The Intestinal Peptide Transporter PEPT1 Is Involved in Food Intake Regulation in Mice Fed a High-Protein Diet

Abstract

High-protein diets are effective in achieving weight loss which is mainly explained by increased satiety and thermogenic effects. Recent studies suggest that the effects of protein-rich diets on satiety could be mediated by amino acids like leucine or arginine. Although high-protein diets require increased intestinal amino acid absorption, amino acid and peptide absorption has not yet been considered to contribute to satiety effects. We here demonstrate a novel finding that links intestinal peptide transport processes to food intake, but only when a protein-rich diet is provided. When mice lacking the intestinal peptide transporter PEPT1 were fed diets containing 8 or 21 energy% of protein, no differences in food intake and weight gain were observed. However, upon feeding a high-protein (45 energy%) diet, Pept1−/− mice reduced food intake much more pronounced than control animals. Although there was a regain in food consumption after a few days, no weight gain was observed which was associated with a reduced intestinal energy assimilation and increased fecal energy losses. Pept1−/− mice on high-protein diet displayed markedly reduced plasma leptin levels during the period of very low food intake, suggesting a failure of leptin signaling to increase energy intake. This together with an almost two-fold elevated plasma arginine level in Pept1−/− but not wildtype mice, suggests that a cross-talk of arginine with leptin signaling in brain, as described previously, could cause these striking effects on food intake.

Mice lacking the intestinal peptide transporter display reduced energy intake and a subtle maldigestion/malabsorption that protects them from diet-induced obesity

“…The animals grow to WT-like size with normal body and organ weights and no genotype-related abnormalities in organ histology (15,21). We recently demonstrated that Pept1 Ϫ/Ϫ mice challenged with a high-protein diet providing 45% of energy from protein showed impairments in development and a markedly reduced food intake and severe weight loss during the first days on the diet (22). Although food intake returned to normal levels after 5 days, Pept1 Ϫ/Ϫ mice did not regain weight and remained significantly leaner than WT animals.…”

“…PEPT1 is mainly expressed in the small intestine with higher levels in the proximal parts than in distal regions. Studies employing Pept1 Ϫ/Ϫ mice have demonstrated a lack of intestinal transport of model dipeptides such as glycylsarcosine (5, 15), but animals otherwise do not show any obvious phenotypic alterations (21,22). We here provide on the analysis of changes in the gastrointestinal tract and of other phenotypic measures in mice deficient of PEPT1 when the animals are fed a diet containing 48 energy% from fat (HFD) compared with a high-carbohydrate/low-fat diet (13 energy% fat).…”

Proton-coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications

“…These same authors (Saito et al, 2008) subsequently showed that a clock-controlled gene, DBP, regulated the circadian oscillation of PepT1 expression during normal and restricted feeding conditions as opposed to other transcription factors (i.e., Sp1, Cdx2 and PPAR-which contribute to the basal, intestine-specific, and fasting-induced expression of PepT1, respectively (Terada and Inui, 2007). Moreover, in vivo studies (Ma et al, 2012) revealed that as little as 16 hours of fasting can cause upregulation of PepT1 protein in duodenal, jejunal and ileal segments of wild-type mice, resulting in significant increases in the oral absorption of GlySar in these mice but not in Slc15a1 knockout animals Nassl et al (2011b). further demonstrated a time-dependence of food intake regulation in male mice fed a high protein diet.…”

Taste and move: glucose and peptide transporters in the gastrointestinal tract

“…In contrast to the impressive phenotypic alterations in C. elegans deficient in PEPT1, mice lacking the transporter were viable and grew at similar rates to wild‐type littermates (Nassl et al . b ). Measurementa of the appearance of amino acids in peripheral and portal venous blood following intragastric administration of a 15 N‐labelled yeast protein in PEPT1‐deficient mice revealed a delayed absorption of some amino acids, although fasting plasma levels of amino acids were increased (Nassl et al .…”