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Integrating Metabolism and Immunity | EK16


The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity


Jan 25, 2021 12:00am ‐ Jan 25, 2021 12:00am

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The Contribution of Arachidonic Acid Metabolites EETs to Inflammation in Obesity Mona Mashayekhi1, Celestine N. Wanjalla1, Christian M. Warren1, Joshua D. Simmons1, Samuel S. Bailin1, Curtis L. Gabriel1, Spyros A. Kalams1, John R. Koethe1, Nancy J. Brown2, J. Matthew Luther1 1Vanderbilt University Medical Center, Nashville, TN; 2Yale School of Medicine, New Haven, CT Background: Obesity is associated with increased prevalence of type 2 diabetes and cardiovascular disease (CVD). Adipose tissue (AT) contains a complex immune environment and is a central contributor to heightened systemic inflammation in obese persons.1 Increased chronic inflammation in obesity contributes to metabolic disease by increasing insulin resistance, and to CVD by causing an atherogenic dyslipidemia and increasing endothelial cell dysfunction and activation.2 Despite these links between inflammation and cardiometabolic disease in obesity, there are no current targeted therapies to prevent or reverse chronic inflammation in AT. Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules that act as potent vasodilators and promote sodium excretion in the kidney. Increasing EETs in rodents protects against hypertension and endothelial dysfunction. In humans, circulating EETs correlate with insulin sensitivity and are decreased in individuals with insulin resistance.3 EETs also decrease the inflammatory response to obesity in animal models, but the effect of EETs on inflammation in humans is currently unknown. EETs are hydrolyzed to less active forms by the enzyme soluble epoxide hydrolase (sEH), and we hypothesized that pharmacologic sEH inhibition with a specific inhibitor GSK2256294 (GSK) in obese patients would decrease AT inflammation. Methods: Thirty-four obese prediabetic individuals were treated with placebo and GSK in a crossover design (NCT03486223). Participants had a seven-week washout in between drugs, and the order of drug was randomized and blinded. In a subgroup of patients, we collected subcutaneous AT by liposuction and characterized T cell phenotypes by flow cytometry (N=7 paired samples). Results: GSK decreased sEH activity in plasma (47.3% vs placebo; P=0.008) and in AT (58.8% vs placebo; P=0.002). GSK also decreased serum F2-isoprostanes (P=0.03), which are markers of oxidative damage and inflammation. In seven paired AT samples stimulated in vitro, T helper (Th) 1 cells producing the pro-inflammatory cytokine IFNγ were reduced by treatment with GSK as compared with placebo (% of total lymphocytes: Placebo 13.6% ± 6.9, GSK 11.0% ± 5.6, P=0.03 Wilcoxon Signed Rank). In this small sample, we did not detect significant differences in the percentage of other IFNγ-producing cells after treatment with GSK (IFNγ+ natural killer: Placebo 19.0% ± 9.0, GSK 13.3% ± 4.9, P=0.18; IFNγ+ CD8: Placebo 12.0 ± 11.0, GSK 6.1 ± 4.6, P=0.61). In addition, we did not detect any change in Th17, Th2, or regulatory T cells. Conclusions: In a pilot study of seven individuals treated with placebo or an sEH inhibitor, we found that the sEH inhibitor decreased pro-inflammatory Th1 cells as compared with placebo in matched AT samples. Understanding the contribution of the EET/sEH pathway to inflammation in obesity could lead to new strategies to modulate AT and systemic inflammation and reduce the risk of CVD. References: 1. Exley MA, Hand L, O'Shea D, Lynch L. Interplay between the immune system and adipose tissue in obesity. J Endocrinol. 2014;223(2):R41-48. 2. Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators Inflamm. 2010;2010:535918. 3. Gangadhariah MH, Dieckmann BW, Lantier L, et al. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017;60(6):1066-1075. Funding sources: T32DK007061, 5UL1TR002243-03, R01DK117875, R01DK112262, AHA 17SFRN33520017, Vanderbilt Faculty Research Scholars Program

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