Duodenal Leptin Stimulates Cholecystokinin Secretion

Abstract

Some of the actions of leptin depend on cholecystokinin (CCK). However, it is unknown whether leptin modulates the release of CCK. Here, we demonstrate in vitro that leptin induces the phosphorylation of extracellular signal-related kinase (ERK)-1/2 proteins and increases CCK release (EC 50 ‫؍‬ 0.23 nmol/l) in CCK-secreting STC-1 cells. We showed that rat duodenal juice contains leptin that circulates free and bound to macromolecules, suggesting that leptin has a lumenal action on the intestine. In vivo in the rat, duodenal infusion of leptin increased plasma CCK at levels comparable to those induced by feeding. Moreover, meal-induced increases in plasma CCK were markedly reduced in obese fa/fa rats, whereas the mobilization of the gastric leptin pool was similar in lean and obese Zucker rats. L eptin, the ob gene product, was initially reported to be produced by adipose cells (1). It is released into the bloodstream and transported across the blood-brain barrier into the hypothalamus, where it activates specific leptin receptors (2,3) and regulates energy homeostasis by altering energy intake and expenditure (4 -6). Leptin regulates food intake by mechanisms involving cross-talk between hypothalamic leptin receptors and various neuropeptides involved in the control of feeding. The leptin receptor (Ob-R) is a member of the gp130 family of cytokine receptors. It occurs in several isoforms resulting from the alternative splicing of the db leptin receptor gene (2,3). It is currently thought that the long isoform, Ob-Rb, can activate the signal transducers and activators of transcription (STAT) pathways, whereas both Ob-Rb and the short isoform (Ob-Ra) can transduce signals through insulin receptor substrates and through mitogen-activated protein kinase (MAPK) pathways (7).The signals that arise from the upper gastrointestinal tract upon feeding are transmitted to the brain by the vagus nerve. These signals are key components in the control of meal-induced satiety. Cholecystokinin (CCK) is secreted from duodenal endocrine I cells and typically functions as one of these short-term satiety signals (8,9). Interestingly, the leptin-induced inhibition of food intake (10) and the stimulation of pancreatic exocrine secretions (11) can be blocked by a CCK-1 receptor antagonist. These data suggest that endogenous CCK is involved in these effects, operating through CCK-1 receptors. However, it is not currently known whether leptin directly modulates the release of CCK.Leptin is also produced by the stomach (12-14) and is mainly secreted into the gastric juice after CCK in rats (12,15) and after secretin or vagal stimulation in humans (14,16). Some of the stomach-derived leptin is not fully degraded by proteolysis, indicating that it reaches the intestine in an active form and thus can initiate biological processes controlling functions of the intestinal tract. Indeed, lumenal leptin increases the activity of the brush border proton-dependent transporter, PepT1, which enhances the intestinal absorption of oligopeptides (17). T...

Anticipatory physiological regulation in feeding biology: Cephalic phase responses

“…Leptin has been shown to inhibit D-galactose absorption (Lostau et al, 1998) and increase the intestinal absorption of small peptides (Morton et al, 1998). Leptin also stimulates cholecystokinin (CCK) secretion (Guilmeau et al, 2003). Leptin and CCK appear to form a positive feedback loop; plasma CCK stimulates gastric leptin secretion (Bado et al, 1998) and duodenal infusion of leptin in rats increased plasma CCK comparable to the effects of feeding (Guilmeau et al, 2003).…”

“…Leptin also stimulates cholecystokinin (CCK) secretion (Guilmeau et al, 2003). Leptin and CCK appear to form a positive feedback loop; plasma CCK stimulates gastric leptin secretion (Bado et al, 1998) and duodenal infusion of leptin in rats increased plasma CCK comparable to the effects of feeding (Guilmeau et al, 2003). Leptin and CCK appear to act synergistically to activate vagal afferent neurons (Peters et al, 2004).…”

Comparison of the metabolic effects of sustained CCK1 receptor activation alone and in combination with upregulated leptin signalling in high-fat-fed mice

“…Furthermore, CCK-8 increases the permeability of the blood-brain barrier to leptin [19] and may also induce leptin release from adipose tissue [20]. In harmony with this, leptin has been shown to stimulate CCK secretion [21]. Thus, leptin and CCK may potentiate their own effects by cross-stimulating their secretion.…”

Hormonal Signaling in the Gut

“…Nonetheless, leptin is unable to bind and activate the Ob-Rb when complexed to the SLR in vitro (78,79). Although the effect of the SLR on leptin action remains unclear, leptin has been detected in duodenal juices and thus reaches the duodenum in its intact form (73). Furthermore, the Ob-Rb is found to be expressed on cells of, or vagal afferents innervating, the small intestine (76, 80 -83), and activation of these receptors results in various functions, such as regulating nutrient transport (84).…”