Downregulation of PGC-1α Prevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice.

Shailendra P Singh,Lars Bellner,Attallah Kappas,John R Falck,Nader G Abraham,Jian Cao,Luca Vanella

doi:10.1155/2016/9039754

Abstract

Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1α in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1α, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-A is a potent inducer of PGC-1α, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC-1α(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO2 effects that were abrogated in PGC-1α-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome.

Highlights

Obesity is a global epidemic and a major risk factor in the development of metabolic syndrome and diabetes associated complications such as cardiovascular disease, kidney disease, hypertension, and neuropathies [1,2,3]
Mitochondrial biogenesis, oxygen consumption, and oxidative phosphorylation are regulated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [13], which in turn is regulated by posttranslational modifications, including phosphorylation and deacetylation by AMPK and SIRT1, respectively [14]
In the second experiment (B) we examined the effect of an Epoxyeicosatrienoic acids (EETs)-A regimen in mice fed a high fat (HF) diet for 24 weeks: for experiment (A) with PGC1α-deficient mice, animals were divided into 4 groups: (1) lean, (2) HFD, (3) HFD+EET-analog [EET-A is sodium (S,Z)2-(13-(3-pentylureido)tridec-8-enamido)succinate], and (4) HFD+EET-A+PGC-1α lentivirus

Summary

Introduction

Obesity is a global epidemic and a major risk factor in the development of metabolic syndrome and diabetes associated complications such as cardiovascular disease, kidney disease, hypertension, and neuropathies [1,2,3]. PGC-1α activates several key components of the adaptive thermogenesis program, including the stimulation of energy uptake, and mitochondrial fatty acid oxidation. Mice that are lacking PGC-1α in adipose tissue and fed HF diet develop insulin resistance and have increased circulating lipid levels [16]. One of the seven mammalian sirtuins, sirtuin 3 (SIRT3), a mitochondrial deacetylase, was recently reported to be the target of PGC-1α and impact mitochondrial processes, such as mitochondrial biogenesis, suppression of ROS, and energy metabolism [23], including mitochondrial fatty acid oxidation [24]. Given the regulatory role of PGC-1α on adipogenesis and mitochondrial function, we hypothesize that the EET-mediated modulation of adiposity and the subsequent increase of mitochondrial fusion, oxidative phosphorylation, and HO-1 expression is dependent upon PGC-1α. The effect of PGC-1α-deficiency on metabolic parameters and mitochondrial biogenesis, function, and fusion potential was performed using lentiviral gene delivery that is effective for 9 months [32]

Materials and Methods

Results

Discussion