title: The phenotype of a knockout mouse identifies flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing.
abstract: We report the production and metabolic phenotype of a mouse line in which the Fmo5 gene is disrupted. In comparison with wild-type (WT) mice, Fmo5(-/-) mice exhibit a lean phenotype, which is age-related, becoming apparent after 20 weeks of age. Despite greater food intake, Fmo5(-/-) mice weigh less, store less fat in white adipose tissue (WAT), have lower plasma glucose and cholesterol concentrations and enhanced whole-body energy expenditure, due mostly to increased resting energy expenditure, with no increase in physical activity. An increase in respiratory exchange ratio during the dark phase, the period in which the mice are active, indicates a switch from fat to carbohydrate oxidation. In comparison with WT mice, the rate of fatty acid oxidation in Fmo5(-/-) mice is higher in WAT, which would contribute to depletion of lipid stores in this tissue, and lower in skeletal muscle. Five proteins were down regulated in the liver of Fmo5(-/-) mice: aldolase B, ketohexokinase and cytosolic glycerol 3-phosphate dehydrogenase (GPD1) are involved in glucose or fructose metabolism and GPD1 also in production of glycerol 3-phosphate, a precursor of triglyceride biosynthesis; HMG-CoA synthase 1 is involved in cholesterol biosynthesis; and malic enzyme 1 catalyzes the oxidative decarboxylation of malate to pyruvate, in the process producing NADPH for use in lipid and cholesterol biosynthesis. Down regulation of these proteins provides a potential explanation for the reduced fat deposits and lower plasma cholesterol characteristic of Fmo5(-/-) mice. Our results indicate that disruption of the Fmo5 gene slows metabolic ageing via pleiotropic effects.
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Sandra G
authors.initials: SG
authors.lastname: Gonzalez Malagon
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Melidoni
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Hernandez
authors.affiliation: School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK.
authors.forename: Bilal A
authors.initials: BA
authors.lastname: Omar
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Lyndsey
authors.initials: L
authors.lastname: Houseman
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Sunil
authors.initials: S
authors.lastname: Veeravalli
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Flora
authors.initials: F
authors.lastname: Scott
authors.affiliation: Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, Kent ME4 4TB, UK.
authors.forename: Dorsa
authors.initials: D
authors.lastname: Varshavi
authors.affiliation: Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, Kent ME4 4TB, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Everett
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Women's Cancer, Institute for Women's Health, University College London, London WC1E 6BT, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Timms
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK; School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Phillips
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, UK. Electronic address: e.shephard@ucl.ac.uk.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Shephard
mesh_terms: D052436:Adipose Tissue, White / Q000201:enzymology*; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D004734:Energy Metabolism / Q000235:genetics; D018703:Founder Effect; D005631:Fructokinases / Q000235:genetics / Q000378:metabolism; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000235:genetics / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000201:enzymology; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology; D010084:Oxidation-Reduction; D010105:Oxygenases / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; D008291:Malate Dehydrogenase; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+); D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D006904:Hydroxymethylglutaryl-CoA Synthase; D005631:Fructokinases; C021475:ketohexokinase; D005634:Fructose-Bisphosphate Aldolase
keywords: Body weight; Cholesterol; Glucose; Malic enzyme 1; White adipose tissue