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Long-term effect of leptin on H+-coupled peptide cotransporter 1 activity and expression in vivo: evidence in leptin-deficient mice.

Authors
  • Hindlet, Patrick
  • André Bado
  • Farinotti, Robert
  • Buyse, Marion
Type
Published Article
Journal
Journal of Pharmacology and Experimental Therapeutics
Publisher
American Society for Pharmacology & Experimental Therapeutics (ASPET)
Publication Date
Oct 19, 2007
Volume
323
Issue
1
Pages
192–201
Identifiers
DOI: 10.1124/jpet.107.125799
PMID: 17622573
Source
USPC - SET - SVS
License
Green

Abstract

The H+-coupled peptide cotransporter 1 (PepT1) mediates absorption of peptides and peptidomimetic drugs. Acute luminal leptin was reported to induce translocation of PepT1 to the enterocyte membrane in vitro and in vivo in the rat, resulting in enhanced peptide and peptidomimetic drug absorption. In this study, we analyzed chronic effects of leptin and leptin deficiency on PepT1 activity and expression in the small intestine. Wistar rats and ob/ob mice were used. Activity of PepT1 was determined by monitoring [3H]glycyl-sarcosine (Gly-Sar) transport using the jejunal loop method. The levels of PepT1 mRNA and protein were quantified by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis, respectively. Induction of chronic hyperleptinemia in rats (1 microg/g/day for 7 days; subcutaneous continuous infusion), caused a significant 25% increase (P < 0.05 versus control) in Gly-Sar transport and uptake. This effect was associated with a significant 2-fold increase in the abundance of PepT1 protein and a 6-fold increase in the levels of PepT1 mRNA. In the leptin-deficient ob/ob mice, PepT1 activity and expression were significantly reduced, and replacement of leptin (10 microg/day for 7 days; subcutaneous continuous infusion) completely restored full PepT1 expression and activity. Moreover, we showed that a 7-day challenge of the Caco-2 cells with 0.2 nM leptin induced a significant increase in PepT1 activity and protein expression, arguing for a direct action. These data demonstrate, for the first time, an impaired activity/expression of PepT1 in leptin-deficient ob/ob mice that could be restored by leptin replacement. These findings may have relevance in modulation of dietary nitrogen supply and PepT1 substrate bioavailability in obesity.

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