Open Access Peer-reviewed Research Article
Authors:
Published: October 21, 2011
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.
Citation:Nässl A-M, Rubio-Aliaga I, Sailer M, Daniel H (2011) The Intestinal Peptide Transporter PEPT1 Is Involved in Food Intake Regulation in Mice Fed a High-Protein Diet. PLoS ONE 6(10): e26407.
Editor:Immo A. Hansen, New Mexico State University, United States of America
Received:July 5, 2011; Accepted:September 26, 2011; Published: October 21, 2011
Copyright: © 2011 Nässl et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding:This work was supported by a grant (DA 190/8-1) from the Deutsche Forschungsgemeinschaft (DFG). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Numerous studies have demonstrated that diets with a high protein content provide higher satiety levels (at least short term) than the other macronutrients. In addition, it has been shown that protein-rich diets can promote weight loss and cause changes in body composition. Intake of dietary protein is sensed in the intestine with concomitant secretion of gastrointestinal hormones and activation of visceral processes that alter gastric motility, stimulate pancreatic secretion, mediate peripheral effects and contribute to satiety. Mainly PYY and CCK but also insulin and leptin are discussed to play a prominent role in satiety control. Yet, in most cases feeding high-protein diets revealed negligible effects on circulating levels of these hormones. Recently, neuronal pathways in the brainstem nucleus of the solitary tract and hypothalamic arcuate nucleus were shown to be activated by high-protein diets. Amongst the possible dietary signals for this hypothalamic sensing, the amino acid leucine has received particular attention. It was demonstrated that leucine contributes to food intake control via AMP-activated protein kinase and mammalian target of rapamycin when supplied to hypothalamic centers. Since plasma levels of branched chain amino acids (BCAA), including leucine, increase when dietary protein supply is increased and brain leucine levels follow plasma levels, a role of leucine in central regulation of satiety seems plausible. However conflicting results on the role of leucine were obtained in animal studies in which extra leucine was supplied by the diet to affect food intake and body weight. Additionally high-protein intake causes also major adaptations in metabolic processes in intestine and liver associated with changes in plasma levels of a variety of amino acids. Although protein-rich diets challenge the digestive tract with large quantities of amino acids and short chain peptides for uptake into epithelial cells and into circulation, a contribution of intestinal transport processes to food intake control has never been anticipated.
Intestinal protein digestion delivers short chain peptides and free amino acids to epithelial cells. Amino acids are taken up through numerous amino acid transporters acting as symporters or antiporters. For absorption of di- and tripeptides only one transport system in the intestine, designated as PEPT1 (SLC15A1) is known. PEPT1 is a low-affinity but high-capacity transport system and handles essentially all possible protein-derived di- and tripeptides, but also a variety of peptidomimetics like aminocephalosporins and various prodrugs. Peptide transport is electrogenic by charge movement as it involves the cotransport of protons. PEPT1 in the intestine is subject to regulation by a variety of hormones and cytokines, but also by the dietary protein content. As demonstrated by Erickson et al, mRNA expression and transport rate of PEPT1 in rat intestine increases 1.5 to 2-fold when animals received a high-protein (50 energy%) diet as compared to a 4% protein diet.
Although the structure and function of PEPT1 has been studied in detail, its contribution to overall amino acid absorption is still unknown. The PEPT1-deficient model organism Caenorhabditis elegans showed reduced body size, impaired brood size and a retarded postembryonic development. We recently reported that the lack of intestinal peptide transport in Pept1−/− mice is not compensated by changes in mRNA expression or transport capacity of intestinal amino acid transporters. Phenotyping of Pept1−/− mice did not reveal any impairments in reproduction, body weight or any other anthropometric or clinical chemistry measures when animals were fed a standard high-carbohydrate diet. Yet, plasma concentrations of amino acids were increased in Pept1−/− when compared to Pept1+/+ mice, suggesting an altered systemic amino acid handling. Moreover, administration of an acute high protein load via gastric gavage also caused differences in plasma concentrations of several amino acids such as citrulline and arginine and most prominently of proline. Based on this finding, feeding trials with Pept1−/− animals with variations in dietary protein content were performed and we here report striking diet-dependent effects on food intake and weight gain that were further characterized by biochemical analysis. Taken together our findings suggest that the intestinal peptide transporter PEPT1 is part of a metabolic network that affects food intake particularly when high-protein diets are consumed.
Determination of food intake and body weight changes in Pept1−/− mice fed for 5 days a LP or C diet did not show any significant alterations when compared to wildtype animals. However when animals were provided with a HP diet, food intake rates immediately declined in all animals but more pronounced in Pept1−/− animals. Whereas wildtype animals increased food consumption again after 2 days, Pept1−/− mice reduced food intake even further over 4 days. This led in Pept1−/− animals also to a decrease in body weight and reduced feces excretion. No differences in water consumption were observed, neither between diets nor genotypes (data not shown). A second feeding trial conducted over a 18 day period revealed a similar initial major reduction in food intake for 4 days in Pept1−/− mice while animals thereafter increased food consumption to reach the same intake rates as observed in wildtype animals, yet, they failed to show any significant weight ga
