Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

Bertola, Adeline; Deveaux, Vanessa; Bonnafous, Stéphanie; Rousseau, Denis; Anty, Rodolphe; Wakkach, Abdelilah; Dahman, M.; Tordjman, Joan; Clément, Karine; McQuaid, Siobhán; Frayn, Keith N.; Huet, Pierre‐Michel; Gugenheim, Jean; Lotersztajn, Sophie; Marchand-Brustel, Y. Le; Tran, Albert; Gual, Philippe

doi:10.2337/db08-0400

Cited by 127 publications

(135 citation statements)

References 43 publications

(53 reference statements)

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“…IL1rn has been reported to be highly upregulated in WAT of obese humans and to regulate insulin sensitivity (21,45), while Il1rn-deficient mice exhibited decreased adiposity and increased energy expenditure (46). Ssp1 expression was found to be elevated in obesity, while neutralization of Ssp1 was shown to inhibit obesity-induced inflammation and insulin resistance (3,28). Thus, the downregulation of Adfp, Il1rn, Ssp1, and likely other genes may have collaboratively promoted insulin sensitivity in ROR␣ sg/sg mice through their interrelated effects on inflammation, adipogenesis, and energy expenditure.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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AM. Transcriptional profiling reveals a role for ROR␣ in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol Genomics 43: 818 -828, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00206.2010.-Retinoid-related orphan receptor (ROR)␣4 is the major ROR␣ isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR␣-deficient staggerer mice (ROR␣ sg/sg ) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR␣ sg/sg mice. In contrast, overexpression of ROR␣ in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR␣ sg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR␣. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR␣ sg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR␣ sg/sg WAT. Moreover, ROR␣ sg/sg mice fed with an HFD were protected from the development of insulin resistance. ROR␣ sg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR␣ plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR␣ may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. staggerer mice; obesity; metabolic syndrome; macrophage; insulinresistance; diabetes; retinoid-related orphan receptors OBESITY IS A MAJOR GLOBAL health concern. In the United States alone, 30% of the general population is obese and an estimated 66% of all adults are overweight (40). Obesity is associated with an elevated risk of several pathologies, including Type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and airway disease (18,36). The molecular links between obesity and these diseases are beginning to be understood. It is now well recognized that obesity is associated with chronic low-grade inflammation and that inflammatory processes play an important role in obesity and related pathologies (18,44,53). Infiltration of macrophages and various T-lymphocytes in hypertrophic adipose tissues have been considered as important early events in the development of obesity-associated complications (14, 38, 57) and the release of proinflammatory cytokines by adipose tissue plays a key ...

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Section: Discussionmentioning

confidence: 99%

“…7G). Increased expression of many of these genes, including Il1rn, Ssp1, and Cd44, has been linked to obesity-associated inflammation and insulin resistance (3,28,45,46).…”

Section: Comparison Of Gene Expression Profilesmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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“…OPN plays a nondispensable role in the development of Con A-induced hepatitis in mice (12)(13)(14), as demonstrated by the fact that neutralizing OPN function by OPN gene deletion or by using OPN small-interfering RNA protects against Con A-induced liver injury. In addition, OPN overexpression occurs in other models of liver injury (15)(16)(17) and OPN dysregulation facilitates inflammation-associated fibrosis in several organs including lung, heart, and liver (18 -20).…”

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confidence: 99%

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

143

110

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Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

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“…Our findings implicate p38 MAPK in the regulation of PPARα activity and sequential OPN expression [41] . Traditionally, inflammatory cells are considered a major source of serum OPN in cases of morbid obesity [9,42] . The contributions of adipose tissue and adipocytes to the circulating levels of OPN remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

Zhang

Tang

et al. 2015

Acta Pharmacol Sin

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Aim: Wogonin (5,7-dihydroxy-8-methoxyflavone), a major bioactive compound of the flavonoid family, is commonly extracted from the traditional Chinese medicine Scutellaria baicalensis and possesses antioxidant and anti-inflammatory activities and is assumed to have anti-diabetes function. Indeed, a current study has shown that it can possibly treat metabolic disorders such as those found in db/db mice. However, the underlying molecular mechanism remains largely unclear. The aim of this study was to investigate the impact of wogonin on osteopontin (OPN) expression in adipose tissue from type 1 diabetic mice and in 3T3-L1 adipocytes. Methods: Type 1 diabetes was induced by streptozotocin (STZ) injection. 3T3-L1 preadipocytes were converted to 3T3-L1 adipocytes through treatment with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IBMX). Western blot analysis and RT-PCR were performed to detect protein expression and mRNA levels, respectively. Results: Wogonin treatment suppressed the increase in serum OPN levels and reduced OPN expression in adipose tissue from STZinduced type 1 diabetic mice. Administration of wogonin enhanced PPARα expression and activity. Silencing of PPARα diminished the inhibitory effects of wogonin on OPN expression in 3T3-L1 adipocytes. Furthermore, the levels of c-Fos and phosphorylated c-Jun were reduced in wogonin-treated adipose tissue and 3T3-L1 adipocytes. In addition, wogonin treatment dramatically mitigated p38 MAPK phosphorylation. Pharmacological inhibition of p38 MAPK by its specific inhibitor SB203580 increased PPARα activity and decreased OPN expression. Conclusion: Our results suggest that wogonin downregulated OPN expression in adipocytes through the inhibition of p38 MAPK and the sequential activation of the PPARα pathway. Given the adverse effects of high OPN levels on metabolism, our results provide evidence for the potential administration of wogonin as a treatment for diabetes.

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Elevated Expression of Osteopontin May Be Related to Adipose Tissue Macrophage Accumulation and Liver Steatosis in Morbid Obesity

Cited by 127 publications

References 43 publications

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

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