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Leptin, a 167 amino acid protein transcribed from theob gene, was originally described as a hormone secreted specifically by adipocytes, that is involved in the central regulation of food intake and energy expenditure.1Circulating concentrations of leptin show a strong positive correlation with fat mass. Leptin acts on the hypothalamus of the brain to regulate body weight by decreasing food intake and increasing physical activity and energy expenditure.2 Theob/ob mouse has a recessive mutation of theob gene which results in absence of circulating leptin leading to hyperphagia, reduced energy expenditure and development of obesity. Subsequent work has shown that leptin, in addition to its role in metabolic control, has important roles in reproduction and neuroendocrine signalling. Both animals and humans with leptin deficiency have increased circulating corticosterone concentrations, reduced thyroxine concentrations, and infertility due to hypogonadotrophic hypogonadism.3 ,4 In theob/ob mouse these changes are reversed by administration of exogenous leptin.4
Contrary to initial reports, leptin is not produced exclusively by fat cells. Glucose and free fatty acids increase leptin expression and protein concentrations in skeletal muscle.5 Leptin mRNA is also expressed in placental tissue suggesting that leptin may have a role in intrauterine and neonatal development.6 Bado and colleagues have now detected leptin in the rat stomach. Leptin mRNA was identified after screening of total RNA extracted from fundic epithelium scrapings using the polymerase chain reaction after reverse transcription of RNA. Leptin mRNA was not detected in any other gastrointestinal tissue including the liver and pancreas. Subsequent studies demonstrated that leptin immunoreactive cells were localised in the lower half of the fundic glands, a site similar to that of the pepsinogen secreting chief cells. Fasting resulted in a fall in plasma leptin concentration but had no significant effect on the fundic content of leptin. Refeeding resulted in a rapid and significant decrease in gastric leptin, concomitant with an increase in plasma leptin concentration. Intraperitoneal administration of cholecystokinin-8 (CCK-8) to fasted animals produced a dose dependent decrease in gastric leptin and an increase in plasma leptin concentrations. Isolated adipocytes did not secrete leptin in response to CCK stimulation, suggesting that the increase in plasma leptin with CCK resulted from mobilisation of gastric leptin stores. Adipocytes are not thought to store leptin and thus the rapid rise (within 15 minutes) in plasma leptin with refeeding may also be due to release of leptin from the gastric epithelium. It is not known whether the effect of feeding on gastric leptin response is mediated by CCK, released from intestinal I cells in response to food ingestion. Gastrin produced similar effects to CCK-8, suggesting that gastric leptin secretion is mediated via the gastrin/CCK-B receptor (which has similar affinity for both CCK peptides and gastrin) rather than the CCK-A receptor which has high affinity only for the CCK peptides.
Bado et al’s study has also shown that the regulation of synthesis and secretion of leptin differs in gastric epithelium and adipocytes. Western blots of leptin from fundic epithelium revealed two immunoreactive bands: a 16K band corresponding to leptin and a 19K band, which was thought to be the leptin precursor. The 19K protein was absent from extracts of fat tissue, which presumably reflects a difference in protein processing and excretion between gastric cells and adipocytes. Obese rats had increased amounts of adipocyte leptin compared with lean rats but gastric leptin was similar in the two groups, suggesting adipocyte specificity of leptin upregulation. Finally, as discussed previously, adipocytes and gastric epithelium differ in their response to food restriction and CCK stimulation.
CCK coordinates gastrointestinal function to ensure optimal conditions for digestion and absorption of nutrients by the intestine. The actions of CCK include stimulation of gall bladder contraction, relaxation of the sphincter of Oddi, inhibition of gastric emptying and finally induction of satiety.7 In view of the well documented effects of leptin on food intake, the authors suggest that gastric leptin may play a role in CCK induced satiety. There was no increase in plasma leptin after administration of CCK at doses previously shown in other studies to be well above those needed for a satiety effect.8 However, fundic leptin content was decreased and leptin may therefore act locally on vagal afferent terminals to mediate CCK induced satiety, or indeed other actions of CCK on the gastrointestinal tract.
The circulating peptide leptin, which is the product of the ob gene, provides feedback information on the size of fat stores to central Ob receptors that control food intake and body-weight homeostasis. Leptin has so far been reported to be secreted only by adipocytes and the placenta. Here we show that leptin messenger RNA and leptin protein are present in rat gastric epithelium, and that cells in the glands of the gastric fundic mucosa are immunoreactive for leptin. The physiological function of this previously unsuspected source of leptin is unknown. However, both feeding and administration of CCK-8 (the biologically active carboxy-terminal end of cholecystokinin) result in a rapid and large decrease in both leptin cell immunoreactivity and the leptin content of the fundic epithelium, with a concomitant increase in the concentration of leptin in the plasma. These results indicate that gastric leptin may be involved in early CCK-mediated effects activated by food intake, possibly including satiety.
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