Heme Oxygenase Gene Targeting to Adipocytes Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High-Fat Diet

Cao, Jian; Peterson, Stephen J.; Sodhi, Komal; Vanella, Luca; Barbagallo, Ignazio; Rodella, Luigi Fabrizio; Schwartzman, Michal Laniado; Abraham, Nader G.; Kappas, Attallah

doi:10.1161/hypertensionaha.112.193805

Cited by 92 publications

(123 citation statements)

References 54 publications

(76 reference statements)

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“…A recent study also showed that MC4R-deficient obese mice treated with long-term (4-23 weeks of age) CoPP administration, exhibited increased oxygen consumption, and CO2 and heat production [224]. Increased adiponectin has also been reported and has been proposed to underpin these beneficial effects [209,[225][226][227][228]. Studies have also shown that the above benefits can be reversed by SnMP treatment [210,217].…”

Section: Ho-1 and Obesitymentioning

confidence: 95%

“…HO-1 induction remodels adipocytes, resulting in hyperplasia instead of hypertrophy. These adipocytes increase the production of AMPK, PPARγ, and adiponectin, at the same time decreasing the production of inflammatory markers and cytokines [209,210,215,243].…”

Section: Ho-1 and Adipocytesmentioning

confidence: 99%

“…Some, but not all [204] evidence suggest that induction of HO-1 has beneficial effects in several disease models including metabolic disorders such as insulin resistance, type 2 diabetes and obesity [195].Thus, the subsequent studies tried to identify effective approaches to induce HO-1 in human [205][206][207]. CoPP [208][209][210] and hemin [208,211,212] were used to induce HO-1 in cell culture and pre-clinical models in most studies. Unlike CoPP, hemin is the derivative of heme which is a HO-1 substrate analog that can serve as both an inducer and a substrate for HO-1 [213,214].…”

Section: Overviewmentioning

confidence: 99%

“…Accumulating evidence has led to the suggestion that induction of HO-1 via CoPP [209,210,215] or Hemin [211,212,216] has a range of beneficial effects on obesity. For example, chronic HO-1 induction in obese mice prevents body weight gain, increases the number and decreases the size of adipocytes, increases circulating adiponectin levels and decreases circulating pro-inflammatory cytokine levels [210,217].…”

Section: Ho-1 and Obesitymentioning

confidence: 99%

“…used lentiviral (aP2-HO-1) construct via intracardiac injection, which successfully increased HO-1 expression in adipose tissue and attenuated high fat diet (HFD) induced body weight increase, decreased adiposity and also improved insulin sensitivity and adiponectin production [209].…”

Section: Genetic Manipulation Of Ho-1mentioning

confidence: 99%

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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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Section: Ho-1 and Obesitymentioning

confidence: 95%

Section: Ho-1 and Adipocytesmentioning

confidence: 99%

Section: Overviewmentioning

confidence: 99%

Section: Ho-1 and Obesitymentioning

confidence: 99%

Section: Genetic Manipulation Of Ho-1mentioning

confidence: 99%

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

Yang¹

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Identification of Phf16 and Pnpla3 as new adipogenic factors regulated by phytochemicals

Chang

Yun

Choi

et al. 2018

J of Cellular Biochemistry

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Adipocyte differentiation is controlled by multiple signaling pathways. To identify new adipogenic factors, C3H10T1/2 adipocytes were treated with previously known antiadipogenic phytochemicals (resveratrol, butein, sulfuretin, and fisetin) for 24 hours. Commonly regulated genes were then identified by transcriptional profiling analysis. Three genes (chemokine (C-X-C motif) ligand 1 [Cxcl1], heme oxygenase 1 [Hmox1], and PHD (plant homeo domain) finger protein 16 [Phf16]) were upregulated while two genes (G0/G1 switch gene 2 [G0s2] and patatin-like phospholipase domain containing 3 [Pnpla3]) were downregulated by these four antiadipogenic compounds. Tissue expression profiles showed that the G0s2 and Pnpla3 expressions were highly specific to adipose depots while the other three induced genes were ubiquitously expressed with significantly higher expression in adipose tissues. While Cxcl1 expression was decreased, expressions of the other four genes were significantly increased during adipogenic differentiation of C3H10T1/2 cells. Small interfering RNA–mediated knockdown including Phf16 and Pnpla3 indicated that these genes might play regulatory roles in lipid accumulation and adipocyte differentiation. Specifically, the silencing of two newly identified adipogenic genes, Phf16 or Pnpla3, suppressed lipid accumulation and expression of adipocyte markers in both 3T3-L1 and C3H10T1/2 cells. Taken together, these data showed previously uncovered roles of Phf16 and Pnpla3 in adipogenesis, highlighting the potential of using phytochemicals for further investigation of adipocyte biology.

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Retracted: Increased HO‐1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21

Hinds

Sodhi

Meadows

et al. 2013

Obesity

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104

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Objective Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development. Design and Methods Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content and lipogenesis were assessed. Results CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, FAS levels involving recruitment of FGF21, PPARα and Glut 1. These beneficial effects were reversed by inhibition of HO activity. Conclusion Increased levels of HO-1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content and fatty liver. The beneficial effect of HO-1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO-1 and HO activity are responsible for fatty liver.

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Heme Oxygenase Gene Targeting to Adipocytes Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High-Fat Diet

Cited by 92 publications

References 54 publications

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

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

Identification of Phf16 and Pnpla3 as new adipogenic factors regulated by phytochemicals

Retracted: Increased HO‐1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21

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