CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model

Int J Obes (Lond). 2019 Mar;43(3):475-486. doi: 10.1038/s41366-018-0037-x. Epub 2018 Feb 20.


Background/objectives: CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6.

Subjects/methods: Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30-34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5-/-) mice and wild type (cyp2a5+/+) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays.

Results: Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21-3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5-/- mice to a greater extent than in cyp2a5+/+ mice, and fatty liver was more pronounced in cyp2a5-/- mice than in cyp2a5+/+ mice. PPARα deficiency in cyp2a5-/- mice developed more severe fatty liver, but body weight was not increased significantly.

Conclusion: CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cytochrome P-450 CYP2A6* / analysis
  • Cytochrome P-450 CYP2A6* / genetics
  • Cytochrome P-450 CYP2A6* / metabolism
  • Diet, High-Fat
  • Female
  • Genome-Wide Association Study*
  • Humans
  • Liver / chemistry
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Obesity* / epidemiology
  • Obesity* / genetics
  • Obesity* / metabolism
  • Polymorphism, Single Nucleotide / genetics


  • CYP2A6 protein, human
  • Cytochrome P-450 CYP2A6