title: Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance.
abstract: The oligopeptide transporter peptide cotransporter-1 Slc15a1 (PEPT1) plays a major role in the regulation of nitrogen supply, since it is responsible for 70% of the dietary nitrogen absorption. Previous studies demonstrated that PEPT1 expression and function in jejunum are reduced in diabetes and obesity, suggesting a nitrogen malabsorption from the diet. Surprisingly, we reported here a decrease in gut nitrogen excretion in high-fat diet (HFD)-fed mice and further investigated the mechanisms that could explain this apparent contradiction. Upon HFD, mice exhibited an increased concentration of free amino acids (AAs) in the portal vein (60%) along with a selective increase in the expression of two AA transporters (Slc6a20a, Slc36a1), pointing to a specific and adaptive absorption of some AAs. A delayed transit time (+40%) and an increased intestinal permeability (+80%) also contribute to the increase in nitrogen absorption. Besides, HFD mice exhibited a 2.2-fold decrease in fecal DNA resulting from a reduction in nitrogen catabolism from cell desquamation and/or in the intestinal microbiota. Indeed, major quantitative (2.5-fold reduction) and qualitative alterations of intestinal microbiota were observed in feces of HFD mice. Collectively, our results strongly suggest that both increased AA transporters, intestinal permeability and transit time, and changes in gut microbiota are involved in the increased circulating AA levels. Modifications in nitrogen homeostasis provide a new insight in HFD-induced obesity and glucose intolerance; however, whether these modifications are beneficial or detrimental for the HFD-associated metabolic complications remains an open issue.
authors.affiliation: Université Pierre et Marie Curie, Paris, Unité Mixte de Recherche S938, Paris, France;
authors.forename: Thi Thu Huong
authors.initials: TT
authors.lastname: Do
authors.forename: Patrick
authors.initials: P
authors.lastname: Hindlet
authors.forename: Anne-Judith
authors.initials: AJ
authors.lastname: Waligora-Dupriet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Kapel
authors.forename: Nathalie
authors.initials: N
authors.lastname: Neveux
authors.forename: Virginie
authors.initials: V
authors.lastname: Mignon
authors.forename: Claudine
authors.initials: C
authors.lastname: Deloménie
authors.forename: Robert
authors.initials: R
authors.lastname: Farinotti
authors.forename: Bruno
authors.initials: B
authors.lastname: Fève
authors.forename: Marion
authors.initials: M
authors.lastname: Buyse
mesh_terms: D052636:Allostasis; D026905:Amino Acid Transport Systems / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D004247:DNA / Q000032:analysis; D059305:Diet, High-Fat / Q000009:adverse effects; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005243:Feces / Q000737:chemistry / Q000382:microbiology; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D006090:Gram-Negative Bacteria / Q000254:growth & development / Q000302:isolation & purification; D006094:Gram-Positive Bacteria / Q000254:growth & development / Q000302:isolation & purification; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007422:Intestines / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009584:Nitrogen / Q000032:analysis / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D000074011:Peptide Transporter 1; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; D000074011:Peptide Transporter 1; C489941:Slc15a1 protein, mouse; C483904:Slc36a1 protein, mouse; C000588564:Slc6a20a protein, mouse; D027981:Symporters; D004247:DNA; D018819:Dipeptidyl Peptidase 4; D009584:Nitrogen
keywords: gut microbiota; peptide cotransporter-1 Slc15a1; type 2 diabetes