title: Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation.
abstract: Leptin is a major determinant of energy homeostasis, acting both centrally and in the gastrointestinal tract. We previously reported that acute leptin treatment enhances the absorption of di- and tripeptides via the proton-dependent PepT1 transporter. In this study, we investigated the long term effect of leptin on PepT1 levels and activity in Caco2 cell monolayers in vitro. We then assessed the significance of the regulation of PepT1 in vivo in a model of diet-induced obesity. We demonstrated that 1) leptin regulated PepT1 at the transcriptional level, via the MAPK pathway, and at the translational level, via ribosomal protein S6 activation, in Caco2 cells and 2) this activation was systematically followed by a time- and concentration-dependent loss of leptin action reflecting desensitization. Deciphering this desensitization, we demonstrated that leptin induced a down-regulation of its own receptor protein and mRNA expression. More importantly, we showed, in mice with diet-induced obesity, that a 4-week hypercaloric diet resulted in a 46% decrease in PepT1-specific transport, because of a 30% decrease in PepT1 protein and a 50% decrease in PepT1 mRNA levels. As shown in Caco2 cells, these changes in PepT1 were supported by a parallel 2-fold decrease in leptin receptor expression in mice. Taken together, these results indicate that during induction of obesity, leptin resistance may also occur peripherally in the gastrointestinal tract, disrupting the absorption of oligopeptides and peptidomimetic drugs.
authors.affiliation: Laboratoire de Pharmacie Clinique (UPRES EA2706) and IFR-141, Faculté de Pharmacie, Université Paris-Sud 11, 92296 Châtenay-Malabry, France. patrick.hindlet@u-psud.fr
authors.forename: Patrick
authors.initials: P
authors.lastname: Hindlet
authors.forename: André
authors.initials: A
authors.lastname: Bado
authors.forename: Peter
authors.initials: P
authors.lastname: Kamenicky
authors.forename: Claudine
authors.initials: C
authors.lastname: Deloménie
authors.forename: Fanchon
authors.initials: F
authors.lastname: Bourasset
authors.forename: Corinne
authors.initials: C
authors.lastname: Nazaret
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D004032:Diet / Q000009:adverse effects*; D004151:Dipeptides / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D020738:Leptin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D000074011:Peptide Transporter 1; D012333:RNA, Messenger / Q000096:biosynthesis; D054411:Receptors, Leptin / Q000096:biosynthesis*; D027981:Symporters / Q000096:biosynthesis*; D013997:Time Factors
chemical_list: D004151:Dipeptides; D020738:Leptin; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; D054411:Receptors, Leptin; C082186:SLC15A1 protein, human; C489941:Slc15a1 protein, mouse; D027981:Symporters