Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse.

Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1-knock out mice. Mice were developed with a global knock-out of the gene; the full-length RNA was undetectable, and mice were viable and fertile. Both male and female Cyp4x1-knock out mice gained significantly more body weight on normal lab chow diet compared to control flox mice on the same genetic background. At necropsy, Cyp4x1-knock out male mice had significantly greater intra-abdominal fat deposits (P<0.01), and enlarged adipocytes. Metabolic rate and locomotor activity as inferred from VO2 measures and crossing of infrared beams in metabolic cages were not significantly affected by the mutation in either gender. The respiratory exchange ratio was significantly decreased in male knock out mice (P<0.05), suggesting a greater degree of fat oxidation, consistent with their higher adiposity. When mice were maintained on a high fat diet, VO2 was significantly decreased in both male and female Cyp4x1-knock out mice. We conclude that the Cyp4x1-knock out mouse strain demonstrates a mildly obese phenotype, consistent with the view that cytochrome P450 4x1 plays a role in regulating fat metabolism.