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

Abstract

The intestinal transporter PEPT1 mediates the absorption of di- and tripeptides originating from breakdown of dietary proteins. Whereas mice lacking PEPT1 did not display any obvious changes in phenotype on a high-carbohydrate control diet (HCD), Pept1(-/-) mice fed a high-fat diet (HFD) showed a markedly reduced weight gain and reduced body fat stores. They were additionally protected from hyperglycemia and hyperinsulinemia. Energy balance studies revealed that Pept1(-/-) mice on HFD have a reduced caloric intake, no changes in energy expenditure, but increased energy content in feces. Cecal biomass in Pept1(-/-) mice was as well increased twofold on both diets, suggesting a limited capacity in digesting and/or absorbing the dietary constituents in the small intestine. GC-MS-based metabolite profiling of cecal contents revealed high levels and a broad spectrum of sugars in PEPT1-deficient mice on HCD, whereas animals fed HFD were characterized by high levels of free fatty acids and absence of sugars. In search of the origin of the impaired digestion/absorption, we observed that Pept1(-/-) mice lack the adaptation of the upper small intestinal mucosa to the trophic effects of the diet. Whereas wild-type mice on HFD adapt to diet with increased villus length and surface area, Pept1(-/-) mice failed to show this response. In search for the origin of this, we recorded markedly reduced systemic IL-6 levels in all Pept1(-/-) mice, suggesting that IL-6 could contribute to the lack of adaptation of the mucosal architecture to the diets.

Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance

“…Besides, we demonstrate a longer villus length, an increase in Ki67-positive cells in HFD mice as previously reported (4,29), and a slower transit time induced by HFD. The latter results in a prolonged contact between enterocyte absorptive surface and the chyme, which could be implicated in the increased AA absorption.…”

“…Compared with mice fed standard diet and in agreement with published results (29), mice fed a HFD for 6 wk exhibited an increase in crypt-villus mean height and in Ki67-positive cells per crypt (26.1% of epithelial crypt cells in HFD mice vs. 13.2% in SC mice), as shown in Fig. 7E.…”

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

“…Mice lacking PEPT1 were in essence protected from diet-induced obesity without any significant differences in food intake. However, metabolite profiling of caecal contents and analysis of intestinal morphology revealed evidence for a subtle malabsorption, with increased levels of unabsorbed fatty acids and amino acids in the caecum, increased energy loss in faeces and an impaired morphological adaptation of the intestine to the high-fat diet (Kolodziejczak et al 2013).…”

Cross-Species Comparison of Genes Related to Nutrient Sensing Mechanisms Expressed along the Intestine

“…More knowledge on this (regional) distribution can provide better insight in the underlying nutrient-sensing mechanisms potentially involved in individual differences in food intake and the likeliness to develop metabolic diseases. The issue of cross-species comparison is important since the vast majority of studies in this field has been performed in rodents, such as the mouse [10], [13]–[15]. Pigs may serve as a more suitable animal model because pigs and humans show more similarity in gut physiology than mice and humans.…”