The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance

Veeravalli, Sunil; Omar, Bilal; Houseman, Lyndsey; Hancock, Matthew; Malagon, Sandra G. Gonzalez; Scott, Fiona; Janmohamed, Azara; Phillips, Ian; Shephard, Elizabeth A.

doi:10.1016/j.bcp.2014.04.007

Cited by 40 publications

(49 citation statements)

References 39 publications

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“…Thus the down-regulation in this study was surprising, but may indicate a compensatory mechanism reflecting increased enzymatic activities. Interestingly, loss of Fmo1 in mice was recently shown to result in a lean phenotype in mice, thus being involved in the regulation of energy homeostasis [29]. We also observed a lower body weight in exposed animals.…”

Section: Discussionsupporting

confidence: 70%

Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

et al. 2016

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Humans are exposed to a large number of environmental chemicals in their daily life, many of which are readily detectable in blood or urine. It remains uncertain if these chemicals can cause adverse health effects when present together at low doses. In this study we have tested whether a mixture of 27 chemicals administered orally to juvenile male rats for three months could leave a pathophysiological footprint. The mixture contained metals, perfluorinated compounds, PCB, dioxins, pesticides, heterocyclic amines, phthalate, PAHs and others, with a combined dose of 0.16 (Low dose), 0.47 (Mid dose) or 1.6 (High dose) mg/kg bw/day. The lowest dose was designed with the aim of obtaining plasma or urine concentrations in rats at levels approaching those observed in humans. Some single congeners were administered at doses representative of combined doses for chemical groups. With this baseline, we found effects on weight, histology and gene expression in the liver, as well as changes to the blood plasma metabolome in all exposure groups, including low-dose. Additional adverse effects were observed in the higher dosed groups, including enlarged kidneys and alterations to the metabolome. No significant effects on reproductive parameters were observed.

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Section: Discussionsupporting

confidence: 70%

Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

et al. 2016

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“…The former study suggested that mFMO3's effects were peroxisome proliferator-activated receptor ␣ (PPAR␣)-and KLF15-mediated, whereas the latter study concluded that mFMO3 affected cholesterol balance through TMAO production, but that mFMO3's effects on lipids and inflammation were mediated by another substrate. Two other reports examining mFmo1 and mFmo5 knock-out mice, respectively, found that both were capable of altering metabolism and energy balance sufficiently to cause gross alterations in body size (58,59). A recent review discusses these mFMO-related effects on carbohydrate and lipid metabolism and energy balance (60).…”

Section: Diabetes and Metabolic Disordersmentioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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“…In mammals, there is relatively limited information on the specific functions of each FMO beyond tissue-specific expression patterns and the role of FMO3 in a single human disease, fish-odor syndrome (23). Mammalian FMOs also have a major role in regulating cholesterol and fat metabolism (24, 25). Abundance of FMO proteins is increased in the tissues, particularly liver, of several long-lived mouse models including Snell dwarf mice, Ames dwarf mice, growth-hormone receptor knockout mice, Little mice, dietary restricted mice, and rapamycin-fed mice (26).…”

mentioning

confidence: 99%

Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span

Leiser

Rossner

et al. 2015

Science

116

154

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Stabilization of the hypoxia-inducible factor-1 (HIF-1) increases lifespan and healthspan in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in C. elegans through a cell non-autonomous signal to the intestine resulting in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This pro-longevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and necessary for DR-mediated lifespan extension, suggesting that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple lifespan-extending interventions in mice, suggesting that these enzymes may play a critical role in promoting health and longevity across phyla.

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The phenotype of a flavin-containing monooyxgenase knockout mouse implicates the drug-metabolizing enzyme FMO1 as a novel regulator of energy balance

Cited by 40 publications

References 39 publications

Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

Juvenile Male Rats Exposed to a Low-Dose Mixture of Twenty-Seven Environmental Chemicals Display Adverse Health Effects

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span

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