Yang Yang, Wu Haoying, Xu Xinyun, Morisseau Christophe, Lee Kin Sing Stephen, Hammock Bruce D, Chen Jiangang, Zhao Ling
Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA.
Department of Entomology and Nematology, Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
Nutrients. 2025 Mar 7;17(6):936. doi: 10.3390/nu17060936.
: 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive metabolites produced from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively, by CYP450s. These metabolites are unstable and quickly metabolized by auto-oxidation, esterification, β-oxidation, or hydrolysis by soluble epoxide hydrolase (sEH). 17,18-EEQ or 19,20-EDP combined with a potent sEH inhibitor -TUCB differentially activated brown adipose tissue in diet-induced obesity. In the current study, we investigated whether these -3 epoxy fatty acids with -TUCB directly promote brown adipocyte differentiation and their thermogenic capacities. : Murine brown preadipocytes were treated with 17,18-EEQ or 19,20-EDP with -TUCB during and post differentiation. Brown marker protein expression and mitochondrial respiration were measured. In addition, the activation of PPARγ and suppression of NFκB reporter by 17,18-EEQ or 19,20-EDP alone or with -TUCB were assessed, and the roles of PPARγ were evaluated with PPARγ knockdown and GW9662. : 17,18-EEQ or 19,20-EDP with -TUCB promoted brown adipogenesis and mitochondrial respiration and uncoupling. Moreover, with -TUCB, both epoxides improved mitochondrial respiration, but only 17,18-EEQ with -TUCB significantly increased mitochondrial uncoupling (and heat production) in the differentiated adipocytes. PPARγ may be required for the effects of epoxides on differentiation but not on the thermogenic function post differentiation. : The results demonstrate that, with -TUCB, 17,18-EEQ and 19,20-EDP promote brown adipogenesis and mitochondrial respiration and uncoupling. 17,18-EEQ also promotes thermogenesis in differentiated brown adipocytes. Together, the results suggest thermogenic potentials of tested -3 epoxides, especially 17,18-EEQ with -TUCB. Translational studies of these -3 epoxides on human brown adipocyte differentiation and functions are warranted.
17,18-环氧二十碳四烯酸（17,18-EEQ）和19,20-环氧二十二碳五烯酸（19,20-EDP）分别是由细胞色素P450（CYP450s）从二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）产生的生物活性代谢产物。这些代谢产物不稳定，会通过自动氧化、酯化、β-氧化或被可溶性环氧化物水解酶（sEH）水解而迅速代谢。17,18-EEQ或19,20-EDP与一种强效的sEH抑制剂——三甲环己酯草酸盐（TUCB）联合使用，可在饮食诱导的肥胖模型中差异性地激活棕色脂肪组织。在本研究中，我们调查了这些含-TUCB的ω-3环氧脂肪酸是否直接促进棕色脂肪细胞分化及其产热能力。：在分化期间及分化后，用含-TUCB的17,18-EEQ或19,20-EDP处理小鼠棕色前脂肪细胞。检测棕色标记蛋白表达和线粒体呼吸。此外，评估单独使用或与-TUCB联合使用时，17,18-EEQ或19,20-EDP对过氧化物酶体增殖物激活受体γ（PPARγ）的激活作用以及对核因子κB（NFκB）报告基因的抑制作用，并用PPARγ基因敲低和GW9662评估PPARγ的作用。：含-TUCB的17,18-EEQ或19,20-EDP促进棕色脂肪生成、线粒体呼吸和解偶联。此外，与-TUCB联合使用时，两种环氧化物均改善了线粒体呼吸，但只有含-TUCB的17,18-EEQ显著增加了分化脂肪细胞中的线粒体解偶联（和产热）。PPARγ可能是环氧化物对分化起作用所必需的，但对分化后的产热功能并非必需。：结果表明，与-TUCB联合使用时，17,18-EEQ和19,20-EDP促进棕色脂肪生成、线粒体呼吸和解偶联。17,18-EEQ还促进分化后的棕色脂肪细胞产热。总之，结果提示了所检测的ω-3环氧化物的产热潜力，尤其是含-TUCB的17,18-EEQ。有必要对这些ω-3环氧化物在人类棕色脂肪细胞分化和功能方面进行转化研究。
