The phenotype of a knockout mouse identifies flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing

Sandra G Gonzalez Malagon,Anna N Melidoni,Diana Hernandez,Bilal A Omar,Lyndsey Houseman,Sunil Veeravalli,Flora Scott,Dorsa Varshavi,Jeremy Everett,Yugo Tsuchiya,John F Timms,Ian R Phillips,Elizabeth A Shephard

doi:10.1016/j.bcp.2015.05.013

Sandra G Gonzalez Malagon, Anna N Melidoni + Show 11 more

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https://doi.org/10.1016/j.bcp.2015.05.013

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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.

Highlights

Flavin-containing monooxygenases (FMOs) (EC 1.14.13.8) of eukaryotes are located in the membranes of the endoplasmic reticulum
The majority of humans, are homozygous for a nonsense mutation of FMO2, which results in the expression of a nonfunctional protein [6,7], and mutations in FMO3 cause the disorder trimethylaminuria [8], which is characterized by an unpleasant body odour, due to defective N-oxygenation of dietary-derived trimethylamine [9]
Mice in which the Fmo5 gene had been inactivated appeared healthy but exhibited a lean phenotype, which was age-related, becoming apparent only at about 20 weeks of age. From this age WT mice continued to increase body weight and this was accompanied by increases in the amount of lipid stored in white adipose tissue (WAT) and in the plasma concentration of cholesterol

Summary

Introduction

Flavin-containing monooxygenases (FMOs) (EC 1.14.13.8) of eukaryotes are located in the membranes of the endoplasmic reticulum. Humans possess five functional FMO genes [1,2], four of which, FMO1, 2, 3 and 4, are clustered on chromosome 1, in the region 1q24.3, whereas FMO5 is located at 1q21.1 [1]. The FMO1 gene displays little genetic variation, with only a few coding-region single-nucleotide polymorphisms (SNPs), each of which is present at low frequency [2,4] and does not affect catalytic activity [5]. The majority of humans, are homozygous for a nonsense mutation of FMO2, which results in the expression of a nonfunctional protein [6,7], and mutations in FMO3 cause the disorder trimethylaminuria [8], which is characterized by an unpleasant body odour, due to defective N-oxygenation of dietary-derived trimethylamine [9]. FMO4 has not been detected in vivo and little is known of its substrates or activity

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