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Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity.

Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R, Wakkach A, Dahman M, Tordjman J, Clément K, McQuaid SE, Frayn KN, Huet PM, Gugenheim J, Lotersztajn S, Le Marchand-Brustel Y, Tran A, Gual P - Diabetes (2008)

Bottom Line: Further, AT did not appear to secrete OPN.In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN.In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, U895, Team 8, Hepatic Complications in Obesity, Nice, France.

ABSTRACT

Objective: Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis.

Research design and methods: OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells.

Results: Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN.

Conclusions: The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury.

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OPN and CD44 mRNA expression is increased in liver and adipose tissue of obese mice. A: OPN and CD44 mRNA expressions were analyzed by real-time quantitative PCR in liver and epididymal white adipose tissue of mice fed a normal diet (ND; n = 8) or HFD (n = 10) for 15 weeks. Data are presented as relative mRNA normalized to 36B4 mRNA and are expressed as means ± SE. B: Correlations between the expression levels of OPN or CD44 mRNA (−ΔCt) and the hepatic triglyceride content were analyzed using Spearman's rank correlation test. *P < 0.05. C: OPN levels were evaluated by ELISA in serum of HFD-induced obese mice (HFD, n = 6) and serum of lean littermates (ND, n = 6). D: Relative expression of OPN and CD44 was analyzed by real-time quantitative PCR in the isolated hepatocytes versus nonparenchymal fraction in the liver of ob/+ mice. Results are expressed as means ± SE of three independent experiments. P values were obtained using the nonparametric Kruskal-Wallis test. *P < 0.05.
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f6: OPN and CD44 mRNA expression is increased in liver and adipose tissue of obese mice. A: OPN and CD44 mRNA expressions were analyzed by real-time quantitative PCR in liver and epididymal white adipose tissue of mice fed a normal diet (ND; n = 8) or HFD (n = 10) for 15 weeks. Data are presented as relative mRNA normalized to 36B4 mRNA and are expressed as means ± SE. B: Correlations between the expression levels of OPN or CD44 mRNA (−ΔCt) and the hepatic triglyceride content were analyzed using Spearman's rank correlation test. *P < 0.05. C: OPN levels were evaluated by ELISA in serum of HFD-induced obese mice (HFD, n = 6) and serum of lean littermates (ND, n = 6). D: Relative expression of OPN and CD44 was analyzed by real-time quantitative PCR in the isolated hepatocytes versus nonparenchymal fraction in the liver of ob/+ mice. Results are expressed as means ± SE of three independent experiments. P values were obtained using the nonparametric Kruskal-Wallis test. *P < 0.05.

Mentions: To corroborate the human findings and to further explore the potential role of OPN in liver complications of morbid obesity, a series of experiments were performed in various animal models. As expected, mice exposed to HFD exhibited increased weight (45.1 ± 3.2 vs. 28.2 ± 1.6 g in low-fat diet–fed controls), increased hepatic triglyceride content (73 ± 14 vs. 37 ± 12 μg/mg liver), hyperglycemia (208 ± 90 vs. 100 ± 16 mg/dl), and hyperinsulinemia (2.31 ± 0.63 vs. 0.95 ± 0.89 μg/l). HFD-induced obesity resulted in increased OPN and CD44 gene expressions in both fatty liver and epididymal WAT (Fig. 6A). Interestingly, the hepatic expressions of OPN and CD44 were also positively correlated with steatosis, as evaluated by hepatic triglyceride content (Fig. 6B). Similar findings were observed in genetic leptin-deficient (ob/ob) mice (n = 5), since OPN and CD44 gene expressions were found to be significantly enhanced in both liver (3.3 ± 0.3, P < 0.05, and 1.6 ± 0.1-fold, P < 0.05, respectively) and adipose tissue (23.4 ± 2.5, P < 0.05, and 5.2 ± 0.8-fold, P < 0.05, respectively) compared with lean littermates (n = 5). In addition, the adipose tissue expressions of OPN and CD44 were correlated with expression of the macrophage marker F4/80 in HFD-induced obese mice (rs = 0.820, P < 0.01, and rs = 0.843, P < 0.01, respectively). Furthermore, serum OPN levels were also significantly increased, but this increase was moderate, as occurred in liver and adipose tissue (Fig. 6C).


Elevated expression of osteopontin may be related to adipose tissue macrophage accumulation and liver steatosis in morbid obesity.

Bertola A, Deveaux V, Bonnafous S, Rousseau D, Anty R, Wakkach A, Dahman M, Tordjman J, Clément K, McQuaid SE, Frayn KN, Huet PM, Gugenheim J, Lotersztajn S, Le Marchand-Brustel Y, Tran A, Gual P - Diabetes (2008)

OPN and CD44 mRNA expression is increased in liver and adipose tissue of obese mice. A: OPN and CD44 mRNA expressions were analyzed by real-time quantitative PCR in liver and epididymal white adipose tissue of mice fed a normal diet (ND; n = 8) or HFD (n = 10) for 15 weeks. Data are presented as relative mRNA normalized to 36B4 mRNA and are expressed as means ± SE. B: Correlations between the expression levels of OPN or CD44 mRNA (−ΔCt) and the hepatic triglyceride content were analyzed using Spearman's rank correlation test. *P < 0.05. C: OPN levels were evaluated by ELISA in serum of HFD-induced obese mice (HFD, n = 6) and serum of lean littermates (ND, n = 6). D: Relative expression of OPN and CD44 was analyzed by real-time quantitative PCR in the isolated hepatocytes versus nonparenchymal fraction in the liver of ob/+ mice. Results are expressed as means ± SE of three independent experiments. P values were obtained using the nonparametric Kruskal-Wallis test. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2606860&req=5

f6: OPN and CD44 mRNA expression is increased in liver and adipose tissue of obese mice. A: OPN and CD44 mRNA expressions were analyzed by real-time quantitative PCR in liver and epididymal white adipose tissue of mice fed a normal diet (ND; n = 8) or HFD (n = 10) for 15 weeks. Data are presented as relative mRNA normalized to 36B4 mRNA and are expressed as means ± SE. B: Correlations between the expression levels of OPN or CD44 mRNA (−ΔCt) and the hepatic triglyceride content were analyzed using Spearman's rank correlation test. *P < 0.05. C: OPN levels were evaluated by ELISA in serum of HFD-induced obese mice (HFD, n = 6) and serum of lean littermates (ND, n = 6). D: Relative expression of OPN and CD44 was analyzed by real-time quantitative PCR in the isolated hepatocytes versus nonparenchymal fraction in the liver of ob/+ mice. Results are expressed as means ± SE of three independent experiments. P values were obtained using the nonparametric Kruskal-Wallis test. *P < 0.05.
Mentions: To corroborate the human findings and to further explore the potential role of OPN in liver complications of morbid obesity, a series of experiments were performed in various animal models. As expected, mice exposed to HFD exhibited increased weight (45.1 ± 3.2 vs. 28.2 ± 1.6 g in low-fat diet–fed controls), increased hepatic triglyceride content (73 ± 14 vs. 37 ± 12 μg/mg liver), hyperglycemia (208 ± 90 vs. 100 ± 16 mg/dl), and hyperinsulinemia (2.31 ± 0.63 vs. 0.95 ± 0.89 μg/l). HFD-induced obesity resulted in increased OPN and CD44 gene expressions in both fatty liver and epididymal WAT (Fig. 6A). Interestingly, the hepatic expressions of OPN and CD44 were also positively correlated with steatosis, as evaluated by hepatic triglyceride content (Fig. 6B). Similar findings were observed in genetic leptin-deficient (ob/ob) mice (n = 5), since OPN and CD44 gene expressions were found to be significantly enhanced in both liver (3.3 ± 0.3, P < 0.05, and 1.6 ± 0.1-fold, P < 0.05, respectively) and adipose tissue (23.4 ± 2.5, P < 0.05, and 5.2 ± 0.8-fold, P < 0.05, respectively) compared with lean littermates (n = 5). In addition, the adipose tissue expressions of OPN and CD44 were correlated with expression of the macrophage marker F4/80 in HFD-induced obese mice (rs = 0.820, P < 0.01, and rs = 0.843, P < 0.01, respectively). Furthermore, serum OPN levels were also significantly increased, but this increase was moderate, as occurred in liver and adipose tissue (Fig. 6C).

Bottom Line: Further, AT did not appear to secrete OPN.In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN.In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications.

View Article: PubMed Central - PubMed

Affiliation: Institut National de la Santé et de la Recherche Médicale, U895, Team 8, Hepatic Complications in Obesity, Nice, France.

ABSTRACT

Objective: Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis.

Research design and methods: OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells.

Results: Hepatic OPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN.

Conclusions: The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury.

Show MeSH
Related in: MedlinePlus