Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity

Weibin Zha, Matthew L. Edin, Kimberly C. Vendrov, Robert N. Schuck, Fred B. Lih, Jawahar Lal Jat, J. Alyce Bradbury, Laura M. DeGraff, Kunjie Hua, Kenneth B. Tomer, J R Falck, Darryl C. Zeldin, Craig R. Lee

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Adipogenesis plays a critical role in the initiation and progression of obesity. Although cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) have emerged as a potential therapeutic target for cardiometabolic disease, the functional contribution of EETs to adipogenesis and the pathogenesis of obesity remain poorly understood. Our studies demonstrated that induction of adipogenesis in differentiated 3T3-L1 cells (in vitro) and obesity-associated adipose expansion in high-fat diet (HFD)-fed mice (in vivo) significantly dysregulate the CYP epoxygenase pathway and evoke a marked suppression of adipose-derived EET levels. Subsequent in vitro experiments demonstrated that exogenous EET analog administration elicits potent anti-adipogenic effects via inhibition of the early phase of adipogenesis. Furthermore, EET analog administration to mice significantly mitigated HFD-induced weight gain, adipose tissue expansion, pro-adipogenic gene expression, and glucose intolerance. Collectively, these findings suggest that suppression of EET bioavailability in adipose tissue is a key pathological consequence of obesity, and strategies that promote the protective effects of EETs in adipose tissue offer enormous therapeutic potential for obesity and its downstream pathological consequences.

Original languageEnglish (US)
Pages (from-to)2124-2136
Number of pages13
JournalJournal of lipid research
Volume55
Issue number10
DOIs
StatePublished - Oct 1 2014

Keywords

  • Adipose tissue
  • Arachidonic acid
  • Eicosanoids
  • High-fat diet
  • Metabolomics
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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    Zha, W., Edin, M. L., Vendrov, K. C., Schuck, R. N., Lih, F. B., Jat, J. L., Bradbury, J. A., DeGraff, L. M., Hua, K., Tomer, K. B., Falck, J. R., Zeldin, D. C., & Lee, C. R. (2014). Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity. Journal of lipid research, 55(10), 2124-2136. https://doi.org/10.1194/jlr.M053199