Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function

Waldman, Maayan; Bellner, Lars; Vanella, Luca; Schragenheim, Joseph; Sodhi, Komal; Singh, Shailendra Pratap; Lin, Dao‐Hong; Lakhkar, Anand; Li, Jiangwei; Hochhauser, Edith; Arad, Michael; Darzynkiewicz, Zbigniew; Kappas, Attallah; Abraham, Nader G.

doi:10.1089/scd.2016.0072

Cited by 66 publications

(79 citation statements)

References 66 publications

(78 reference statements)

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“…Pre-adipocytes; 3T3-L1 were maintained and cultured in adipogenic medium as described [12]. Cells were treated with the HO activity inhibitor, SnMP (2 μM, Tin mesoporphyrin), every 3-days and harvested as described [12].…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Cells were treated with the HO activity inhibitor, SnMP (2 μM, Tin mesoporphyrin), every 3-days and harvested as described [12].…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…For in vitro Western blot analysis pelleted cells were lysed and HO-1 and other signaling proteins were measured [12], [44].…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Increased heme levels are essential to increase adipocyte terminal differentiation and adipogenesis in vivo [10], [11]. However, an excessive increase in heme in conjunction with a decrease in HO-1 function may lead the adipocyte to proceed to terminal differentiation and inflammation [12], [13]. An increase in heme and a reduction in HO-1 levels, as seen in HO-1 deletion, results in a detrimental cellular effect due to increased ROS levels triggered by heme and H 2 O 2 , with as a consequence an increase in the inflammatory properties of both monocytes and macrophages [14], [15] and increased adipocyte dysfunction [16], [17], [18].…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…Cells were treated with the HO activity inhibitor, SnMP (2 μM, Tin mesoporphyrin), every 3-days and harvested as described [12].…”

Section: Cell Culture and Treatmentmentioning

confidence: 99%

“…For in vitro Western blot analysis pelleted cells were lysed and HO-1 and other signaling proteins were measured [12], [44].…”

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

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“…by which CoPP promotes a reduction in weight gain may include a reduction in food/energy intake, as reported here and elsewhere [220], and or an increase in metabolic rates [279], possibly via increased mitochondrial biogenesis and 'browning' of white preadipocytes/adipocytes [315]. With respect to the latter, we did not observe any increase in Ucp-1 expression, a marker of brown adipocytes, in epididymal or subcutaneous adipose tissue from CoPP-treated mice ( Supp Fig 4.11a).…”

Section: Discussionsupporting

confidence: 51%

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Yang¹

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The prevalence of obesity is growing at an alarming rate worldwide, and current therapies have limited benefits. Therefore, it is essential to increase our understanding of the underlying mechanisms so that new strategies can be developed to reduce the incidence of obesity related diseases. Adiponectin is an adipocyte-derived hormone that regulates glucose and lipid metabolism via direct and indirect mechanisms and has anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. Hypoadiponectinemia is implicated in the aetiology of obesity-related diseases making strategies to increase circulating adiponectin levels therapeutically attractive.Emerging evidence, predominantly from preclinical studies, suggests induction of heme-oxygenase-1 (HO-1) increases adiponectin production concomitant with decreased inflammatory tone prompting the proposal of a "HO-1 -adiponectin axis." However, the underlying mechanisms of increased adiponectin production via HO-1 induction are poorly defined; indeed a direct relationship has not been demonstrated. Thus, the overarching aim of this thesis is to investigate the effects of HO-1 induction on adiponectin production as well as adipocyte and adipose tissue remodelling and metabolic parameters using cellular and mouse models.Initial studies were designed to characterize the direct effect of HO-1 induction on adiponectin production. We found that treatment with the widely used HO-1 inducer cobalt protoporphyrin (CoPP) or hemin for 24-48 h increased HO-1 expression and activity without affecting adiponectin expression and secretion, in human mature adipocyte under a variety of experimental scenarios.Treatment of adipocytes with TNFα reduced adiponectin production and induced pro-inflammatory cytokines production. HO-1 induction failed to reverse these effects. These results do not support a direct HO-1 -adiponectin axis.However, literature suggests that chronic induction of HO-1 via CoPP administration throughout differentiation, promotes adiponectin secretion, albeit in the context of reduced adipogenesis. While our previous findings argued against the existence of a direct "HO-1 -adiponectin axis," they did not address the potential effects of chronic induction of HO-1 on adiponectin production. Thus, we extended our study to characterise the effects of chronic HO-1 induction throughout differentiation of human preadipocytes. In this study we demonstrate that chronic induction of HO-1 with CoPP or hemin throughout differentiation results in dose-dependent inhibition of adipogenesis and adiponectin production as well as induction of additional NRF2 target genes. Co-treatment with SnMP (HO-1 activity inhibitor) and HO-1 siRNA did not prevent these effects. These findings suggest that the chronic treatment with CoPP or hemin inhibits adipogenesis and adiponectin production potentially by a HO-1-independent mechanism that may be downstream of NRF2.iii However, our results contradict the majority of reports in the literature. One possibility is that the ...

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Mesoderm‐specific transcript localization in the ER and ER‐lipid droplet interface supports a role in adipocyte hypertrophy

Prudovsky

Anunciado‐Koza

Jacobs

et al. 2017

J of Cellular Biochemistry

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Highly variable expression of mesoderm-specific transcript (Mest) in adipose tissue among genetically homogeneous mice fed an obesogenic diet, and its positive association with fat mass expansion, suggests that Mest is an epigenetic determinant for the development of obesity. Although the mechanisms by which MEST augments fat accumulation in adipocytes have not been elucidated, it has sequence homology and catalytic peptide motifs which suggests that it functions as an epoxide hydrolase or as a glycerol- or acylglycerol-3-phosphate acyltransferase. To better understand MEST function, detailed studies were performed to precisely define the intracellular organelle localization of MEST using immunofluorescence confocal microscopy. Lentiviral-mediated expression of a C-terminus Myc-DDK-tagged MEST fusion protein expressed in 3T3-L1 preadipocytes/adipocytes, and ear-derived mesenchymal stem cells (EMSC) from mice was observed in the endoplasmic reticulum (ER) membranes and is consistent with previous studies showing endogenous MEST in the membrane fraction of adipose tissue. MEST was not associated with the Golgi apparatus or mitochondria; however, frequent contacts were observed between MEST-positive ER and mitochondria. MEST-positive domains were also shown on the plasma membrane (PM) of non-permeabilized cells but they did not co-localize with ER-PM bridges. Post-adipogenic differentiated 3T3-L1 adipocytes and EMSC showed significant co-localization of MEST with the lipid droplet surface marker perilipin at contact points between the ER and lipid droplet. Identification of MEST as an ER-specific protein that co-localizes with lipid droplets in cells undergoing adipogenic differentiation supports a function for MEST in the facilitation of lipid accumulation and storage in adipocytes.

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Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which Is Required for HO-1 Expression and Increased Mitochondrial Function

Cited by 66 publications

References 66 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

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Mesoderm‐specific transcript localization in the ER and ER‐lipid droplet interface supports a role in adipocyte hypertrophy

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