title: Effects ofG6pc2deletion on body weight and cholesterol in mice.
abstract: Genome-wide association study (GWAS) data have linked theG6PC2gene to variations in fasting blood glucose (FBG).G6PC2encodes an islet-specific glucose-6-phosphatase catalytic subunit that forms a substrate cycle with the beta cell glucose sensor glucokinase. This cycle modulates the glucose sensitivity of insulin secretion and hence FBG. GWAS data have not linkedG6PC2to variations in body weight but we previously reported that female C57BL/6JG6pc2-knockout (KO) mice were lighter than wild-type littermates on both a chow and high-fat diet. The purpose of this study was to compare the effects ofG6pc2deletion on FBG and body weight in both chow-fed and high-fat-fed mice on two other genetic backgrounds. FBG was reduced inG6pc2KO mice largely independent of gender, genetic background or diet. In contrast, the effect ofG6pc2deletion on body weight was markedly influenced by these variables. Deletion ofG6pc2conferred a marked protection against diet-induced obesity in male mixed genetic background mice, whereas in 129SvEv mice deletion ofG6pc2had no effect on body weight.G6pc2deletion also reduced plasma cholesterol levels in a manner dependent on gender, genetic background and diet. An association betweenG6PC2and plasma cholesterol was also observed in humans through electronic health record-derived phenotype analyses. These observations suggest that the action of G6PC2 on FBG is largely independent of the influences of environment, modifier genes or epigenetic events, whereas the action of G6PC2 on body weight and cholesterol are influenced by unknown variables.
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Kayla A
authors.initials: KA
authors.lastname: Boortz
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Syring
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Lynley D
authors.initials: LD
authors.lastname: Pound
authors.affiliation: Department of Biomedical InformaticsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Mo
authors.affiliation: Department of Biomedical InformaticsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Oeser
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.affiliation: Department of Biomedical InformaticsVanderbilt University School of Medicine, Nashville, Tennessee, USA.|Department of MedicineVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Department of Molecular Physiology and BiophysicsVanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001835:Body Weight / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D059305:Diet, High-Fat; D005215:Fasting; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D056726:Genetic Association Studies; D000068617:Genetic Background; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D001786:Blood Glucose; D007328:Insulin; D002784:Cholesterol; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse
keywords: body weight; cholesterol; fasting blood glucose; glucose-6-phosphatase