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Cyp2b-null Mice are Susceptible to High-Fat Diet Induced Obesity

William S. Baldwin, Clemson University

31 August 2018

CYP2B metabolizes multiple endo- and xenobiotics, including drugs. Recent studies using the cytochrome P450 oxidoreductase knockout mouse revealed steatosis coupled with induced Cyp2b10. Data from our laboratory using RNAi-mediated Cyp2b-knockdown mouse indicated that the older knockdown mice were heavier and contain greater serum lipid concentrations, especially males. To investigate the role played by CYP2B in lipid metabolism Dr. Baldwin's lab has developed a CYP2B triple knockout lacking Cyp2b9, 10 and 13 using CRISPR/Cas9.  They treated them with a 60% fat diet (HFD) for 10 weeks and determined physiological, metabolic and molecular changes in WT and Cyp2b-null mice. Male but not female Cyp2b-null mice weigh approximately 15% more than WT counterparts fed a HFD, primarily due to an increase in white adipose tissue. Serum parameters indicate increased b-hydroxybutyrate in Cyp2b-null HFD-fed mice, a marker of ketosis.  In addition, leptin, adiponectin, and cholesterol were increased in HFD-fed Cyp2b-null male mice compared to HFD-fed WT mice. Liver triglycerides were significantly higher than their similarly treated WT counterparts (ND and HFD), indicating a role for Cyp2b in fatty acid metabolism regardless of diet.  This probably contributed to the lower levels of triglycerides in Cyp2b-null mice. Interestingly, RNAseq demonstrates that hepatic gene expression in ND-fed Cyp2b-null mice is similar to HFD-fed WT mice.  Overall the data indicates that the repression or chemical inhibition of CYP2B may exacerbate metabolic disorders and cause obesity by perturbing fatty acid metabolism.