Date of Award

5-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

Committee Member

Dr. William S Baldwin, Committee Chair

Committee Member

Dr. Lisa J Bain

Committee Member

Dr. Peter Van den Hurk

Committee Member

Dr. David M. Feliciano

Abstract

The Cytochrome P450s (CYP) in families 1-3 are integral to the metabolism of xenobiotics such as pharmaceuticals, pesticides and plasticizers as well as endobiotics such as hormones, bile salts and fatty acids. Recently, hepatic CYP activity was associated with fatty liver and potentially obesity. The CYPs in the 3A and 2B families are critical in xenobiotic detoxification and are regulated by transcription factors that control toxic responses in addition to energy homeostasis. Therefore, we assessed the significance of CYP3A and CYP2B in obesity and hepatic energy metabolism using Cyp3a or Cyp2b knockout mouse models. Cyp3a-null and Cyp2b-null mice were challenged with a high fat diet (HFD) for 8-10 weeks to test whether these mice were more susceptible to obesity and fatty liver disease. We determined changes in body weight, organ weight, white adipose tissue mass, hepatic lipids, glucose metabolism and sensitivity, hormone changes in these mice after 8-10 weeks of HFD treatments. We hypothesized that the lack of Cyp2b / Cyp3a will increase the susceptibility of the -null mice to diet-induced obesity. Our results indicate that Cyp2b’s are crucial in protection of HFD-induced obesity. Cyp2b-null male but not Cyp2b-null female mice gained more body weight coupled with increased white adipose tissue mass compared to their wild-type counterparts following a HFD. The response in Cyp3a-null mice were not as strong; however, gender-based differences were observed in both models. Cyp3a-null female mice were moderately protected from HFD-induced obesity. We also observed significant increase in liver triglycerides in the Cyp3a-null and Cyp2b-null mice. In conclusion, loss of Cyp2b exacerbates obesity, while loss of Cyp3a mitigates the development of HFD-induced obesity.

Share

COinS