title: Mouse aldehyde-oxidase-4 controls diurnal rhythms, fat deposition and locomotor activity.
abstract: Aldehyde-oxidase-4 (AOX4) is one of the mouse aldehyde oxidase isoenzymes and its physiological function is unknown. The major source of AOX4 is the Harderian-gland, where the enzyme is characterized by daily rhythmic fluctuations. Deletion of the Aox4 gene causes perturbations in the expression of the circadian-rhythms gene pathway, as indicated by transcriptomic analysis. AOX4 inactivation alters the diurnal oscillations in the expression of master clock-genes. Similar effects are observed in other organs devoid of AOX4, such as white adipose tissue, liver and hypothalamus indicating a systemic action. While perturbations of clock-genes is sex-independent in the Harderian-gland and hypothalamus, sex influences this trait in liver and white-adipose-tissue which are characterized by the presence of AOX isoforms other than AOX4. In knock-out animals, perturbations in clock-gene expression are accompanied by reduced locomotor activity, resistance to diet induced obesity and to hepatic steatosis. All these effects are observed in female and male animals. Resistance to obesity is due to diminished fat accumulation resulting from increased energy dissipation, as white-adipocytes undergo trans-differentiation towards brown-adipocytes. Metabolomics and enzymatic data indicate that 5-hydroxyindolacetic acid and tryptophan are novel endogenous AOX4 substrates, potentially involved in AOX4 systemic actions.
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Maria Monica
authors.initials: MM
authors.lastname: Barzago
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Mami
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Borsotti
authors.affiliation: Laboratory of Biochemistry and Protein Chemistry, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.affiliation: Laboratory of Neurodegenerative diseases, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Micotti
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Carli
authors.affiliation: Laboratory of Neurochemistry and Behaviour, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Roberto William
authors.initials: RW
authors.lastname: Invernizzi
authors.affiliation: Analytical Instrumentation Unit, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Bagnati
authors.affiliation: Analytical Instrumentation Unit, Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Passoni
authors.affiliation: Laboratory of Mass Spectrometry, Department of Environmental Health Sciences; IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pastorelli
authors.affiliation: Laboratory of Mass Spectrometry, Department of Environmental Health Sciences; IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Brunelli
authors.affiliation: Department of Agricultural and Environmental Sciences; Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Toschi
authors.affiliation: Department of Agricultural and Environmental Sciences; Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cesari
authors.affiliation: Graduate School of Biochemical and Health Sciences, Hiroshima University, Hiroshima Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.affiliation: Laboratory of Molecular Biology, Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156, Milano, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050218:Body Fat Distribution; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D005260:Female; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D005420:Flavoproteins; D000445:Aldehyde Oxidoreductases; C443117:aldehyde oxidase homolog 2, mouse; D056926:CLOCK Proteins