light–dark cycle. Rats were anesthetized with a mixture of ketamine/xylazine and placed in a stereotaxic device. 23-G stainless steel cannulas were angled into the third cerebral ventricle from a skull site 1 mm lateral to midline at a site 1 mm posterior to bregma. The cannula tip was lowered to a point 7 mm ventral to the dura. Cannula placements were
Results
The effects of gastric nutrient preload and leptin on Ensure liquid diet intake are demonstrated in Fig. 1. ANOVA revealed main effects for both gastric load (F1,24=114.48, P<.001) and leptin (F1,24=18.31, P<.001) administration and a significant gastric load by leptin interaction (F1,24=16.74, P<.001). Planned t pairwise comparisons revealed that gastric load alone significantly decreased intake relative to the baseline condition (P<.05), and the gastric load/leptin combination significantly
Discussion
The results of behavioral experiments demonstrate that leptin administered 1 h prior to food access has the ability to significantly increase the magnitude of suppression produced by an intragastric nutrient infusion. The c-Fos data suggest two potential sites of action for this result: the PVN and the NTS. The leptin/gastric load combination produced elevated levels of Fos expression within the PVN, a hypothalamic site where either treatment alone resulted in c-Fos activation. Leptin's actions
Acknowledgements
This work was supported by National Institute of Diabetes and Digestive and Kidney Disease grant DK19302.
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