Direct Effect of Leptin on Gastric Ghrelin Secretion

Introduction

Ghrelin is an orexigenic hormone of gastric origin, and contributes to food intake and body weight regulation [1] [2]. Its postprandial secretion is attenuated by carbohydrate-rich meals [3] [4], while carbohydrate-poor food stimulates ghrelin release [5]. Gastrointestinal factors such as gastrin, somatostatin, or GLP-1 are good candidates for ghrelin inhibitors [6]. Also, there is solid evidence that insulin is a powerful inhibitor of ghrelin release in vivo [7] [8] and in vitro [6].

Apart from the short-term regulation of ghrelin secretion in response to the changes of food ingestion, ghrelin levels differ according to the nutritional state of the subject. Thus, high levels have been observed in underweight anorectic patients, while decreased plasma concentrations have been described in obese subjects [8] [9] [10], which implies tonic control over this gastric short-term feeding regulator through factors related to the energy reserve of the organism. Ideally, secretory products of fat cells are most suitable for such a feedback control system. Interestingly, ghrelin itself can have regulatory effects on fat-cell secretory products such as adiponectin [11]. Leptin deserves serious attention in this context, since its plasma levels change with alterations in fat-cell mass, and leptin deficiency has been found to be causally related to the development of obesity [12].

Accordingly, obesity-related suppression of ghrelin levels could be due to increased leptin concentrations. On the other hand, obesity is associated with elevated insulin levels, which makes discriminating between the effects of these two hormones difficult. Moreover, in contrast to the well-confirmed inverse relationship between insulin and ghrelin [6] [7] [8], the role of leptin is rather controversial. Leptin application in normal mice and rats has been shown to result in a decrease in ghrelin mRNA and plasma ghrelin, respectively [13] [14].

In normal-weight humans, however, the leptin application for up to 3 days had no effect on plasma ghrelin levels [15]. In view of the inverse relationship between basal ghrelin and leptin concentrations in obese subjects, the data mentioned above raise the possibility that fat-cell secretory products other than leptin could be responsible for ghrelin suppression. An important prerequisite for a regulatory role of leptin in ghrelin secretion would be a direct influence on gastric ghrelin secretion. We have used a model of the isolated perfused rat stomach to assess such a possible effect without having to consider various systemic interactions.

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