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

Journal of Lipid Research

Jawahar Lal Jat¹  John R. Falck¹  Weibin Zha²  Robert N. Schuck²  Kimberly C. Vendrov²  Darryl C. Zeldin³  Laura M. DeGraff³  J. Alyce Bradbury³  Kenneth B. Tomer³  Fred B. Lih³  Matthew L. Edin³  Craig R. Lee⁴  Kunjie Hua⁵ 

[1] Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX;Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC;Laboratory of Respiratory Biology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC;To whom correspondence should be addressed;UNC Nutrition Obesity Research Center, University of North Carolina, Chapel Hill, NC;

关键词: adipose tissue;    arachidonic acid;    eicosanoids;    high-fat diet;    metabolomics;    soluble epoxide hydrolase;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown