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

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

doi:10.1155/2016/9039754

Cited by 35 publications

(35 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Concomitantly inhibition of HO activity reduces mitochondrial quality control by inhibition of mitochondrial fusion mediator Mfn1, Mfn2 and Opa1 but activation of mitochondrial fission mediator Fis1 [42], [43]. Hence, our study offers a portal on the unique role of HO-1 in adipose tissue by its ability to maintain mitochondrial quality and biogenesis.…”

Section: Discussionmentioning

confidence: 71%

See 1 more Smart Citation

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

Singh

Grant

Meissner

et al. 2017

Hormone Molecular Biology and Clinical Investigation

Self Cite

View full text Add to dashboard Cite

Abstract:Background: Hmox1 plays an important role in the regulation of mitochondrial bioenergetics and function by regulating cellular heme-derived CO and bilirubin. Previous studies have demonstrated that global disruption of HO-1 in humans and mice resulted in severe organ dysfunction. Methods: We investigated the potential role of adipose-specific-HO-1 genetic ablation on adipose tissue function, mitochondrial quality control and energy expenditure by generating an adipo-HO-1 knockout mouse model (Adipo-HO-1 −/− ) and, in vitro, adipocyte cells in which HO activity was inhibited. Adiposity, signaling proteins, fasting glucose and oxygen consumption were determined and compared to adipocyte cultures with depressed levels of both HO-1/HO-2. Results: Adipo-HO-1 −/− female mice exhibited increased adipocyte size, and decreases in the mitochondrial fusion to fission ratio, PGC1, and SIRT3. Importantly, ablation of HO-1 in adipose tissue resulted in fat acquiring many properties of visceral fat such as decreases in thermogenic genes including pAMPK and PRDM16. Deletion of HO-1 in mouse adipose tissue led to complete metabolic dysfunction, an increase in white adipose tissue, a reduction of beige fat and associated increases in FAS, aP2 and hyperglycemia. Mechanistically, genetic deletion of HO-1 in adipose tissues decreased the mitochondrial fusion to fission ratio; disrupted the activity of the PGC1 transcriptional axis and thermogenic genes both in vitro and in vivo. Conclusion: Ablation of adipose tissue-HO-1 abridged PGC1 expression promoted mitochondrial dysfunction and contributed to an increase of pro-inflammatory visceral fat and abrogated beige-cell like phenotype.

show abstract

Section: Discussionmentioning

confidence: 71%

“…Specific TaqMan ® Gene Expression Assays probes for mouse HO-1, PGC1α, COX-IV (cytochrome c oxidase subunit-IV), adiponectin, TNFα, and other signaling RNA were determined as previously described [42], [43].…”

Section: Rna/real-time Polymerase Chain Reaction (Pcr) Of Thermogenicmentioning

confidence: 99%

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

Singh

Grant

Meissner

et al. 2017

Hormone Molecular Biology and Clinical Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…Adipo-ORF-HO-1 lentivirus and adipo-Sh-HO-1 clone were cultured. A similar procedure was used to isolate TWIST silencing, as previously described [10,35,36].…”

Section: Generation Of Lentiviral Vector-mediated Ho-1 Overexpressed mentioning

confidence: 99%

“…Obesity is associated with inflammation of the heart, often leading to myocardial infarction, reduction in left ventricular function, and reduced ejection fraction [5,6]. White fat, whether epicardial or visceral, is considered a major source of inflammation [7][8][9] and leads to a reduction in mitochondrial thermogenesis and biogenesis signaling [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In addition, endothelium‐specific CYP2J2 overexpression alleviates high‐fat diet‐induced hyperlipidemia via increased fatty acid oxidation mediated by the AMPK pathway (Zhang et al., ). It has also been reported that EET‐A (an EET analogue) increased mitochondrial biogenesis and insulin sensitivity, thereby providing metabolic syndrome protection in high‐fat diet‐induced obesity in mice (Singh, Bellner et al., ; Singh, Schragenheim et al., ). These studies reinforce the importance of the development of EETs as promising drugs for the treatment of insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Endothelium‐specific CYP2J2 overexpression attenuates age‐related insulin resistance

et al. 2018

View full text Add to dashboard Cite

SummaryAmple evidences demonstrate that cytochrome P450 epoxygenase‐derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti‐inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium‐specific CYP2J2 overexpression on age‐related insulin resistance and metabolic dysfunction. Endothelium‐specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2‐CYP2J2‐Tr mice) was utilized. The effects of endothelium‐specific CYP2J2 overexpression on aging‐associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2‐CYP2J2‐Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16‐month‐old CYP2J2‐Tr mice. In addition, CYP2J2 overexpression‐mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging‐associated increases in fat mass and adipocyte size were only observed in 16‐month‐old wild‐type mice, and CYP2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2‐CYP2J2‐Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2‐CYP2J2‐Tr mice were also associated with increased muscle blood flow, enhanced active‐phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium‐specific CYP2J2 overexpression alleviated age‐related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase‐EET system as a potential target for combating aging‐related metabolic disorders.

show abstract

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

Cited by 35 publications

References 63 publications

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

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

Endothelium‐specific CYP2J2 overexpression attenuates age‐related insulin resistance

Contact Info

Product

Resources

About