Circulating and Adipose Tissue Gene Expression of Zinc-α2-Glycoprotein in Obesity: Its Relationship with Adipokine and Lipolytic Gene Markers in Subcutaneous and Visceral Fat

Ceperuelo-Mallafré, Victòria; Näf, S; Escoté, Xavier; Caubet, Enric; Gómez, José Manuel; Miranda, Merce; Chacón, Matilde R.; González-Clemente, José Miguel; Gallart, L.; Gutiérrez, Cristina; Vendrell, Joan

doi:10.1210/jc.2009-0764

Cited by 74 publications

(79 citation statements)

References 18 publications

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“…53 ZAG gene and protein expression has also been shown to be downregulated in subcutaneous and visceral adipose tissue of obese men and women in comparison with lean controls. [54][55][56] Interestingly, a negative correlation between adipose-derived ZAG and body mass index or total body fat mass in human subjects has been demonstrated by studies from our group and from others. 41,55,56 Reduced ZAG expression in adipose tissue in the obese state may therefore be linked to impaired adipose tissue metabolism in obesity.…”

Section: Zag Expression and Body Fat Masssupporting

confidence: 69%

“…41,56 An inverse relationship has also been found between ZAG mRNA and plasma C-reactive protein or monocyte chemotactic protein-1, both of which are important in inflammatory responses and predict an increased risk of type 2 diabetes. 41 Moreover, ZAG mRNA levels in subcutaneous depot were downregulated in patients with the metabolic syndrome compared with those without.…”

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

“…41 Moreover, ZAG mRNA levels in subcutaneous depot were downregulated in patients with the metabolic syndrome compared with those without. 56 Thus, decreased ZAG expression with increased insulin resistance may indicate a protective role of ZAG in maintaining appropriate fat mass and insulin sensitivity. However, the data on serum ZAG levels in relation to obesity are inconsistent, being reported as decreased, 52,55 unchanged 57 or increased.…”

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

“…However, the data on serum ZAG levels in relation to obesity are inconsistent, being reported as decreased, 52,55 unchanged 57 or increased. 58 Circulating ZAG levels have been shown to be negatively 56 or positively 58 correlated with insulin and the insulin resistance indices. It is possible that adipose tissue-derived ZAG is more important locally through its autocrine/paracrine actions.…”

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

“…Recent studies by our group and others reveal a positive association between ZAG mRNA and adiponectin mRNA levels in both visceral and subcutaneous fat of human subjects. 41,56 Adiponectin, primarily expressed in adipocytes, is considered to have insulin-sensitizing as well as anti-inflammatory properties. 62 Contrary to other adipokines, such as leptin, TNFa and monocyte chemotactic protein-1, whose levels increase with fat mass accumulation, 63,64 circulating adiponectin decreases in obesity.…”

Section: Zag: a Candidate Gene For Obesitymentioning

confidence: 99%

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Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

et al. 2010

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The importance of white adipose tissue in the control of energy balance is now firmly recognized. In addition to fuel storage, adipocytes secrete an array of proteins factors (adipokines), which regulate multiple physiological and metabolic processes as well as influence body fat accumulation. Zinc-a2-glycoprotein (ZAG), a lipid mobilizing factor initially characterized as a tumor product associated with cachexia, has recently been identified as a novel adipokine. Although the exact role of ZAG in adipose tissue remains to be clarified, there is evidence that ZAG expression appears to be inversely related to adiposity, being upregulated in cachexia whereas reduced in obesity. Investigations on the regulation of ZAG give insights into its potential function in adipose tissue with a link to lipid mobilization and an anti-inflammatory action. Recent work shows that ZAG stimulates adiponectin secretion by human adipocytes. Data from genetic studies suggest that ZAG may be a candidate gene for body weight regulation; this is supported by the demonstration that ZAG-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing ZAG exhibit weight loss. The present review summarizes these new perspectives of ZAG and the potential mechanisms by which it might modulate adipose tissue mass and function.

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Section: Zag Expression and Body Fat Masssupporting

confidence: 69%

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

Section: Zag Expression and Body Fat Massmentioning

confidence: 99%

Section: Zag: a Candidate Gene For Obesitymentioning

confidence: 99%

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Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

et al. 2010

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Subcutaneous adipose tissue zinc‐α2‐glycoprotein is associated with adipose tissue and whole‐body insulin sensitivity

Baláž

Vician

Janakova

et al. 2014

Obesity

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Objective: To examine the regulatory aspects of zinc-a2-glycoprotein (ZAG) association with obesityrelated insulin resistance. Methods: ZAG mRNA and protein were analyzed in subcutaneous adipose tissue (AT) and circulation of lean, obese, prediabetic, and type 2 diabetic men; both subcutaneous and visceral AT were explored in lean and extremely obese. Clinical and ex vivo findings were corroborated by results of in vitro ZAG silencing experiment. Results: Subcutaneous AT ZAG was reduced in obesity, with a trend to further decrease with prediabetes and type 2 diabetes. ZAG was 3.3-fold higher in subcutaneous than in visceral AT of lean individuals. All differences were lost in extreme obesity. Obesity-associated changes in AT were not paralleled by alterations of circulating ZAG. Subcutaneous AT ZAG correlated with adiposity, adipocyte hypertrophy, whole-body and AT insulin sensitivity, mitochondrial content, expression of GLUT4, PGC1a, and adiponectin. Subcutaneous AT ZAG and adipocyte size were the only predictors of insulin sensitivity, independent on age and BMI. Silencing ZAG resulted in reduced adiponectin, IRS1, GLUT4, and PGC1a gene expression in primary human adipocytes. Conclusions: ZAG in subcutaneous, but not in visceral AT, was markedly reduced in obesity. Clinical, cellular, and molecular evidence indicate that ZAG plays an important role in modulating whole-body and AT insulin sensitivity.

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Zinc‐α₂‐glycoprotein is associated with insulin resistance in children

Barraco

Luciano

Manco

2014

Obesity

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TO THE EDITOR:We read with great interest the article by Balaz et al. (1), published in the April 2014 issue of the Journal. The authors investigated the association of zinc-a 2 -glycoprotein (ZAG) with obesity and insulin metabolism, finding a positive association between ZAG mRNA in subcutaneous adipose tissue (SAT) and both whole-body (as estimated by euglycemic-hyperinsulinemic clamp) and adipocytes insulin sensitivity. Given that ZAG is selectively present in subcutaneous and not in visceral adipose tissue, the authors speculated that this association is independent of obesity (1). The silencing of the ZAG gene in primary human adipocytes impaired both the cell oxidative metabolism (trough the reduced expression of PGC1a mRNA) and the insulin action (i.e., down-regulating the expression of insulin receptor substrate 1 and glucose transporter type 4; 1). No data are available in literature about circulating levels of ZAG and its relationship with indexes of adiposity and insulin resistance in childhood.We estimated serum levels of ZAG (Enzyme Immunoassay, RayBiotech, Norcross, GA) in 303 children [159 (52.48%) males; 138 (45.5%) normal-weight, 165 (54.5%) overweight/obese; mean age 6 SEM 5.49 6 0.09 years, range 2-7.9]. In overweight and obese patients, levels of ZAG were significantly lower than in normal-weight peers (mean 6 SEM: 66.19 6 7.40 vs. 185.20 6 15.90 ng/ ml, P < 0.0001), even after stratifying for age groups (2-4 years 5 52.08 6 5.77 vs. 155 6 16.52 ng/ml, P < 0.0001; 5-6 years 5 72.66 6 15.43 vs. 192.6 6 24.05 ng/ml, P < 0.00001; and 7-8 years 5 68.38 6 15.46 vs. 271.30 6 71.15 ng/ml, P 5 0.02). Indeed, serum ZAG trended to rise with aging in normal-weight children ( Figure 1 ZAG levels were inversely correlated with insulin resistance, as measured by the Homeostasis Model Assessment, HOMA-IR (q 5 20.18; P 5 0.002), body mass index (q 5 20.4; P < 0.001) and fasting insulin (q 5 20.18; P 5 0.001). They were also inversely correlated with age (q 5 20.17; P 5 0.003). Our findings in children are in agreement with evidence supporting a role of ZAG in the pathogenesis of insulin resistance (2).ZAG is an extremely fascinating molecule that resembles the behavior of adiponectin, being mainly secreted by the SAT. As adiponectin, also ZAG has a beneficial role on insulin metabolism and energy homeostasis. Indeed, its levels are positively correlated with insulin sensitivity even in patients with impaired glucose metabolism (i.e., impaired tolerance, newly diagnosed type 2 diabetes mellitus and polycystic ovary syndrome; (3). When administered in lean and obese mice, ZAG induces weight loss and reduction of adiposity (2) owing to its ability to mobilize lipids and serve as insulinsensitizer.ZAG may deserve investigation in humans as potential therapeutic target. Particularly in children, the "browning" capacity of adipose tissue might be enhanced and ZAG levels increase as visceral adipose tissue enlarges from infancy to prepuberty. Increased release of ZAG from the subcutaneous depots might represent a ...

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Circulating and Adipose Tissue Gene Expression of Zinc-α2-Glycoprotein in Obesity: Its Relationship with Adipokine and Lipolytic Gene Markers in Subcutaneous and Visceral Fat

Abstract: The present study provides evidence of a role of ZAG gene in adipose tissue metabolism, with a close association with adiponectin gene expression in sc and visceral fat.

Cited by 74 publications

References 18 publications

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

Subcutaneous adipose tissue zinc‐α2‐glycoprotein is associated with adipose tissue and whole‐body insulin sensitivity

Zinc‐α₂‐glycoprotein is associated with insulin resistance in children

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Circulating and Adipose Tissue Gene Expression of Zinc-α2-Glycoprotein in Obesity: Its Relationship with Adipokine and Lipolytic Gene Markers in Subcutaneous and Visceral Fat

Abstract: The present study provides evidence of a role of ZAG gene in adipose tissue metabolism, with a close association with adiponectin gene expression in sc and visceral fat.

Cited by 74 publications

References 18 publications

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

Subcutaneous adipose tissue zinc‐α2‐glycoprotein is associated with adipose tissue and whole‐body insulin sensitivity

Zinc‐α2‐glycoprotein is associated with insulin resistance in children

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Zinc‐α₂‐glycoprotein is associated with insulin resistance in children