Increased CYP2J3 Expression Reduces Insulin Resistance in Fructose-Treated Rats and db/db Mice

Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Diabetes (Impact Factor: 8.47). 04/2010; 59(4):997-1005. DOI: 10.2337/db09-1241
Source: PubMed

ABSTRACT Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play crucial and diverse roles in cardiovascular homeostasis. The anti-inflammatory, antihypertensive, and pro-proliferative effects of EETs suggest a possible beneficial role for EETs on insulin resistance and diabetes.
This study investigated the effects of CYP2J3 epoxygenase gene therapy on insulin resistance and blood pressure in diabetic db/db mice and in a model of fructose-induced hypertension and insulin resistance in rats.
CYP2J3 gene delivery in vivo increased EET generation, reduced blood pressure, and reversed insulin resistance as determined by plasma glucose levels, homeostasis model assessment insulin resistance index, and glucose tolerance test. Furthermore, CYP2J3 treatment prevented fructose-induced decreases in insulin receptor signaling and phosphorylation of AMP-activated protein kinases (AMPKs) in liver, muscle, heart, kidney, and aorta. Thus, overexpression of CYP2J3 protected against diabetes and insulin resistance in peripheral tissues through activation of insulin receptor and AMPK pathways.
These results highlight the beneficial roles of the CYP epoxygenase-EET system in diabetes and insulin resistance.

Download full-text


Available from: Matthew L Edin, Mar 19, 2014
  • Source
    • "Another potential mechanism that may contribute to some of the effects of chronic s-EH inhibition is activation of AMP-activated protein kinase (AMPK). Recent studies indicate that arachidonic acid epoxygenase metabolites activate AMPK which acts as a sensor of cellular energy status and may contribute to the effects of EETs-mediated improvement of diabetes and insulin resistance [24]. Thus, it is possible that the improvement of insulin resistance and weight loss after s-EH inhibition may be due, at least in part, to increased activation of AMPK signaling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study evaluated the responses to soluble epoxide hydrolase (s-EH) inhibition, an essential enzyme in the metabolism of arachidonic acid, on food intake, body weight and metabolic parameters in mice fed a high fat-high fructose diet (HFD) for 10 weeks. After 5 weeks of HFD, mice were divided into two groups: 1) s-EH inhibitor (AR9281, 200mg/kg/day by gavage twice daily), and 2) vehicle (0.3ml per gavage). Food intake, body weight, oxygen consumption (VO(2)), carbon dioxide production (VCO(2)), respiratory quotient (RQ), and motor activity were measured weekly for more 5 weeks. HFD increased body weight (37±1 vs. 26±1g), and plasma of glucose (316±8 vs. 188±27mg/dl), insulin (62.1±8.1 vs. 15.5±5.0μU/ml), and leptin levels (39.4±3.6 vs. 7.5±0.1ng/ml) while reducing VO(2), VCO(2) and motor activity. s-EH inhibition for 5 weeks decreased caloric intake by ~32% and increased VO(2) by ~17% (42.8±1.4 vs. 50.2±1.5ml/kg/min) leading to significant weight loss. Inhibition of s-EHi also caused significant reductions in plasma leptin levels and visceral fat content. Uncoupling protein 1 (UCP1) content in brown adipose tissue was also elevated by ~50% during s-EH inhibition compared to vehicle treatment. These results suggest that s-EH inhibition with AR9281 promotes weight loss by reducing appetite and increasing metabolic rate, and that increased UCP1 content may contribute to the increase in energy expenditure.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 12/2010; 22(7):598-604. DOI:10.1016/j.numecd.2010.10.017 · 3.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new type of oscillator element for spatially injection locked arrays is presented. The element consists of an FET oscillator equipped with two patch antennas: one for reception for the injection signal and the other for radiating the oscillator output power. This element exhibits much broader locking bandwidths for a given injection signal than previous approaches. Prototype circuits operating at 6 GHz exhibit a 270-MHz locking range with 46.5-dB isotropic gain. The elements operate independently, so that the array is synchronized only when the injection signal is present. Using this approach, broad locking bandwidths are achieved with relatively low injected signal levels. In addition, using the elements described, arrays can be constructed which focus the radiated field
    Microwave Symposium Digest, 1992., IEEE MTT-S International; 07/1992
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study we propose a state-dependent restoration scheme, which preplans an alternate VP route for each working VP against each failure scenario. In this scheme, the routes of alternate VPs are prepared by an optimization model which considers network-wide resource utilization and rerouting costs. We propose an exact algorithm to solve the suggested model effectively within reasonable time in medium-size ATM networks. We also present two heuristic algorithms for preplanning large ATM network restoration. In a computer simulation study, the suggested state-dependent preplanned scheme shows the advantages such as spare resource utilization, rerouting cost efficiency and rerouting speed
    Global Telecommunications Conference, 1998. GLOBECOM 98. The Bridge to Global Integration. IEEE; 02/1998
Show more