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The Role of Intestinal-derived FGF15 and Vertical Sleeve Gastrectomy on Plasma Bile Acid Composition in Mice

ABSTRACT: Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective long-term metabolic improvements in individuals with obesity and/or Type 2 diabetes. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Previous data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma concentrations of the human ortholog FGF19 and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2; Fgf15f/f) mice and controls, which were maintained on 60% high-fat diet. VSG resulted in increased plasma bile acid levels. However, intestinal-specific FGF15 knock out mice had considerably higher levels of circulating total and hydrophobic bile acids after VSG. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG as a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density and bone marrow adipose tissue observed after VSG in control mice was even greater in intestinal-specific FGF15 knock out mice, perhaps secondary to anemia and elevated erythropoietin/FGF23. Finally the effect of VSG to improve glucose tolerance and to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of bile acid toxicity after VSG.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Blood

SUBMITTER: Randy Seeley

PROVIDER: ST001743 | MetabolomicsWorkbench | Tue Apr 13 00:00:00 BST 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice were generated that lacked Runx1 expression in epithelial cells of the GI tract. These mice were crossed onto the ApcMin background, sacrificed, and their intestinal tumor phenotypes were compared with ApcMin Runx1 wildtype control mice. Apc-wildtype Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wildtype mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium, to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc-wildtype mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1 deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. A total of 8 colon tissue RNA samples were analyzed, comprising 4 colon samples from wild-type mice (Villin-Cre negative / Runx1-floxed) and 4 colon samples from mice that lack epithelial expression of Runx1 (Villin-Cre positive/Runx1-floxed).

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The Role of Intestinal-derived FGF15 and Vertical Sleeve Gastrectomy on Plasma Bile Acid Composition in Mice

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