Abstract
Background and AimsThe small intestine is the major site of absorption of dietary sugars. The rate at which they enter and exit the intestine has a major effect on blood glucose homeostasis. In this study, we determine the effects of luminal leptin on activity/expression of GLUT2 and GLUT5 transporters in response to sugars intake and analyse their physiological consequences.MethodologyWistar rats, wild type and AMPKα2 −/− mice were used. In vitro and in vivo isolated jejunal loops were used to quantify transport of fructose and galactose in the absence and the presence of leptin. The effects of fructose and galactose on gastric leptin release were determined. The effects of leptin given orally without or with fructose were determined on the expression of GLUT2/5, on some gluconeogenesis and lipogenic enzymes in the intestine and the liver.Principal FindingsFirst, in vitro luminal leptin activating its receptors coupled to PKCβII and AMPKα, increased insertion of GLUT2/5 into the brush-border membrane leading to enhanced galactose and fructose transport. Second in vivo, oral fructose but not galactose induced in mice a rapid and potent release of gastric leptin in gastric juice without significant changes in plasma leptin levels. Moreover, leptin given orally at a dose reproducing comparable levels to those induced by fructose, stimulated GLUT5-fructose transport, and potentiated fructose-induced: i) increase in blood glucose and mRNA levels of key gluconeogenesis enzymes; ii) increase in blood triglycerides and reduction of mRNA levels of intestinal and hepatic Fasting-induced adipocyte factor (Fiaf) and iii) increase in SREBP-1c, ACC-1, FAS mRNA levels and dephosphorylation/activation of ACC-1 in liver.Conclusion/SignificanceThese data identify for the first time a positive regulatory control loop between gut leptin and fructose in which fructose triggers release of gastric leptin which, in turn, up-regulates GLUT5 and concurrently modulates metabolic functions in the liver. This loop appears to be a new mechanism (possibly pathogenic) by which fructose consumption rapidly becomes highly lipogenic and deleterious.
Highlights
The small intestine is involved in delivering sugars to the systemic circulation through absorption of the products arising from carbohydrate digestion
We demonstrated that luminal leptin, acting from lumen of the intestinal epithelium, increases glucose transporter number 2 (GLUT2) and glucose/fructose transporter number 5 (GLUT5) transport activities through leptin-receptor coupled to activation of protein kinase C subunit bII (PKCbII) and 59AMP-activated protein kinase subunit a (AMPKa)
In this combined in vivo and in vitro approaches, we showed that intestinal GLUT2 and GLUT5 transporters are direct targets of luminal leptin detected in the intestinal lumen and originating from the stomach
Summary
The small intestine is involved in delivering sugars to the systemic circulation through absorption of the products arising from carbohydrate digestion. In prandial state, when higher concentrations of glucose or galactose are found in the intestinal lumen, apical GLUT2 becomes active providing the small intestine with an absorptive capacity to match dietary intake during meal [1]. This apical GLUT2 transporter participates to fructose transport in addition to the main and specific GLUT5 transporter [3]. All these membrane transporters are highly regulated during food intake by changing their activity levels, their location within the enterocyte and by regulating the expression of the encoding genes [4]. We determine the effects of luminal leptin on activity/expression of GLUT2 and GLUT5 transporters in response to sugars intake and analyse their physiological consequences
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