Identification of Flavin-Containing Monooxygenase 5 (FMO5) as a Regulator of Glucose Homeostasis and a Potential Sensor of Gut Bacteria.

Flora Scott,Elizabeth A Shephard,Diede Fennema,Ian R Phillips,Sandra G Gonzalez Malagon,Clarissa R Coveney,Brett A O’Brien,Sunil Veeravalli

doi:10.1124/dmd.117.076612

Abstract

We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5−/− mice). In comparison with wild-type (WT) counterparts, Fmo5−/− mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals. When fed a high-fat diet, they are protected against weight gain and reduction of insulin sensitivity. The phenotype of Fmo5−/− mice is independent of diet and the gut microbiome and is determined solely by the host genotype. Fmo5−/− mice have metabolic characteristics similar to those of germ-free mice, indicating that FMO5 plays a role in sensing or responding to gut bacteria. In WT mice, FMO5 is present in the mucosal epithelium of the gastrointestinal tract where it is induced in response to a high-fat diet. In comparison with WT mice, Fmo5−/− mice have fewer colonic goblet cells, and they differ in the production of the colonic hormone resistin-like molecule β. Fmo5−/− mice have lower concentrations of tumor necrosis factor α in plasma and of complement component 3 in epididymal white adipose tissue, indicative of improved inflammatory tone. Our results implicate FMO5 as a regulator of body weight and of glucose disposal and insulin sensitivity and, thus, identify FMO5 as a potential novel therapeutic target for obesity and insulin resistance.

Highlights

Flavin-containing monooxygenases (FMOs) (Enzyme Commission #1.14.13.8) of mammals play an important role in the NADPHdependent oxidative metabolism of a wide array of foreign chemicals (Krueger and Williams, 2005)
Mice in which the Fmo5 gene had been disrupted, Fmo52/2 mice, were resistant to these changes in glucose homeostasis and maintained the higher glucose tolerance and insulin sensitivity that is characteristic of young animals
Fmo52/2 mice were resistant to these changes, indicating that their metabolic phenotype is independent of diet

Summary

Introduction

Flavin-containing monooxygenases (FMOs) (Enzyme Commission #1.14.13.8) of mammals play an important role in the NADPHdependent oxidative metabolism of a wide array of foreign chemicals (Krueger and Williams, 2005). FMOs 1, 2, and 3 catalyze the N- and S-oxygenation of a structurally diverse range of xenobiotic agents, including therapeutic drugs, dietary components, and environmental pollutants (Krueger and Williams, 2005; Phillips et al, 2007). FMO5 catalyzes the N-oxygenation of short-chain aliphatic primary amines such as N-octylamine (Overby et al, 1995) and the S-oxygenation of S-methylesonarimod, an active metabolite of the antirheumatic agent esonarimod (Ohmi et al, 2003; Zhang et al, 2007), it is apparently more efficient in catalyzing the oxygenation of a variety of carbonyl compounds, via a BaeyerVilliger process (Fiorentini et al, 2016), including the anticancer drug E7016 (Lai et al, 2011) and the antibacterial agent MRX-I (Meng et al, 2015).

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