- Email: [email protected]
Cord blood adiponectin in large-for-gestational age newborns
American Journal of Obstetrics and Gynecology (2005) 193, 1238–42
www.ajog.org
Cord blood adiponectin in large-for-gestational age newborns Shali Mazaki-Tovi, MD,a Hannah Kanety, PhD,b Clara Pariente, MSc,b Rina Hemi, PhD,b Eyal Schiff, MD,a Eyal Sivan, MDa,* Department of Obstetrics and Gynecology,a and Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine,b Tel Aviv University, Tel Aviv, Israel Received for publication February 28, 2005; revised May 2, 2005; accepted May 11, 2005
KEY WORDS Adiponectin Leptin LGA Macrosomia Fetal growth
Objective: The purpose of this study was to disclose the relationship between adiponectin and birth weight in a large group of newborns with normal and aberrant growth (‘‘overweight’’). Study design: Eighty-one healthy, term newborns were divided into 2 groups: 20 in the large-forgestational age (LGA; 4297 G 207 g), and 61 newborns in the appropriate-for-gestational age (AGA; 3384 G 368 g). Cord blood was analyzed for adiponectin, leptin, and insulin levels. Results: Mean adiponectin level was significantly lower in LGA newborns (29.4 G 13.8 vs 35.0 G 9.9 mg/mL, P ! .04). Both leptin and insulin levels were higher in LGA than AGA newborns, and leptin levels positively correlated with birth weight in both groups. Insulin levels positively correlated with birth weight in AGA newborns. Conclusion: The results of this study imply that adiponectin may have a role in fetal growth and support the notion of negative feedback exerted by adipose tissue on adiponectin levels, as previously shown in adults. Ó 2005 Mosby, Inc. All rights reserved.
Adiponectin is a plasma protein that has been recently discovered1,2 and circulates at relatively high concentrations.1-3 This adipocytokine is produced abundantly and exclusively in adipose tissue.4 A large body of evidence from experimental and epidemiologic studies in adults has supported the important role of adiponectin in regulation of insulin resistance and glucose homeostasis. Although the precise mechanism of adiponectin regulation is yet to be clarified, weight reduction Presented at the Twenty-Fifth Annual Meeting of the Society for Maternal Fetal Medicine, February 7-12, 2005, Reno, Nev. * Reprint requests: Eyal Sivan, MD, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Israel 52621. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.05.049
in obese individuals is accompanied by an increase in plasma adiponectin concentrations,5 suggesting that adipose tissue may exert a negative feedback on adiponectin production. Given the significance of glucose and insulin in intrauterine fetal growth, and the fundamental role of adiponectin in insulin metabolism, it is reasonable to assume that adiponectin may play a regulatory role in aberrant fetal growth. Only a handful of studies have addressed this issue. In contrary to adults, a positive correlation between cord blood adiponectin levels and birth weight has been found.6-10 In addition, cord blood adiponectin levels were relatively higher when compared with adults.6-8,11,12 Furthermore, a recent study has shown that adiponectin (produced only in adipose
Mazaki-Tovi et al tissue in adults) may be expressed in extra-adipose tissue in the fetus.13 Finally, adiponectin receptors were found abundantly in human placenta.14 Taken together, these findings imply that adiponectin may have an important role in fetal growth. While the levels of adiponectin in appropriate-forgestational age (AGA) newborns have been described, little is known about the relationship between adiponectin and overweight newborns (large-for-gestational age [LGA]). This group is characterized by fetal adiposity,15 thus increasing the risk for both neonatal and childhood complication such as obesity,16 known to be associated with high blood pressure, hyperlipidemia, and increased insulin resistance. The aim of this study was to disclose the relationship between adiponectin and birth weight in a large group of term newborns, with normal (AGA) and aberrant growth (LGA, ‘‘overweight’’).
Material and methods Subjects Eighty-one healthy, normal term newborns were included in the study. They were divided by birth weight percentile into 2 groups (Table): 20 in the LGA groupdabove the 90th percentile (mean birth weight of 4297 G 207 g, range 4005-4895 g), and 61 newborns in the AGA groupdbirth weight between 10th and 90th percentile (3384 G 368 g, range 2580-3995 g). Birth weight percentiles were calculated according to published standards.17 All neonates were normal and did not suffer from any complication. Twenty-two (27.1%) neonates were born by elective caesarean section, and 59 (72.8%) by vaginal delivery. Forty-four of the neonates were females (54.3%), and 37 (45.6%) were males. Maternal characteristics (age, body mass index [BMI], and gestational age) did not differ between the AGA and LGA groups (Table).
1239 Table Comparison between AGA and LGA newborns cord blood adiponectin, leptin, insulin, birth weight, and maternal data AGA (n = 61) Maternal age (y) Maternal BMI (kg/m2) Gestational age (wk) Birth weight (g) Birth weight percentile Adiponectin (mg/mL) Leptin(ng/mL) Insulin (mIU/L)
31.2 G 27.0 G 39.9 G 3384 G 45.9 G 35.0G 9.2 G 4.5 G
LGA (n = 20) 4.5 3.3 1.3 368 22.4 9.9 7.9 2.5
32.6 28.9 40.0 4297 95.0 29.4 15.3 13.7
G G G G G G G G
P value 4.4 4.6 1.0 207 2.9 13.8 9.0 13.0
NS NS NS .0001 .0001 .04 .001 .03
BMI, Body mass index; NS, not statistically significant.
Maternity Wing at Sheba Medical Center. The indications for the operative delivery were previous cesarean section, breech presentation, or maternal request. All mothers had an unremarkable postpartum course. The protocol was approved by the Institutional Review Board at the Sheba Medical Center, and all women provided informed consent.
Adiponectin, leptin, and insulin measurements Serum samples, obtained by centrifugation of cord blood, were immediately frozen and stored at ÿ70(C until further analysis. Adiponectin and leptin levels were determined using radioimmunoassay (RIA) kits (Linco Research, Inc, St Charles, Mo). The sensitivity of the adiponectin assay was 1 ng/ml, and the interassay coefficient of variation (CV) ranged from 6.9% to 9.3%. The sensitivity of the leptin assay was 0.5 ng/ mL, and the interassay CV ranged from 3% to 6%. Insulin levels were measured by a chemiluminiscent immunometric method (Immulite 2000, Diagnostic Products Corp, Los Angeles, Calif). The sensitivity of the assay was 2 mU/L, and the interassay CV ranged from 4% to 5%.
Methods
Statistical analysis
Cord blood was obtained from the neonates at the time of delivery and before the separation of the placenta and tested for adiponectin, leptin, and insulin levels. Mean (GSD) maternal age, BMI, and gestational week of delivery for each group are presented in the Table. Gestational age at delivery was calculated according to the last menstrual period and confirmed by ultrasound examination during the first trimester or early second trimester. Gestational diabetes was ruled out by normal glucose tolerance test (GCT) or normal oral glucose tolerance test (OGTT) in cases when GCT was abnormally high. These tests were performed between 25 to 29 gestation weeks. All women who were scheduled for elective cesarean section underwent the surgery at the
Data are presented as mean G SD. Associations between continuous variables are described by correlation coefficients (Pearson and Spearman). Mean serum adiponectin concentrations and other measures of the groups were compared by Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks. Adiponectin, leptin, and insulin levels were compared by unpaired t tests.
Results Mean adiponectin concentration was 35.0 G 9.9 and 29.4 G 13.8 mg/mL for AGA and LGA groups, respectively (Table, Figure, A). Mean LGA serum adiponectin
1240
Mazaki-Tovi et al levels were significantly lower compared with AGA (P ! .04). Both leptin and insulin levels were significantly higher in the LGA group (15.3 G 9.0 vs 9.2 G 7.9 ng/mL, P ! .001 and 13.7 G 13.0 vs 4.5 G 2.5 mIU/L, P ! .03, respectively; Figure, B and C). There was no correlation between adiponectin and birth weight, leptin and insulin in both groups. Leptin was positively correlated with birth weight and insulin in AGA group (r = 0.3; P ! .001 and r = 0.3; P ! .02, respectively) and with birth weight in LGA group (r = 0.5; P ! .01).
Comment
Figure Comparison of cord blood adiponectin (A, *P!.04), leptin (B, *P!.001), and insulin (C, *P!.03) levels in AGA (n = 61) and LGA (n = 20) newborns.
There are paucity of scientific data regarding the relationship between adiponectin and fetal growth and development. Nevertheless, previous studies have shown that adiponectin can be found in relatively high levels in cord blood, and a positive correlation with birth weight was found. Adiponectin levels in the LGA group, although lower than those found in AGA group (29.4 G 13.8 vs 35.0 G 9.9 mg/mL, P ! .04), are still relatively high when compared to children or adults.3,18 This finding is in partial agreement with a previous study,6 which also described increased levels of adiponectin in term newborns. However, adiponectin levels were significantly higher in LGA newborns, a finding that is not in accordance with both excess weight and lower insulin levels found in these newborns. One possible explanation for this discrepancy may lay in the fact that our LGA group includes solely macrosomic newborns (O4000 g). As expected, leptin, a thoroughly investigated adipocytokine, was found in significantly higher levels in LGA newborns when compared with AGA group (15.3 G 9.0 vs 9.2 G 7.9 ng/mL, P ! .001), and correlated positively with birth weight. This finding is consistent with the results of previous studies.6,19 Insulin levels were also higher in the LGA newborns (13.7 G 13.0 vs 4.5 G 2.5 mIU/L, P ! .03) as shown earlier by others.20 Several lines of evidence indicate that an increase in fat mass leads to down-regulation of adiponectin. Body weight reduction5 results in elevation of adiponectin concentrations. Likewise, high adiponectin levels were found in anorectic patients whose percentage of fat mass is obviously very low.21,22 Taken together, these findings imply that fat mass may exert a negative feedback on adiponectin production. Indeed, LGA newborns have increased amount concentration of adipose tissue15 and, thus, lower adiponectin levels are to be expected. Furthermore, LGA newborns have not only excessive amount of adipose tissue, but also larger adipocytes.23 Several studies have shown that adiponectin expression is reduced in hypertrophic adipocytes.24 In addition, these studies have indicated that the levels of expression of adiponectin may be more closely related to adipocyte
Mazaki-Tovi et al size than to the total amount of adipocytes or body weight. Therefore, both the large number and size of adipocytes in LGA newborns may account for the lower adiponectin levels. These findings imply that the alleged negative feedback of adipose tissue on adiponectin levels, previously demonstrated only in adults, can be a part of the mechanism regulating adiponectin in fetal life. Several previous studies,6,8-10 including by our group,7 have described a positive correlation between adiponectin and birth weight. Nevertheless, most of those studies7-10 included not only term, AGA newborns, but also preterm or small-for-gestational age (SGA) newborns. It is important to mention that both birth weight and gestational age can affect adiponectin levels.12 Both preterm and SGA newborns are known to have smaller body fat mass as compared with term or AGA/LGA newborns. Furthermore, when the correlation between adiponectin and birth weight was limited to term newborns, no correlation was found.12 One possible explanation for these findings can be that adipose tissue can exert its negative feedback on adiponectin levels only when it reaches a critical mass. Thus, when the total adipose tissue is low (ie, preterm or SGA newborns), there is little, if any, negative feedback and adiponectin is positively correlated with birth weight. However, when the total adipose tissue increases (ie, in AGA newborns), the adipose tissue exerts its negative feedback mechanism and the correlation with birth weight is disrupted. When the quantity of adipose tissue is abnormally higher (ie, LGA newborns), the negative feedback intensifies to a degree that depresses the levels of adiponectin. Both lack of correlation and lower levels of adiponectin, found in this study, support this hypothesis. The hypoadiponectinemia that accompanies weight and fat gain in infancy and early childhood25 also support this hypothesis. The results of this study imply that adiponectin may play a role in fetal growth. The relatively high cord blood levels in both groups suggest that this hormone may participate in the regulation of fetal growth. The lower levels of adiponectin in LGA newborns support the notion of negative feedback exerted by adipose tissue on adiponectin production, as previously shown in adults.
References 1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746-9. 2. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286-9. 3. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adipo-
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nectin, in obesity. Biochem Biophys Res Commun 1999;257: 79-83. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 2002;13:84-9. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, et al. Weight reduction increases plasma levels of an adiposederived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86:3815-9. Tsai PJ, Yu CH, Hsu SP, Lee YH, Chiou CH, Hsu YW, et al. Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity. Clin Endocrinol (Oxf) 2004;61:88-93. Sivan E, Mazaki-Tovi S, Pariente C, Efraty Y, Schiff E, Hemi R, et al. Adiponectin in human cord blood: relation to fetal birth weight and gender. J Clin Endocrinol Metab 2003;88:5656-60. Chan TF, Yuan SS, Chen HS, Guu CF, Wu LC, Yeh YT, et al. Correlations between umbilical and maternal serum adiponectin levels and neonatal birthweights. Acta Obstet Gynecol Scand 2004;83:165-9. Pardo IM, Geloneze B, Tambascia MA, Barros-Filho AA. Hyperadiponectinemia in newborns: relationship with leptin levels and birth weight. Obes Res 2004;12:521-4. Kamoda T, Saitoh H, Saito M, Sugiura M, Matsui A. Serum adiponectin concentrations in newborn infants in early postnatal life. Pediatr Res 2004;56:690-3. Lindsay RS, Walker JD, Havel PJ, Hamilton BA, Calder AA, Johnstone FD. Adiponectin is present in cord blood but is unrelated to birth weight. Diabetes Care 2003;26:2244-9. Kajantie E, Hytinantti T, Hovi P, Andersson S. Cord plasma adiponectin: a 20-fold rise between 24 weeks gestation and term. J Clin Endocrinol Metab 2004;89:4031-6. Corbetta S, Bulfamante G, Cortelazzi D, Barresi V, Cetin I, Mantovani G, et al. Adiponectin expression in human fetal tissues during mid- and late gestation. J Clin Endocrinol Metab 2005;90:2397-402. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 2003;423:762-9. Galan HL, Rigano S, Radaelli T, Cetin I, Bozzo M, Chyu J, et al. Reduction of subcutaneous mass, but not lean mass, in normal fetuses in Denver, Colorado. Am J Obstet Gynecol 2001;185: 839-44. Vohr BR, McGarvey ST. Growth patterns of large-for-gestationalage and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year. Diabetes Care 1997;20:1066-72. Battaglia FC, Lubchenco LO. A practical classification of newborn infants by weight and gestational age. J Pediatr 1967;71: 159-63. Yannakoulia M, Yiannakouris N, Bluher S, Matalas AL, KlimisZacas D, Mantzoros CS. Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab 2003;88:1730-6. Christou H, Connors JM, Ziotopoulou M. Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab 2001;86:935-8. Wolf HJ, Ebenbichler CF, Huter O, Bodner J, Lechleitner M, Foger B, et al. Fetal leptin and insulin levels only correlate in large-for-gestational age infants. Eur J Endocrinol 2000;142: 623-9. Delporte ML, Brichard SM, Hermans MP, Beguin C, Lambert M. Hyperadiponectinaemia in anorexia nervosa. Clin Endocrinol (Oxf) 2003;58:22-9. Pannacciulli N, Vettor R, Milan G, Granzotto M, Catucci A, Federspil G, et al. Anorexia nervosa is characterized by
1242 increased adiponectin plasma levels and reduced nonoxidative glucose metabolism. J Clin Endocrinol Metab 2003;88: 1748-52. 23. Tasca C, Chelaru E, Sdrobici D. Fat cell sizedbody weight correlation in newborn. Endocrinologie 1978;16:287-9. 24. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, et al. The mechanisms by which both heterozygous
Mazaki-Tovi et al peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem 2001;276:41245-54. 25. Iniguez G, Soto N, Avila A, Salazar T, Ong K, Dunger D, et al. Adiponectin levels in the first two years of life in a prospective cohort: relations with weight gain, leptin levels and insulin sensitivity. J Clin Endocrinol Metab 2004;89:5500-3.
www.ajog.org
Cord blood adiponectin in large-for-gestational age newborns Shali Mazaki-Tovi, MD,a Hannah Kanety, PhD,b Clara Pariente, MSc,b Rina Hemi, PhD,b Eyal Schiff, MD,a Eyal Sivan, MDa,* Department of Obstetrics and Gynecology,a and Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer, Israel; Sackler School of Medicine,b Tel Aviv University, Tel Aviv, Israel Received for publication February 28, 2005; revised May 2, 2005; accepted May 11, 2005
KEY WORDS Adiponectin Leptin LGA Macrosomia Fetal growth
Objective: The purpose of this study was to disclose the relationship between adiponectin and birth weight in a large group of newborns with normal and aberrant growth (‘‘overweight’’). Study design: Eighty-one healthy, term newborns were divided into 2 groups: 20 in the large-forgestational age (LGA; 4297 G 207 g), and 61 newborns in the appropriate-for-gestational age (AGA; 3384 G 368 g). Cord blood was analyzed for adiponectin, leptin, and insulin levels. Results: Mean adiponectin level was significantly lower in LGA newborns (29.4 G 13.8 vs 35.0 G 9.9 mg/mL, P ! .04). Both leptin and insulin levels were higher in LGA than AGA newborns, and leptin levels positively correlated with birth weight in both groups. Insulin levels positively correlated with birth weight in AGA newborns. Conclusion: The results of this study imply that adiponectin may have a role in fetal growth and support the notion of negative feedback exerted by adipose tissue on adiponectin levels, as previously shown in adults. Ó 2005 Mosby, Inc. All rights reserved.
Adiponectin is a plasma protein that has been recently discovered1,2 and circulates at relatively high concentrations.1-3 This adipocytokine is produced abundantly and exclusively in adipose tissue.4 A large body of evidence from experimental and epidemiologic studies in adults has supported the important role of adiponectin in regulation of insulin resistance and glucose homeostasis. Although the precise mechanism of adiponectin regulation is yet to be clarified, weight reduction Presented at the Twenty-Fifth Annual Meeting of the Society for Maternal Fetal Medicine, February 7-12, 2005, Reno, Nev. * Reprint requests: Eyal Sivan, MD, Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Israel 52621. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.ajog.2005.05.049
in obese individuals is accompanied by an increase in plasma adiponectin concentrations,5 suggesting that adipose tissue may exert a negative feedback on adiponectin production. Given the significance of glucose and insulin in intrauterine fetal growth, and the fundamental role of adiponectin in insulin metabolism, it is reasonable to assume that adiponectin may play a regulatory role in aberrant fetal growth. Only a handful of studies have addressed this issue. In contrary to adults, a positive correlation between cord blood adiponectin levels and birth weight has been found.6-10 In addition, cord blood adiponectin levels were relatively higher when compared with adults.6-8,11,12 Furthermore, a recent study has shown that adiponectin (produced only in adipose
Mazaki-Tovi et al tissue in adults) may be expressed in extra-adipose tissue in the fetus.13 Finally, adiponectin receptors were found abundantly in human placenta.14 Taken together, these findings imply that adiponectin may have an important role in fetal growth. While the levels of adiponectin in appropriate-forgestational age (AGA) newborns have been described, little is known about the relationship between adiponectin and overweight newborns (large-for-gestational age [LGA]). This group is characterized by fetal adiposity,15 thus increasing the risk for both neonatal and childhood complication such as obesity,16 known to be associated with high blood pressure, hyperlipidemia, and increased insulin resistance. The aim of this study was to disclose the relationship between adiponectin and birth weight in a large group of term newborns, with normal (AGA) and aberrant growth (LGA, ‘‘overweight’’).
Material and methods Subjects Eighty-one healthy, normal term newborns were included in the study. They were divided by birth weight percentile into 2 groups (Table): 20 in the LGA groupdabove the 90th percentile (mean birth weight of 4297 G 207 g, range 4005-4895 g), and 61 newborns in the AGA groupdbirth weight between 10th and 90th percentile (3384 G 368 g, range 2580-3995 g). Birth weight percentiles were calculated according to published standards.17 All neonates were normal and did not suffer from any complication. Twenty-two (27.1%) neonates were born by elective caesarean section, and 59 (72.8%) by vaginal delivery. Forty-four of the neonates were females (54.3%), and 37 (45.6%) were males. Maternal characteristics (age, body mass index [BMI], and gestational age) did not differ between the AGA and LGA groups (Table).
1239 Table Comparison between AGA and LGA newborns cord blood adiponectin, leptin, insulin, birth weight, and maternal data AGA (n = 61) Maternal age (y) Maternal BMI (kg/m2) Gestational age (wk) Birth weight (g) Birth weight percentile Adiponectin (mg/mL) Leptin(ng/mL) Insulin (mIU/L)
31.2 G 27.0 G 39.9 G 3384 G 45.9 G 35.0G 9.2 G 4.5 G
LGA (n = 20) 4.5 3.3 1.3 368 22.4 9.9 7.9 2.5
32.6 28.9 40.0 4297 95.0 29.4 15.3 13.7
G G G G G G G G
P value 4.4 4.6 1.0 207 2.9 13.8 9.0 13.0
NS NS NS .0001 .0001 .04 .001 .03
BMI, Body mass index; NS, not statistically significant.
Maternity Wing at Sheba Medical Center. The indications for the operative delivery were previous cesarean section, breech presentation, or maternal request. All mothers had an unremarkable postpartum course. The protocol was approved by the Institutional Review Board at the Sheba Medical Center, and all women provided informed consent.
Adiponectin, leptin, and insulin measurements Serum samples, obtained by centrifugation of cord blood, were immediately frozen and stored at ÿ70(C until further analysis. Adiponectin and leptin levels were determined using radioimmunoassay (RIA) kits (Linco Research, Inc, St Charles, Mo). The sensitivity of the adiponectin assay was 1 ng/ml, and the interassay coefficient of variation (CV) ranged from 6.9% to 9.3%. The sensitivity of the leptin assay was 0.5 ng/ mL, and the interassay CV ranged from 3% to 6%. Insulin levels were measured by a chemiluminiscent immunometric method (Immulite 2000, Diagnostic Products Corp, Los Angeles, Calif). The sensitivity of the assay was 2 mU/L, and the interassay CV ranged from 4% to 5%.
Methods
Statistical analysis
Cord blood was obtained from the neonates at the time of delivery and before the separation of the placenta and tested for adiponectin, leptin, and insulin levels. Mean (GSD) maternal age, BMI, and gestational week of delivery for each group are presented in the Table. Gestational age at delivery was calculated according to the last menstrual period and confirmed by ultrasound examination during the first trimester or early second trimester. Gestational diabetes was ruled out by normal glucose tolerance test (GCT) or normal oral glucose tolerance test (OGTT) in cases when GCT was abnormally high. These tests were performed between 25 to 29 gestation weeks. All women who were scheduled for elective cesarean section underwent the surgery at the
Data are presented as mean G SD. Associations between continuous variables are described by correlation coefficients (Pearson and Spearman). Mean serum adiponectin concentrations and other measures of the groups were compared by Kruskal-Wallis one-way analysis of variance (ANOVA) on ranks. Adiponectin, leptin, and insulin levels were compared by unpaired t tests.
Results Mean adiponectin concentration was 35.0 G 9.9 and 29.4 G 13.8 mg/mL for AGA and LGA groups, respectively (Table, Figure, A). Mean LGA serum adiponectin
1240
Mazaki-Tovi et al levels were significantly lower compared with AGA (P ! .04). Both leptin and insulin levels were significantly higher in the LGA group (15.3 G 9.0 vs 9.2 G 7.9 ng/mL, P ! .001 and 13.7 G 13.0 vs 4.5 G 2.5 mIU/L, P ! .03, respectively; Figure, B and C). There was no correlation between adiponectin and birth weight, leptin and insulin in both groups. Leptin was positively correlated with birth weight and insulin in AGA group (r = 0.3; P ! .001 and r = 0.3; P ! .02, respectively) and with birth weight in LGA group (r = 0.5; P ! .01).
Comment
Figure Comparison of cord blood adiponectin (A, *P!.04), leptin (B, *P!.001), and insulin (C, *P!.03) levels in AGA (n = 61) and LGA (n = 20) newborns.
There are paucity of scientific data regarding the relationship between adiponectin and fetal growth and development. Nevertheless, previous studies have shown that adiponectin can be found in relatively high levels in cord blood, and a positive correlation with birth weight was found. Adiponectin levels in the LGA group, although lower than those found in AGA group (29.4 G 13.8 vs 35.0 G 9.9 mg/mL, P ! .04), are still relatively high when compared to children or adults.3,18 This finding is in partial agreement with a previous study,6 which also described increased levels of adiponectin in term newborns. However, adiponectin levels were significantly higher in LGA newborns, a finding that is not in accordance with both excess weight and lower insulin levels found in these newborns. One possible explanation for this discrepancy may lay in the fact that our LGA group includes solely macrosomic newborns (O4000 g). As expected, leptin, a thoroughly investigated adipocytokine, was found in significantly higher levels in LGA newborns when compared with AGA group (15.3 G 9.0 vs 9.2 G 7.9 ng/mL, P ! .001), and correlated positively with birth weight. This finding is consistent with the results of previous studies.6,19 Insulin levels were also higher in the LGA newborns (13.7 G 13.0 vs 4.5 G 2.5 mIU/L, P ! .03) as shown earlier by others.20 Several lines of evidence indicate that an increase in fat mass leads to down-regulation of adiponectin. Body weight reduction5 results in elevation of adiponectin concentrations. Likewise, high adiponectin levels were found in anorectic patients whose percentage of fat mass is obviously very low.21,22 Taken together, these findings imply that fat mass may exert a negative feedback on adiponectin production. Indeed, LGA newborns have increased amount concentration of adipose tissue15 and, thus, lower adiponectin levels are to be expected. Furthermore, LGA newborns have not only excessive amount of adipose tissue, but also larger adipocytes.23 Several studies have shown that adiponectin expression is reduced in hypertrophic adipocytes.24 In addition, these studies have indicated that the levels of expression of adiponectin may be more closely related to adipocyte
Mazaki-Tovi et al size than to the total amount of adipocytes or body weight. Therefore, both the large number and size of adipocytes in LGA newborns may account for the lower adiponectin levels. These findings imply that the alleged negative feedback of adipose tissue on adiponectin levels, previously demonstrated only in adults, can be a part of the mechanism regulating adiponectin in fetal life. Several previous studies,6,8-10 including by our group,7 have described a positive correlation between adiponectin and birth weight. Nevertheless, most of those studies7-10 included not only term, AGA newborns, but also preterm or small-for-gestational age (SGA) newborns. It is important to mention that both birth weight and gestational age can affect adiponectin levels.12 Both preterm and SGA newborns are known to have smaller body fat mass as compared with term or AGA/LGA newborns. Furthermore, when the correlation between adiponectin and birth weight was limited to term newborns, no correlation was found.12 One possible explanation for these findings can be that adipose tissue can exert its negative feedback on adiponectin levels only when it reaches a critical mass. Thus, when the total adipose tissue is low (ie, preterm or SGA newborns), there is little, if any, negative feedback and adiponectin is positively correlated with birth weight. However, when the total adipose tissue increases (ie, in AGA newborns), the adipose tissue exerts its negative feedback mechanism and the correlation with birth weight is disrupted. When the quantity of adipose tissue is abnormally higher (ie, LGA newborns), the negative feedback intensifies to a degree that depresses the levels of adiponectin. Both lack of correlation and lower levels of adiponectin, found in this study, support this hypothesis. The hypoadiponectinemia that accompanies weight and fat gain in infancy and early childhood25 also support this hypothesis. The results of this study imply that adiponectin may play a role in fetal growth. The relatively high cord blood levels in both groups suggest that this hormone may participate in the regulation of fetal growth. The lower levels of adiponectin in LGA newborns support the notion of negative feedback exerted by adipose tissue on adiponectin production, as previously shown in adults.
References 1. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 1995;270:26746-9. 2. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286-9. 3. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al. Paradoxical decrease of an adipose-specific protein, adipo-
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