Positive Regulatory Control Loop between Gut Leptin and Intestinal GLUT2/GLUT5 Transporters Links to Hepatic Metabolic Functions in Rodents

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.

Luminal leptin inhibits l-glutamine transport in rat small intestine: involvement of ASCT2 and B0AT1

“…A similar effect was previously reported in vitro (2,16,18,21) with implication of both PKC and PKA activation (4,16). Interestingly, luminal leptin enhances the intestinal transport of dipeptides by the Hϩ/peptide transporter PEPT1 and CD147/medium-chain triglyceride (MCT)-1 mediated uptake of butyrate in mice and Caco-2 cells (9, 10), as well as fructose transport by the facilitative glucose transporter GLUT5 in rat intestine in vivo (25). Given that leptin seems to regulate different nutrient transporters, one could anticipate that it may also modulate amino acid transporters in the intestine.…”

Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

“…Decreased GLUT-2 stimulates appetite (33), which is coherent with the observed decline caused by fasting found here, while the increase in NeoON rats would serve as a signal to decrease food intake. Leptin modulates glucose transporters in different tissues (74)(75)(76), and this cytokine decreased with fasting and increased in NeoON rats. However, chronic icv treatment decreased both hypothalamic GLUT-2 and -3, but had no effect on GLUT-1 levels, and we found no evidence of a direct effect of chronic leptin treatment on GLUT-1, -2, or -3 mRNA or GLUT-2 protein levels in astrocytes.…”

In vivo regulation of intestinal absorption of amino acids by leptin

“…This study was followed by the demonstration that the chief cells also secreted the leptin soluble receptor (Cammisotto et al 2006), and that leptin remains stable in the gastric juices because binding to this receptor protects it from the acidic pH and the proteolytic activity of the stomach, favoring its arrival to the small intestine (Guilmeau et al 2003(Guilmeau et al , 2004. All these results supported our initial discovery about the role of luminal leptin as regulator of intestinal sugar absorption, and were followed by further studies on leptin modulation of sugar transport (Barrenetxe et al 2001, Iñigo et al 2004, 2007, Ducroc et al 2005, Sakar et al 2009). With regard to amino acid absorption, we have recently shown in vitro using rat intestine and Caco-2 cells that leptin also inhibits glutamine (Gln) and phenylalanine transport by the regulation of gene expression and protein activity of the implicated transporters, ASCT2 and B 0 AT1 (Ducroc et al 2010, Fanjul et al 2012.…”

“…Similarly, leptin can enhance the amount of GLUT2 and GLUT5 transporters in the apical membranes of enterocytes explaining the increase in absorption of Gal and fructose observed (Sakar et al 2009). …”

“…During the last 15 years, our group and the group of A Bado have been investigating the physiological role of leptin in absorption of nutrients using different physiological and biochemical approaches (Lostao et al 1998, Barrenetxe et al 2001, Ducroc et al 2005, 2010, Iñigo et al 2007, Sakar et al 2009, Fanjul et al 2012. All these results lead to the conclusion that leptin can be considered to be a new gastrointestinal hormone, which is secreted by the stomach (Cammisotto & Bendayan 2012), and rapidly regulates intestinal absorption of nutrients acting from the apical membrane of the enterocytes (Lostao et al 1998, Ducroc et al 2005, 2010, Iñigo et al 2007, Fanjul et al 2012.…”