Characterisation of the Metabolic Phenotype of the Fmo5 Knockout Mouse

Through the use of a knockout mouse line, we have identified flavin-containing monooxygenase 5 (FMO5) as a regulator of energy homeostasis. The characterisation of the FMO5 knockout (FMO5 KO) phenotype reveals the mutant animals are resistant to age-related and diet-induced weight gain when compared to age-matched wild-type (WT) controls. The FMO5 KO mice exhibit higher insulin sensitivity and need lower circulating insulin to maintain normal glycaemia. The knockout mice are also more responsive to an exogenous dose of insulin and they do not gain weight when fed a high fat diet. FMO5 is expressed in the murine digestive tract of WT animals and is further induced in high-fat feeding. Investigations into the intestine of the knockout animal reveal differences in the intestinal microbiota and a different processing of a colonic hormone, RELMβ. This hormone is involved in intestinal inflammation and less was detected in circulation of the knockout mouse. Furthermore, lower levels of circulating cytokine TNFα was detected and inflammation of adipose tissue, peripheral to the intestine, was found to be lower in the knockout mice. The findings implicate FMO5 to be a modulator of the intestinal environment and an mediator of inflammation. By influencing the processing of RELMβ, the protein contributes to the systemic inflammatory profile of the animal. Reduced inflammation of sites such as adipose tissue in the absence of the protein correlates with higher insulin sensitivity and a leaner animal.