Journal
JOURNAL OF LIPID RESEARCH
Volume 55, Issue 10, Pages 2124-2136Publisher
ELSEVIER
DOI: 10.1194/jlr.M053199
Keywords
adipose tissue; arachidonic acid; eicosanoids; high-fat diet; metabolomics; soluble epoxide hydrolase
Categories
Funding
- American Heart Association
- Robert A. Welch Foundation [GM31278]
- Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01 ES050167, Z01 ES025034]
- [R01 GM088199]
- [P30 DK34987]
- [P30 DK056350]
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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.
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