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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.

SUBMITTER: Hindlet P

PROVIDER: S-EPMC2652284 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation.

Hindlet Patrick P Bado André A Kamenicky Peter P Deloménie Claudine C Bourasset Fanchon F Nazaret Corinne C Farinotti Robert R Buyse Marion M

The Journal of biological chemistry 20090114 11

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 t ...[more]

PMID: 19144638

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Project description:Background: A high-fat Western diet is a risk factor for obesity and steatosis. Reducing intestinal absorption of a high-fat diet (HFD) is a feasible strategy to control obesity. Sulfosuccinimidyl oleate (SSO) inhibits intestinal fatty acid transport. Therefore, the aim of this study was to investigate the effects of SSO on HFD-induced glucose and lipid metabolism in mice and its possible underlying mechanisms. Methods: Male C57/BL were fed a HFD (60% calories) for 12 weeks and were administered an oral dose of SSO (50 mg/kg/day). The expression of lipid absorption genes (CD36, MTTP, and DGAT1) and the serum levels of triglycerides (TGs), total cholesterol (TC), and free fatty acids (FFAs) were detected. Lipid distribution in the liver was detected by oil red and hematoxylin and eosin staining. In addition, serum levels of inflammatory factors, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured to detect side effects. Results: SSO was effective in the treatment of obesity and metabolic syndrome induced by HFD in mice. It attenuated the assembly of intestinal epithelial chylomicrons by inhibiting intestinal epithelial transport and absorption of fatty acids, thereby reducing the gene expression levels of MTTP and DGAT1, resulting in decreased plasma TG and FFA levels. At the same time, it inhibited the transport of fatty acids in the liver and improved the steatosis induced by a HFD. The results of oil red staining showed that SSO treatment can reduce lipid accumulation in the liver by 70%, with no drug-induced liver injury detected on the basis of interleukin-6, C-reactive protein, ALT, and AST levels. In addition, SSO treatment significantly improved insulin resistance, decreased fasting blood glucose levels, and improved glucose tolerance in HFD-fed mice. Conclusion: SSO is effective in the treatment of obesity and metabolic syndrome induced by a HFD in mice. SSO reduces intestinal fatty acid absorption by reducing the inhibition of intestinal CD36 expression, followed by decreased TG and FFA levels, which attenuates HFD-induced fatty liver.

Dataset Information

Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation.

Publications

Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation.

Similar Datasets

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