Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model

Abstract

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

Involvement of HO-1 and Autophagy in the Protective Effect of Magnolol in Hepatic Steatosis-Induced NLRP3 Inflammasome Activation In Vivo and In Vitro

“…Excessive free fatty acids and lipid accumulation in the liver result in lipotoxicity, leading to mitochondrial dysfunction and the production of reactive oxygen species (ROS) [ 40 ]. Oxidative stress and inflammatory responses play an essential role in the pathogenesis of NAFLD and metabolic diseases [ 3 , 41 ]. Therefore, it is conceivable that the induction of cellular antioxidant systems may provide beneficial effects against NAFLD.…”

“…The pathogenesis includes a broad spectrum of hepatic changes such as steatosis, steatohepatitis, and cirrhosis [ 2 ]. Excess free fatty acid, inflammatory disorders, and oxidative stress are the main risk factors in the pathological changes of NAFLD [ 3 , 4 ]. Although many medications have been investigated to address the therapeutic potentials of NAFLD, no effective treatment has so far been approved.…”

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice

“…One of the pathways most impacted by dietary-induced obesity is the inflammatory pathway. Hepatic inflammation and oxidative stress result in mitochondrial damage and changes in mitochondrial dynamics [3,45]. This manifests as hepatocellular oxidative damage, resulting in hepatic inflammation (non-alcoholic steatohepatitis).…”

“…In the United States, obesity affects 33% of the population, and the prevalence is expected to increase to 50% by 2030 [1]. Obesity is associated with an increased risk of metabolic syndrome, type 2 diabetes, hypertension, and cardiovascular disease [1][2][3]. The metabolic syndrome causes a spectrum of liver injury resulting in nonalcoholic fatty liver disease (NAFLD), which can progress to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma [4,5].…”

Transcriptional Regulation of HMOX1 Gene in Hezuo Tibetan Pigs: Roles of WT1, Sp1, and C/EBPα

“…Heme oxygenase (HO) is a stress-inducing enzyme that catalyzes heme to produce free iron, carbon monoxide (CO), and biliverdin [7]. Heme oxygenase 1 (HMOX1), one of the main members of the HO family, has a variety of cardiovascular protective functions [8][9][10] and plays an important role in anti-inflammatory, anti-apoptotic, and antioxidant activities among others [11][12][13]. HMOX1 exerts protective effects under stress conditions mainly through the active gas CO and antioxidant bilirubin produced by its decomposition [14,15].…”