{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST001743","ANALYSIS_ID":"AN002836","VERSION":"1","CREATED_ON":"April 15, 2021, 3:52 pm"},

"PROJECT":{"PROJECT_TITLE":"The Role of Intestinal-derived FGF15 and Vertical Sleeve Gastrectomy on Plasma Bile Acid Composition in Mice","PROJECT_SUMMARY":"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.","INSTITUTE":"University of Michigan","DEPARTMENT":"MRC2","LABORATORY":"Metabolomics core","LAST_NAME":"Kachman","FIRST_NAME":"Maureen","ADDRESS":"1000 Wall St., 5458","EMAIL":"mkachman@med.umich.edu","PHONE":"734-232-0842","FUNDING_SOURCE":"NIH: 1U2CDK110678-01, P30-AR069620, P30 DK089503, DK097153, 5T32DK108740, 5T32DK071212-12, UL1TR002240, DK020572, DK089503, DK107282, DK121995, RO1 DK62876 , R24 DK092759, American Diabetes Association grants 1-19-IBS-252 and 1-18-PDF-087"},

"STUDY":{"STUDY_TITLE":"The Role of Intestinal-derived FGF15 and Vertical Sleeve Gastrectomy on Plasma Bile Acid Composition in Mice","STUDY_TYPE":"MS analysis","STUDY_SUMMARY":"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.","INSTITUTE":"University of Michigan","DEPARTMENT":"Surgery","LABORATORY":"Seeley Lab","LAST_NAME":"Seeley","FIRST_NAME":"Randy","ADDRESS":"Ann Arbor, MI, 48105, USA","EMAIL":"seeleyrj@umich.edu","PHONE":"734-615-2880"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090","GENDER":"Male"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"380",
"Sample ID":"S00046232",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046232-1-N.d"}
},
{
"Subject ID":"407",
"Sample ID":"S00046233",
"Factors":{"Genotype":"CTRL","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046233-2-N.d"}
},
{
"Subject ID":"342",
"Sample ID":"S00046234",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046234-3-N.d"}
},
{
"Subject ID":"463",
"Sample ID":"S00046235",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046235-4-N.d"}
},
{
"Subject ID":"464",
"Sample ID":"S00046236",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046236-5-N.d"}
},
{
"Subject ID":"496",
"Sample ID":"S00046237",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046237-6-N.d"}
},
{
"Subject ID":"469",
"Sample ID":"S00046238",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046238-7-N.d"}
},
{
"Subject ID":"498",
"Sample ID":"S00046239",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046239-8-N.d"}
},
{
"Subject ID":"479",
"Sample ID":"S00046240",
"Factors":{"Genotype":"CTRL","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046240-9-N.d"}
},
{
"Subject ID":"340",
"Sample ID":"S00046241",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046241-10-N.d"}
},
{
"Subject ID":"471",
"Sample ID":"S00046242",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046242-11-N.d"}
},
{
"Subject ID":"501",
"Sample ID":"S00046244",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046244-13-N.d"}
},
{
"Subject ID":"412",
"Sample ID":"S00046245",
"Factors":{"Genotype":"CTRL","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046245-14-N.d"}
},
{
"Subject ID":"472",
"Sample ID":"S00046247",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046247-16-N.d"}
},
{
"Subject ID":"429",
"Sample ID":"S00046248",
"Factors":{"Genotype":"CTRL","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046248-17-N.d"}
},
{
"Subject ID":"435",
"Sample ID":"S00046249",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046249-18-N.d"}
},
{
"Subject ID":"478",
"Sample ID":"S00046250",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046250-19-N.d"}
},
{
"Subject ID":"474",
"Sample ID":"S00046251",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046251-20-N.d"}
},
{
"Subject ID":"468",
"Sample ID":"S00046252",
"Factors":{"Genotype":"CTRL","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046252-21-N.d"}
},
{
"Subject ID":"465",
"Sample ID":"S00046253",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046253-22-N.d"}
},
{
"Subject ID":"485",
"Sample ID":"S00046254",
"Factors":{"Genotype":"CTRL","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046254-23-N.d"}
},
{
"Subject ID":"499",
"Sample ID":"S00046256",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"VSG"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046256-25-N.d"}
},
{
"Subject ID":"500",
"Sample ID":"S00046257",
"Factors":{"Genotype":"FGF15INT-KO","Surgery":"Sham"},
"Additional sample data":{"RAW_FILE_NAME":"20200827-EX01051-A014-IN0026-S00046257-26-N.d"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Mouse blood collection","SAMPLE_TYPE":"Blood (plasma)"},

"TREATMENT":{"TREATMENT_SUMMARY":"HFD diet after sham or VSG surgery"},

"SAMPLEPREP":{"SAMPLEPREP_SUMMARY":"Standard bile acid analysis sample prep","SAMPLEPREP_PROTOCOL_FILENAME":"Bile_Acids_Assay.pdf"},

"CHROMATOGRAPHY":{"CHROMATOGRAPHY_TYPE":"Reversed phase","INSTRUMENT_NAME":"Agilent 6410","COLUMN_NAME":"Waters XBridge C18 (150mm x 2.1mm, 3.5um)"},

"ANALYSIS":{"ANALYSIS_TYPE":"MS"},

"MS":{"INSTRUMENT_NAME":"Agilent 6410 QQQ","INSTRUMENT_TYPE":"Triple quadrupole","MS_TYPE":"ESI","ION_MODE":"NEGATIVE","MS_COMMENTS":"Agilent Data Acquisition/Agilent Quant"},

"MS_METABOLITE_DATA":{
"Units":"nM",

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}

}