@article{831f928637ce4f149680a60538ca5112,
title = "EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance",
abstract = "We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET)–producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water-soluble EET analog restores insulin signaling in vivo in Cyp2c44−/− mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44−/− mice treated with the analog disodium 13-(3-pentylureido)tridec-8(Z)-enoyl)-LL-aspartate2 (EET-A) for 4 weeks improved fasting glucose and glucose tolerance compared with Cyp2c44−/− mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes, and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor-β (IRβ) is impaired in primary Cyp2c44−/− hepatocytes and that this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane-rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.",
author = "Kakali Ghoshal and Xiyue Li and Dungeng Peng and Falck, {John R.} and Anugu, {Raghunath Reddy} and Manuel Chiusa and Stafford, {John M.} and Wasserman, {David H.} and Roy Zent and Luther, {James M.} and Ambra Pozzi",
note = "Funding Information: Funding. This work was supported in part by American Diabetes Association no. 1-19-IBS-282 (A.P.), National Institutes of Health National Heart, Lung and Blood Institute grant R01-HL144846 (J.M.S.), National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK109102 (J.M.S.) U24-DK059537 (D.H.W.), R01-DK050277 (D.H.W.), R01-DK069921 (R.Z.), R01-DK117875 (J.M.L.), P30-DK114809 (A.P.), and R01-DK119212 (A.P.), the Robert A. Welch Foundation (I-0011, J.R.F.), and by Department of Veterans Affairs Merit Reviews BX005459 (J.M.S.), 1I01BX002196 (R.Z.), and 1I01BX002025 (A.P.). A.P. is the recipient of a Department of Veterans Affairs Senior Research Career Scientist Award. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. K.G. conducted experiments, acquired data, analyzed data, and wrote the manuscript. X.L., D.P., and M.C. conducted experiments. J.R.F. and R.R.A. provided reagents. J.M.S., D.H.W., R.Z., and J.M.L. contributed to discussion and reviewed and edited the manuscript. A.P. designed research studies and wrote the manuscript. A.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: This work was supported in part by American Diabetes Association no. 1-19-IBS-282 (A.P.), National Institutes of Health National Heart, Lung and Blood Institute grant R01-HL144846 (J.M.S.), National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK109102 (J.M.S.) U24-DK059537 (D.H.W.), R01-DK050277 (D.H.W.), R01-DK069921 (R.Z.), R01-DK117875 (J.M.L.), P30-DK114809 (A.P.), and R01-DK119212 (A.P.), the Robert A. Welch Foundation (I-0011, J.R.F.), and by Department of Veterans Affairs Merit ReviewsBX005459 (J.M.S.), 1I01BX002196 (R.Z.), and 1I01BX002025 (A.P.). A.P. is the recipient of a Department of Veterans Affairs Senior Research Career Scientist Award. Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",
year = "2022",
month = jan,
doi = "10.2337/db21-0298",
language = "English (US)",
volume = "71",
pages = "83--92",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "1",
}