Date of Award
Doctoral Dissertation - Restricted (NYMC/Touro only) Access
Doctor of Philosophy
Basic Medical Sciences
Dr. Michal L. Schwartzman
Studies in humans and animal models have shown that levels of 20-Hydroxyeicosatetraenoic acid (20-HETE), the omega-hydroxylation product of arachidonic acid, positively correlate with body mass index, hyperglycemia and plasma insulin levels. In the present study, we seek to identify a causal relationship between 20-HETE and obesity-driven insulin resistance using two distinct transgenic mouse models with overexpression of Cyp4a12-20-HETE-synthase. These include the Cyp4a14 knockout (Cyp4a14-/-) mice which is an androgen-driven model of 20-HETE overproduction and the Cyp4a12 transgenic mice (Cyp4a12tg) which is an androgen-independent doxycycline (DOX)-inducible model of 20-HETE overproduction. Cyp4a14-/- male mice were fed a regular control (CD) or high-fat diet (HFD) for 15 weeks. 20-SOLA [2,5,8,11,14,17-hexaoxanonadecan-19-yl20-hydroxyeicosa-6(Z),15(Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed Cyp4a14-/- male mice gained significant weight (16.7 ± 3.2 vs. 3.8 ± 0.35 g, P < 0.05) and developed hyperglycemia (157 ± 3 vs. 121 ± 7 mg/dl, P < 0.05) and hyperinsulinemia (2.3 ± 0.4 vs. 0.5 ± 0.1 ng/ml, P < 0.05) compared with corresponding CD-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 ± 1 vs. 16.7 ± 3 g, P < 0.05) and normalized the hyperglycemia (157 ± 7 vs. 102 ± 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 ± 0.1 vs. 2.3 ± 0.4 ng/ml, P < 0.05). The Cyp4a12tg mice in which 20-HETE overproduction occurs in response to DOX were fed either i) control diet (No Dox + CD); ii) high-fat diet (No Dox + HFD); iii) control diet with doxycycline (Dox + CD); or iv) high-fat diet with doxycycline (Dox + HFD) for 15 weeks. 20-SOLA was administered in drinking water from week 0 of HFD (Dox or No Dox). Dox + HFD-fed mice gained significant body weight compared to regular diet-fed mice (20.63 ± 2.9 vs. 3.75 ± 0.6 g, P < 0.05) or mice receiving HFD alone (20.63 ± 2.9 vs. 13.51 ± 0.94 g, P < 0.05). Mice fed HFD with doxycycline developed hyperglycemia (144 ± 3.53 vs. 101.2 ± 6.1 mg/dl, P < 0.05) and hyperinsulinemia (2.52 ± 0.58 vs. 0.55 ± 0.10 ng/ml, P < 0.05) compared to CD-fed mice. However, this effect was not seen in mice fed HFD without doxycycline. 20-SOLA attenuated HFD-induced weight gain (11.37 ± 1.78 vs. 20.63 ± 2.9 g, P < 0.05) and normalized the hyperglycemia (104.2 ± 9.13 vs 144.4 ± 3.53 mg/dl, P < 0.05) and hyperinsulinemia (0.71 ± 0.09 vs 2.52 ± 0.58 ng/ml, P < 0.05) in animals receiving doxycycline. 20-SOLA did not change body-weight gain, plasma glucose levels or plasma insulin levels in animals fed a HFD without doxycycline.
Both transgenic mice overexpressing Cyp4a12-20-HETE synthase, viz. the Cyp4a14-/- and the Cyp4a12tg mice, displayed HFD-induced impairment of glucose homeostasis and insulin resistance evident by reduced insulin and glucose tolerance which was ameliorated by 20-SOLA treatment. HFD feeding to transgenic mice overexpressing Cyp4a12-20-HETE synthase resulted in a significant increase in circulatory and adipose tissue 20-HETE levels correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, hyperglycemia and insulin resistance, possibly by interfering with insulin signaling and glucose homeostasis.
Gilani, Ankit, "Role of 20-HETE in Diet-Induced Obesity and Insulin Resistance: Interference with Insulin Signaling" (2019). NYMC Student Theses and Dissertations. 7.
Available for download on Wednesday, January 01, 2020