Mouse aldehyde-oxidase-4 controls diurnal rhythms, fat deposition and locomotor activity

Mineko Terao, Maria Monica Barzago, Mami Kurosaki, Maddalena Fratelli, Marco Bolis, Andrea Borsotti, Paolo Bigini, Edoardo Micotti, Mirjana Carli, Roberto William Invernizzi, Renzo Bagnati, Alice Passoni, Roberta Pastorelli, Laura Brunelli, Ivan Toschi, Valentina Cesari, Seigo Sanoh, Enrico Garattini

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number30343
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Jul 26 2016

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