Absence of the Peptide Transporter 1 Induces a Prediabetic and Depressive-Like Phenotype in Mice

Abstract

<b><i>Introduction:</i></b> Protein-enriched diets improve glycemic control in diabetes or emotional behavior in depressive patients. In mice, these benefits depend on intestinal gluconeogenesis activation by di-/tripeptides. Intestinal di-/tripeptides absorption is carried out by the peptide transporter 1, PEPT1. The lack of PEPT1 might thus alter glucose and emotional balance. <b><i>Methods:</i></b> To determine the effects of PEPT1 deficiency under standard dietary conditions or during a dietary challenge known to promote both metabolic and cognitive dysfunction, insulin sensitivity, anxiety, and depressive-like traits, hippocampal serotonin (5-HT) and insulin signaling pathway were measured in wild-type (WT) and Pept1^−/− mice fed either a chow or a high-fat high-sucrose (HF-HS) diet. <b><i>Results:</i></b> Pept1^−/− mice exhibited slight defects in insulin sensitivity and emotional behavior, which were aggravated by an HF-HS diet. Pept1^−/− mice fed a chow diet had lower hippocampal 5-HT levels and exhibited cerebral insulin resistance under HF-HS diet. These defects were independent of intestinal gluconeogenesis but might be linked to increased plasma amino acids levels. <b><i>Conclusion:</i></b> Pept1^−/− mice develop prediabetic and depressive-like traits and could thus be used to develop strategies to prevent or cure both diseases.