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April 2001, Volume 25, Number 4, Pages 491-495
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Paper
Relatively low serum leptin levels in adults born with intra-uterine growth retardation
D Jaquet, A Gaboriau, P Czernichow and C Levy-Marchal

INSERM Unit 457, Hôpital Robert Debré, Paris, France

Correspondence to: D Jaquet, INSERM Unit 457, Hôpital R Debré, 48 Bd Sérurier 75019 Paris, France. E-mail: djacquet@infobiogen.fr

Abstract

BACKGROUND: In-utero under-nutrition dramatically alters the development of adipose tissue, during the fetal and the neonatal period.

THE AIM OF THE STUDY: To investigate whether adults born with intra-uterine growth retardation (IUGR) show evidence of impaired adipose tissue development and leptin regulation.

DESIGN: Serum leptin concentrations were measured in 26 healthy adults born with IUGR and 25 controls aged 24 y who have been studied previously, 3 y ago.

RESULTS: The IUGR group demonstrated a significant increase of body mass index (BMI) in comparison to controls between 21 and 24 y of age (4.8±7.7%, P=0.004 vs 0.8±6.7%, P=0.70). Percentage of total body fat mass was significantly higher in IUGR-born subjects than in controls (27.2±7.6 vs 22.0±7.3%, P=0.02). Fasting insulin was significantly higher in the IUGR group (7.5±3.8 vs 5.3±2.3 muU/ml, P=0.03). Surprisingly, crude serum leptin concentrations did not significantly differ between the two groups. Moreover, adjusted means of serum leptin levels were significantly lower in IUGR-born subjects than in controls when corrected for body fat mass, gender and fasting insulin (11.3 vs 13.8 ng/ml, P=0.02).

SUMMARY: Adults born with IUGR developed an excess of adipose tissue associated with relatively low serum leptin levels suggestive of an altered adipocyte function. Considering the close relationship between adipose tissue and insulin-sensitivity, these observations point to the potential implication of abnormal adipose tissue development in the long-term metabolic consequences associated with in-utero undernutrition.

International Journal of Obesity (2001) 25, 491-495

Keywords

serum leptin; fetal undernutrition; IUGR; fasting insulin; insulin-resistance

Introduction

The association between in-utero undernutrition and the later development of the insulin-resistance syndrome and type 2 diabetes is well-documented.1,2,3 We previously showed that intra-uterine growth retardation (IUGR) is associated with hyperinsulinemia and insulin resistance early in adulthood.4,5

The association between adiposity and insulin resistance has been well established. Obesity is known to be associated with insulin-resistance. Hence it is a fundamental component of the insulin-resistance syndrome.6 Additionally, leptin, the adipocyte hormone involved in the regulation of body weight and food intake,7 appears to be involved in the control of insulin sensitivity.8,9,10,11,12

IUGR has severe consequences on fetal and neonatal development. The intra-uterine development of adipose tissue is dramatically altered. Consequently, adipose growth is postponed to the neonatal period.13,14 In previous studies, we demonstrated that the regulation of serum leptin concentrations is affected in newborns and children born with IUGR.15,16 We hypothesized that the abnormal adipose tissue development might be involved in the metabolic complications observed in IUGR-born adults.

The aim of the present study was therefore to investigate whether being born with IUGR would impair adipose tissue development and leptin regulation in adulthood. Serum leptin concentrations were measured in 24-y-old subjects born with IUGR in comparison to controls born with normal birthweight and analyzed with respect to the usual determinants of leptin levels. Concomitantly, we investigated the evolution of adipose tissue between 21 and 24 y of age using anthropometric parameters.

Subjects and methods

Study population

The study population included two groups of healthy volunteers aged 21-27 y who demonstrated normal glucose tolerance under an oral glucose tolerance test according to both WHO and ADA criteria.17,18 All subjects were randomly selected according to their birth data, from a cohort created 3 y before in order to investigate the metabolic complications associated with in-utero undernutrition.4 The IUGR group included 26 subjects and the control group included 25 subjects. IUGR was defined as a birth weight below the third percentile of the local distribution for gestational age and gender established from a population based-registry.19 Control subjects were selected with birthweight between the 25th and 75th percentiles of the same distribution.

In the present study, the etiology of IUGR was gestational hypertension (50%), smoking (30%), congenital abnormalities (7%), maternal short stature (7%) and unknown (6%). Three subjects had more than one cause. Gestational age did not significantly differ between the two groups (39.6±1.3 vs 39.9±1 weeks). According to the selection criteria, mean birthweight and mean ponderal index were significantly lower in IUGR-born subjects than in controls (2414±244 vs 3460±187 g; P<0.0001 and 22.4±2.8 vs 26.9±1.1 kg/m3´100; P<0.0001). Cigarette smoking was reported in seven of the 26 IUGR-born subjects and 13 of the 25 controls (P=0.12). Alcohol consumption was reported in one subject of the IUGR group vs two of the control group (P=0.96).

All subjects gave their written informed consent and the study protocol was reviewed and approved by the ethical committee of Paris/St Louis University.

Methods

Height was measured twice to the nearest 0.1 cm using a wall-mounted stadiometer. The average value was used in the analysis. Body weight was measured to the nearest 0.1 kg using an electronic scale. The same stadiometer and the same scale were used in the previous study and in the present study. Weight for height was assessed as body mass index (BMI: weight (kg)/height2 (m)). Waist circumference was measured at the level of the umbilicus and hip circumference at the level of the greater trochanter.

The percentage of total body fat mass was derived from bioelectrical impedance analysis (50 kHz, 800 muA; RJL Systems, Clinton Township, NJ, USA) according to a standardized procedure after emptying the bladder and 15 min rest. The percentage of total body fat mass was calculated using the equation of Lukaski et al which has been previously validated in adults.20

After an overnight fast, blood was drawn for measurements of fasting plasma glucose, serum insulin and serum leptin concentrations.

Analytical methods

  • Fasting blood glucose was measured by enzymatic methods.
  • Serum insulin concentration was measured using a double-antibody radioimmunoassay (ERIA Diagnostics Pasteur, France). Cross-reactivity with proinsulin and derived metabolites was less than 1%. Assay sensitivity was 1.2 pmol/l.
  • Serum leptin concentration was measured using a specific radioimmunoassay (Linco-Research, St Charles, USA). The sensitivity of the assay was 0.5 ng/ml with intra-and inter-assay coefficient of variation (CVs) of 5.2% and 8.7% respectively, at 2.3 ng/ml.

Statistical analysis

All data were entered and analyzed using the SAS statistical package (SAS Institute, Cary, NC).

The differences between the IUGR and control groups were tested by chi2 test for qualitative variables and Student's t-test for quantitative variables. Serum insulin and serum leptin values were log transformed before statistical analyses.

Variations of anthropometric parameters between the two periods were tested in each group by a paired t-test.

The independent effect of IUGR on serum leptin concentration was tested using a general linear model (GLM procedure). Serum leptin was the dependent variable and percentage of body fat mass, gender and fasting insulin concentrations were the explanatory variables.

Correlation between serum leptin concentrations and anthropometric parameters and serum insulin were tested using linear regression models. A P-value £0.05 was considered significant.

Results

Clinical characteristics at 24 y of age

Table 1 shows the clinical characteristics of the IUGR and control subjects at the time of the study. Mean age and gender distributions were similar in the two groups. Mean height was significantly reduced in the IUGR-born subjects. Body weight, BMI and the waist to hip ratio did not significantly differ between the IUGR and control groups. In contrast, the percentage of body fat was significantly higher in subjects born with IUGR (P=0.02).

Evolution of anthropometric parameters between 21 and 24 y of age

All subjects had been investigated 3 y earlier in a previous study. Mean age of IUGR-born and control subjects were 21.2±1.3 and 21.2±1.7 y, respectively (P=0.94). At this age, neither body weight (66.0±16.4 vs 71.8±13.7 kg, P=0.18), BMI (23.2±4.5 vs 23.6±3.1 kg/m2, P=0.73), nor waist-to-hip ratio (0.82±0.08 vs 0.85±0.07, P=0.23) significantly differed between the IUGR and control groups.

Between 21 and 24 y of age, the control group did not demonstrate significant variations in body weight (0.7±6.6%, P=0.82) or BMI (0.8±6.7%, P=0.70) (Figure 1). Neither did the waist-to-hip ratio significantly vary (-2.1±5.1%, P=0.06).

In contrast, the IUGR group demonstrated a statistically significant increase in body weight (4.9±7.8%, P=0.005) and BMI (4.8±7.7%, P=0.004) during the same period (Figure 1). As with the controls, waist-to-hip ratio did not vary significantly in the IUGR-born subjects (-2.0±5.8%, P=0.08).

Metabolic parameters

In the present study, fasting blood glucose did not differ significantly between IUGR and control groups (90±7 vs 89±6 mg/dl; P=0.98). Mean fasting serum insulin was significantly higher in subjects born with IUGR (7.5±3.8 vs 5.3±2.3 muU/ml, P=0.03). The difference in mean fasting serum insulin levels remained significant between the two groups after adjusting for BMI (P=0.03).

Serum leptin concentrations

Crude mean serum leptin values did not differ significantly between the IUGR and control groups (13.4±10.3 vs 10.1+8.8 ng/ml; P=0.26). However, the IUGR group demonstrated significantly higher body fat mass and serum insulin concentrations, both known to influence serum leptin levels. Therefore, the independent effect of being born with IUGR was tested after adjustment for percentage of body fat mass, gender and serum insulin concentration using a multivariate analysis (see method section). In this model, being born with IUGR showed a significant independent effect on serum leptin values (P=0.02). Furthermore, adjusted mean values of serum leptin were significantly lower in IUGR-born subjects than in controls (11.3 vs 13.8 ng/ml) (Figure 2). As expected, percentage of body fat had a strong independent effect (P<0.0001) as well as fasting insulin levels (P=0.0001) and gender (P=0.03).

The relationships between serum leptin values and the usual regulatory factors were tested in the IUGR group. Serum leptin values were closely correlated to BMI (r=0.72; P<0.0001), percentage of body fat mass (r=0.83; P<0.0001) and fasting insulin (r=0.51; P=0.008) but not to waist-to-hip ratio (r=0.18; P=0.37). The gender difference was statistically significant in the IUGR group (15.9±8.5 vs 8.0±7.1 ng/ml (female vs male); P=0.03).

Discussion

Our study provides an additional example of the metabolic consequences of in-utero undernutrition that occur in adulthood. In our study, young adults born with IUGR had lower serum leptin concentrations relative to their body fat mass and insulin concentrations than controls. The effect of IUGR was statistically independent of the usual factors known to up-regulate serum leptin concentrations.21,22,23 This observation is consistent with a previous study reporting that size at birth has a significant effect on serum leptin concentrations.24 However, in the latter study, serum leptin levels tended to be higher in people who were smaller at birth but the difference was not statistically significant. It should be pointed out that the previous authors had on the same cohort, shown that plasma insulin concentrations were higher in subjects born with low birthweight.1 However the variation of serum leptin concentrations with respect to the increase in plasma insulin concentrations from high birthweight to low birthweight was not documented.

Body fat distribution influences serum leptin levels. Leptin expression is higher in subcutaneous adipose tissue than in visceral fat mass.25 In addition, it has been shown in obese subjects, that serum leptin levels were negatively correlated to waist-to-hip ratio, a good clinical marker for visceral adiposity.22 The IUGR group of the present study showed significantly higher body fat mass than controls. However, waist-to-hip ratio were comparable in both groups. This observation could indicate that the increased total body fat mass observed in IUGR-born subjects is not associated with an abnormal fat distribution but reflects an increase of both subcutaneous and visceral adipose tissue. Therefore, we consider that abnormal body fat distribution is not involved in the low serum leptin levels observed in IUGR-born subjects investigated in the present study.

Adipose tissue development is severely altered in IUGR fetuses.13 Accordingly, serum leptin concentrations are low in IUGR newborns.15 An increased growth velocity, involving the adipose tissue, is one of the major features of post-natal development of IUGR babies.14 During this period, dysregulation of leptin secretion has been documented and expressed as the loss of significant effect of BMI and gender, normally observed at this age, on serum leptin levels.16 In the present study, our results indicate that, in contrast to IUGR-born babies, adipocytes in adults are able to respond to the usual leptin stimulatory factors. However the relatively low serum leptin levels observed in this group suggest that the adipocyte sensitivity might have been altered during the fetal and post-natal development in these subjects.

It has been reported that fetal undernutrition might favor obesity in adulthood.26 Indeed, the IUGR group of the present study demonstrated a significant increase of body weight and BMI between 21 and 24 y of age, which was not observed in controls. This observation is consistent with the relative increase of BMI observed in the whole IUGR group (n=236) between 6 and 20 y of age.27 Ravussin et al have previously reported that relatively low serum leptin concentrations predict weight gain in Pima Indians.28 It is therefore tempting to speculate that such a mechanism might contribute to the susceptibility for obesity observed in IUGR-born adults. Investigation of the further evolution of both anthropometric parameters and serum leptin levels in this population will be very helpful to confirm this hypothesis.

In-utero undernutrition is associated with insulin-resistance.3,29 We previously showed, in the same study groups, that subjects born with IUGR demonstrate insulin-resistance in comparison to controls.5 Several recent studies have emphasized the role of leptin on insulin-sensitivity. Prolonged hyperinsulinemia is known to increase circulating leptin levels.8,9,20 In rodents, both in vivo and in vitro studies have demonstrated that leptin increases peripheral glucose uptake and improves glucose metabolism in skeletal muscles.10,11,12 Therefore, according to the results obtained in animal models, we cannot exclude the theory that increased leptin production could be a regulatory component aimed at improving, at least in part, insulin-sensitivity. These observations highlight the complexity of the relationship between adipose tissue and insulin-sensitivity. Nevertheless, if this hypothesis holds true, the inability of adipocytes to adequately produce leptin in IUGR-born subjects would further increase the well-documented susceptibility to insulin resistance of this population.3,5,29 In summary, we demonstrated that IUGR-born subjects developed an excess of adipose tissue associated with an impaired leptin secretion in adulthood. Our data argue in favor of adipocyte dysfunction as a result of the altered fetal and neonatal development of adipose tissue. Considering the close relationships between adipose tissue and insulin-sensitivity, we cannot exclude that this impaired leptin secretion would be involved in the long-term metabolic consequences of in-utero undernutrition.

Acknowledgements

D Jaquet was supported by a fellowship from 'l'Institut National de la Santé et de la Recherche Médicale (INSERM)' sponsorded by Bayer-France. This study was supported by Pharmacia-Upjohn, France. The authors acknowledge the contribution of C Traband, Dr C Collin, Dr JL Boerher and the laboratory staff at the Hôpital of the city of Haguenau.

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Figures

Figure 1 Mean percent change in body mass index in the IUGR and control groups between 21 and 24 y of age. The IUGR group (n=26) is represented as a solid bar and the control group (n=25) as an open bar. Results are given as (mean±s.e.m.). P-values refer to the statistical comparison between baseline and follow-up in each group.

Figure 2 Mean fasting serum leptin concentrations adjusted for percentage of body fat, gender and fasting insulin concentrations. The IUGR group (n=26) is represented as a solid bar and the control group (n=25) as an open bar. In the inset, are indicated the crude mean serum leptin values in the two groups (mean±s.d.).

Tables

Table 1 Clinical characteristics of the subjects included in the IUGR and control groups

Received 4 July 2000; revised 10 October 2000; accepted 1 November 2000
April 2001, Volume 25, Number 4, Pages 491-495
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