Abstract P172: Activation of Pgc1α by EET Stimulates Insulin Sensitivity, Normalizes Blood Pressure and Increases Mitochondrial Oxphos in Obese Mice
Background/Objectives: Obesity is a risk factor in the development of type 2 diabetes mellitus (DM2), which is associated with increased morbidity and mortality, predominantly as a result of cardiovascular complications. Increased adiposity is a systemic condition characterized by increased oxidative stress (ROS), inflammation, inhibition of anti-oxidant genes such as HO-1 and increased degradation of epoxyeicosatrienoic acids (EETs). Hypothesis: We postulate that EETs increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) activity, which controls mitochondrial function, oxidative metabolism and may also increase antioxidants and HO-1 gene expression. Methods: C57/B16 mice were fed a high fat (HF) diet for 26 wks. The protocol comprised three groups: A) WT, B) HF control and C) HF-treated with EET agonist (EET-A). Renal and visceral fat tissues were harvested to measure signaling protein. Consumption was measured at 6 and 24 wks. Mice were used to assess insulin levels, insulin sensitivity, blood pressure and mitochondrial OXPHOS and mitochondrial biogenesis (Mfn1, 2 and Opa1), and oxygen consumption (VO 2 ). Results: Animals on a HF diet exhibited increased body weight, fat content, fasting blood glucose levels, systolic blood pressure (BP) and a significant reduction in VO 2 . Administration of EET-A to HF-fed mice decreased the RQ (VCO 2 /VO 2 ) ratio and normalized BP. The HF diet produced increased levels of the adipogenic markers MEST, aP2, C/EBPα and FAS. EET-A attenuated these perturbations through an increase in renal and adipose tissue PGC1α levels. The EET-mediated HO-1 induction increased mitochondrial function as measured by OXPHOS, MnSOD and thermogenic genes, TFAM, UCP1 and SIRT 1. EET-A also increased adiponectin levels, and insulin receptor phosphorylation IRP Tyr 972 and 1146 and normalized glucose levels. Conclusion: These data show that an EET agonist increased PGC-1α-HO-1 levels thereby providing metabolic protection and increased VO 2 consumption in HF-induced obesity in mice. This novel finding suggests that the EET-mediated PGC-1α activation is essential to increase HO-1 levels, mitochondrial biogenesis, and to decrease mitochondrial ROS and adiposity.