Obesity
Letter to the Editor PEDIATRIC OBESITY
Zinc-a2-Glycoprotein is Associated with Insulin Resistance in Children Gloria Maria Barraco1, Rosa Luciano2, and Melania Manco1 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-a2-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, Panel A; P 5 0.4) but not in obese children (Figure 1, Panel B). Figure 1 shows also mean values of HOMA-IR in the different groups. The serum ZAG levels increase with aging and parallel increased HOMA-IR levels in both groups. No between-gender difference was observed in ZAG levels. 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 mechanism
Figure 1 Bars represent levels of serum ZAG and HOMA-IR (mean 6 SEM) in (A) normal-weight and (B) overweight/obese children stratified in three age groups. Serum ZAG trended to rise with aging in normal-weight children (P 5 0.4) but not in obese children. HOMA-IR was statistically different in overweight/obese and normalweight children across age classes (Panel A: 7-8 years 5 0.87 6 0.07 vs. 2-4 years 5 0.63 6 0.05, P < 0.001 and vs. 5-6 years 5 0.82 6 0.06, P 5 0.002; Panel B: 7-8 years 5 1.80 6 0.18 vs. 2-4 years 5 0.83 6 0.16, P 5 0.016 and vs. 5-6 years 5 1.14 6 0.15, P 5 0.04).
www.obesityjournal.org
Obesity | VOLUME 23 | NUMBER 1 | JANUARY 2015
5
Obesity
to counteract the increase of visceral adiposity and the associated metabolic derangement. O C 2014 The Obesity Society V
References 1. Balaz M, Vician M, Janakova Z, et al. Subcutaneous adipose tissue zinc-alpha2-glyco- protein is associated with adipose tissue and whole-body insulin sensitivity. Obesity (Silver Spring) 2014; 22: 1821-1829.
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2. Ceperuelo-Mallafre V, Naf S, Escote X, et al. Circulating and adipose tissue gene expression of zincalpha2-glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat. J Clin Endocrinol Metab 2009;94: 5062-5069. 3. Yang M, Liu R, Li S, et al. Zinc-alpha2glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes. Diabetes Care 2013;36: 1074-1082.
Obesity | VOLUME 23 | NUMBER 1 | JANUARY 2015
1 Research Unit for Multi-factorial Diseases, Scientific Directorate Bambino Ges u Children’s Hospital, Rome, Italy. 2 Department of Laboratory Medicine, Bambino Ges u Children’s Hospital, Rome, Italy. Correspondence: Melania Manco ([email protected])
Disclosure: The authors declared no conflict of interest. doi: 10.1002/oby.20948
www.obesityjournal.org
Letter to the Editor PEDIATRIC OBESITY
Zinc-a2-Glycoprotein is Associated with Insulin Resistance in Children Gloria Maria Barraco1, Rosa Luciano2, and Melania Manco1 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-a2-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, Panel A; P 5 0.4) but not in obese children (Figure 1, Panel B). Figure 1 shows also mean values of HOMA-IR in the different groups. The serum ZAG levels increase with aging and parallel increased HOMA-IR levels in both groups. No between-gender difference was observed in ZAG levels. 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 mechanism
Figure 1 Bars represent levels of serum ZAG and HOMA-IR (mean 6 SEM) in (A) normal-weight and (B) overweight/obese children stratified in three age groups. Serum ZAG trended to rise with aging in normal-weight children (P 5 0.4) but not in obese children. HOMA-IR was statistically different in overweight/obese and normalweight children across age classes (Panel A: 7-8 years 5 0.87 6 0.07 vs. 2-4 years 5 0.63 6 0.05, P < 0.001 and vs. 5-6 years 5 0.82 6 0.06, P 5 0.002; Panel B: 7-8 years 5 1.80 6 0.18 vs. 2-4 years 5 0.83 6 0.16, P 5 0.016 and vs. 5-6 years 5 1.14 6 0.15, P 5 0.04).
www.obesityjournal.org
Obesity | VOLUME 23 | NUMBER 1 | JANUARY 2015
5
Obesity
to counteract the increase of visceral adiposity and the associated metabolic derangement. O C 2014 The Obesity Society V
References 1. Balaz M, Vician M, Janakova Z, et al. Subcutaneous adipose tissue zinc-alpha2-glyco- protein is associated with adipose tissue and whole-body insulin sensitivity. Obesity (Silver Spring) 2014; 22: 1821-1829.
6
2. Ceperuelo-Mallafre V, Naf S, Escote X, et al. Circulating and adipose tissue gene expression of zincalpha2-glycoprotein in obesity: its relationship with adipokine and lipolytic gene markers in subcutaneous and visceral fat. J Clin Endocrinol Metab 2009;94: 5062-5069. 3. Yang M, Liu R, Li S, et al. Zinc-alpha2glycoprotein is associated with insulin resistance in humans and is regulated by hyperglycemia, hyperinsulinemia, or liraglutide administration: cross-sectional and interventional studies in normal subjects, insulin-resistant subjects, and subjects with newly diagnosed diabetes. Diabetes Care 2013;36: 1074-1082.
Obesity | VOLUME 23 | NUMBER 1 | JANUARY 2015
1 Research Unit for Multi-factorial Diseases, Scientific Directorate Bambino Ges u Children’s Hospital, Rome, Italy. 2 Department of Laboratory Medicine, Bambino Ges u Children’s Hospital, Rome, Italy. Correspondence: Melania Manco ([email protected])
Disclosure: The authors declared no conflict of interest. doi: 10.1002/oby.20948
www.obesityjournal.org
