Size at birth and plasma leptin concentrations in adult life

Abstract

To determine whether low birthweight is associated with higher plasma leptin concentrations in adult life and whether leptin contributes to the metabolic alterations in adults that are associated with reduced foetal growth.
Measurement of plasma leptin concentrations in a group of 502 men and women, aged 61-73, who were born in Hertfordshire and for whom records of birth and infant weight are available. Glucose tolerance was measured with a standard 75 g oral glucose tolerance test.
Leptin concentrations were assayed in fasting plasma samples using a radioimmunoassay.
Leptin concentrations ranged from 1.4 to 128.9 (mean 13.4) ng/ml and were higher in the 193 women than the 309 men (23.4 vs. 7.1 ng/ml). In both sexes leptin concentrations correlated positively with body mass index (r=0.65 in both men and women). Leptin concentration also correlated with fasting insulin (r=0.41) and with glucose and insulin concentrations 2 h after a glucose load (r=0.19 and 0.49). Adults with lower birth or infant weight had higher leptin concentrations than those of higher birthweight with similar degrees of obesity (P=0.02 and 0.06, respectively). Although both 2 h glucose and insulin concentrations negatively correlated with birthweight (r=-0.17, P<0.001 and r=-0.18, P<0.001, respectively), regression analysis suggested that the higher levels of leptin in adults who had low birthweight did not explain the association between low birthweight and glucose or insulin concentrations.
These results suggest that adults who had had low birthweight had higher plasma concentrations of leptin than would be expected from their degree of obesity. The higher leptin concentrations, however, do not account for the association between birthsize and glucose tolerance. They may be a consequence of the altered body composition, hyperinsulinaemia, and other long-term endocrine changes associated with reduced foetal growth.

Full text

Size at birth and plasma leptin concentrations
in adult life
DIW Phillips
1
*, CHD Fall
1
, C Cooper
1
, RJ Norman
2
, JS Robinson
2
and PC Owens
2
1
MRC Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK;
2
Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia, Australia
OBJECTIVE: To determine whether low birthweight is associated with higher plasma leptin concentrations in adult
life and whether leptin contributes to the metabolic alterations in adults that are associated with reduced foetal
growth.
DESIGN: Measurement of plasma leptin concentrations in a group of 502 men and women, aged 61 ± 73, who were
born in Hertfordshire and for whom records of birth and infant weight are available. Glucose tolerance was measured
with a standard 75 g oral glucose tolerance test.
MEASUREMENTS: Leptin concentrations were assayed in fasting plasma samples using a radioimmunoassay.
RESULTS: Leptin concentrations ranged from 1.4 to 128.9 (mean 13.4) ng=ml and were higher in the 193 women than
the 309 men (23.4 vs. 7.1 ng=ml). In both sexes leptin concentrations correlated positively with body mass index
(r0.65 in both men and women). Leptin concentration also correlated with fasting insulin (r0.41) and with glucose
and insulin concentrations 2 h after a glucose load (r0.19 and 0.49). Adults with lower birth or infant weight had
higher leptin concentrations than those of higher birthweight with similar degrees of obesity (P0.02 and 0.06,
respectively). Although both 2 h glucose and insulin concentrations negatively correlated with birthweight (r70.17,
P<0.001 and r70.18, P<0.001, respectively), regression analysis suggested that the higher levels of leptin in
adults who had low birthweight did not explain the association between low birthweight and glucose or insulin
concentrations.
CONCLUSION: These results suggest that adults who had had low birthweight had higher plasma concentrations of
leptin than would be expected from their degree of obesity. The higher leptin concentrations, however, do not account
for the association between birthsize and glucose tolerance. They may be a consequence of the altered body
composition, hyperinsulinaemia, and other long-term endocrine changes associated with reduced foetal growth.
Keywords: leptin; foetal growth; birthweight; glucose tolerance; insulin resistance; programming
Introduction
A series of epidemiological studies in Europe and
North America have shown that people who were
small at birth have a high prevalence of impaired
glucose tolerance and type 2 diabetes in adult life.
1±3
Small size at birth is also associated with insulin
resistance and an increased prevalence of the meta-
bolic or insulin resistance syndrome (glucose intoler-
ance, raised blood pressure and hypertri-
glyceridaemia) in adults.
4±7
The mechanisms under-
lying these associations are not understood, but an
increasing body of evidence suggests that resetting of
major hormonal axes controlling growth and metabo-
lism may contribute to these associations.
8,9
Leptin, the peptide hormone encoded by the obese
(ob) gene, is involved in the regulation of growth and
metabolism.
10
Leptin is produced by adipocytes and
appears to function as a sensor of fat mass acting on
receptors in the hypothalamus.
11
Plasma leptin con-
centrations are closely correlated with body weight
and fat mass.
12,13
Recent data, however, suggest that
the actions of leptin and insulin are interrelated and
that leptin may play an important role in the regula-
tion of intermediary metabolism. There is evidence
that the ob gene is itself regulated by insulin both in
vivo and in vitro.
14,15
Furthermore, leptin may in¯u-
ence insulin action. A number of insulin-responsive
tissues, including liver, express variants of the ob
receptor.
16
Exposure of cell cultures derived from
these tissues to leptin modulates insulin action.
16
Moreover in animal models leptin administration
selectively decreases visceral fat and enhances insulin
action.
17
Plasma leptin concentrations are low in growth-
retarded or premature babies and predict weight gain
during early infancy.
18,19
Whether birthweight pre-
dicts adult levels of leptin is not known. We have
therefore studied a group of men and women to
determine whether birth or infant weight is associated
with plasma leptin concentrations in adult life and the
extent to which these correlate with adult body weight
and glucose tolerance.
*Correspondence: Dr David Phillips, MRC Environmental
Epidemiology Unit, Southampton General Hospital,
Southampton SO16 6YD, UK.
E-mail: diwp@mrc.soton.ac.uk
Received 9 February 1999; revised 16 April 1999; accepted
25 May 1999
International Journal of Obesity (1999) 23, 1025±1029
ß1999 Stockton Press All rights reserved 0307±0565/99 $15.00
http://www.stockton
-
press.co.uk/ijo

Methods
In the county of Hertfordshire, from 1911 onwards,
details of all births were noti®ed by the attending
midwife. Almost all of these births took place at
home. The name and address of the baby, the date
of birth, and the birthweight were registered. A health
visitor saw the baby periodically through its ®rst year
and recorded its manner of feeding and its weight at
the age of 1 year. With the help of the National Health
Service Central Register at Southport, and the Hert-
fordshire Family Health Service Authority, we traced
men who were born during 1920 ± 1930 and women
born between 1923 and 1930 in the six districts of
East Herfordshire, who still lived there. Because of
the change of name on marriage, it is dif®cult to trace
women born before 1923.
As previously described, a group of 370 men and
285 women still living in East Hertfordshire took part
in a study of cardiovascular risk factors, which
included measurements of glucose tolerance and
blood pressure.
1,20
The subjects gave informed con-
sent and local ethical committee approval was
obtained. Initially, the men and women were inter-
viewed at home. Height was measured with a portable
stadiometer to the nearest centimetre (CMS weighing
equipment, Camden, London) and weight with a
portable SECA scale to the nearest 0.1 kg (SECA
Ltd, Birmingham, UK). Body mass index (BMI) was
calculated as the weight (kg) divided by the height (m)
squared. Subjects were classi®ed into three groups of
obesity according to whether their BMI was
<25 kg=m
2
, 25 ± 30 kg=m
2
,or >30 kg=m
2
.
21
Waist
and hip circumference were measured with a steel
tape measure at the level of the umbilicus and greater
trochanter, respectively. Following the home visit the
men and women were asked if they would be willing
to attend a local clinic between 9.00 and 9.30 in the
morning after an overnight fast for a standard 75 g oral
glucose tolerance test. Plasma glucose and insulin
were measured fasting, and 30 and 120 min after the
oral glucose load.
A total of 309 men and 193 women agreed and
provided fasting blood samples for the present study.
Plasma was separated and stored at 770C. We
assayed leptin in the fasting plasma by radioimmuno-
assay (human leptin RIA kit HL-81K, Linco Research
Inc., St Charles, MD). the assay coef®cient of varia-
tion was 6.9% at 2.9 ng=ml and 4.1% at 13.4 ng=ml.
Plasma glucose and insulin were measured as pre-
viously described.
1
Statistical analysis
Before examination of association between measure-
ments, the concentrations of glucose, insulin and
leptin were log
e
transformed to obtain normal distri-
butions. Linear regression was used to examine the
association between birth or infant weight and leptin
concentrations. The in¯uence of potential confound-
ing variables was examined using multiple regression.
P-values refer to analyses using continuously distrib-
uted variables.
Results
In this sample of men and women, aged 61 ± 73 y
(mean 66 y), the fasting plasma leptin concentrations
ranged from 1.4 to 128.9 ng=ml (mean 13.4;
s.d. 12.4). Women had higher leptin concentrations
than men (23.4 vs 7.1 ng=ml, P<0.001). The char-
acteristics of the subjects are shown in Table 1. In
both sexes plasma leptin concentrations were posi-
tively correlated with body mass index (r0.65,
P<0.0001 in both sexes). Leptin was also positively
correlated with the ratio of the waist circumference to
hip circumference (r0.47, P<0.0001 in men and
r0.23, P0.002 in women). There was no correla-
tion between age and plasma leptin within the age
range of the subjects. In both genders leptin concen-
trations were positively correlated with plasma insulin
concentrations in blood obtained before and 120 min
after ingestion of glucose (men: before, r0.49,
P<0.0001, and after, r0.47, P<0.0001; women:
before, r0.34, P<0.0001, and after, r0.27,
P<0.001). Plasma leptin was not related to fasting
glucose (r70.07) in either gender, but was posi-
tively correlated with plasma glucose concentrations
120 min after the oral glucose load in men (r0.25,
P<0.001), but not women. The correlations between
plasma insulin and leptin concentrations remained
statistically signi®cant after adjustment for the current
body mass index (BMI).
Plasma leptin concentrations did not correlate with
birth or infant weights in either men or women.
However, in a multiple regression analysis with
leptin as the dependent variable and birthweight,
BMI and gender as independent variables, low birth-
weight signi®cantly predicted leptin concentrations
(P0.02) as did gender (P<0.001) and BMI
Table 1 Characteristics of the subjects
Men (s.d.) Women (s.d.)
No. of subjects 309 193
Age (y) 66.8 (3.2) 66.2 (2.8)
Body mass index (kg=m
2
) 26.9 (3.5) 27.0 (4.3)
Waist circumference 98.1 (9.6) 83.3 (9.4)
Hip circumference 104.6 (7.1) 104.3 (8.4)
Waist to hip ratio 0.94 (0.05) 0.80 (0.05)
Fasting insulin (pM)
a
40.9 (1.9) 48.4 (1.8)
2 h OGTT insulin (pM)
a
147 (2.3) 244.7 (1.9)
Fasting glucose (mM)
a
6.0 (1.2) 5.7 (1.1)
Fasting leptin (ng=ml)
a
7.1 (1.8) 23.4 (1.8)
2 h glucose (mM)
a
6.6 (1.4) 7.1 (1.4)
No. with IGT 51 57
No. with type 2 diabetes 19 10
IGT: impaired glucose tolerance.
a
Geometric s.d.
Foetal and infant growth and adult leptin
DIW Phillips
et al
1026

(P<0.001). In similar regression analysis replacing
birthweight with weight at one year, the effect of
infant weight was weaker (P0.06). The trends with
birthweight and BMI were similar in both genders.
(Tables 2 and 3). At any level of BMI, plasma leptin
concentrations were higher in people who were smal-
ler at birth. In both genders, the highest plasma leptin
concentrations were found in people who were small
at birth and obese in adult life. They were lowest in
people who were large at birth and non-obese in adult
life. A similar trend to higher leptin concentrations in
adults who were smaller at birth was obtained after
adjusting for waist or hip circumference.
In blood samples obtained 2 h after the oral ingestion
of 75 g glucose, both glucose and insulin concentrations
correlated negatively with birthweight (r70.17,
P<0.001 and r70.18, P<0.001, respectively).
In a multiple regression model (Table 4, model 1)
with 2 h plasma glucose as the dependent variable,
and birthweight, BMI, gender and age as independent
variables, the effects of birthweight (P<0.001), BMI
(P<0.001), and age (P0.01), but not gender
(P0.07), predicted 2 h plasma glucose concentra-
tions. Plasma leptin concentration, however, was not
independently predictive of 2 h plasma glucose. In a
multiple regression model with 2 h plasma glucose as
the dependent variable and leptin concentration, birth-
weight, BMI, gender and age as independent variables,
birthweight (P<0.001), BMI (P0.002) and age
(P0.015), but not leptin, predicted 2 h plasma glu-
cose concentrations (Table 4, model 2). Similar results
were obtained with models predicting 2 h plasma insu-
lin concentrations. The weight at one year of age also
predicted 2 h glucose and insulin concentrations. How-
ever, further regression analyses showed that the rela-
tionships between infant weight and 2 h glucose or
insulin measurements were unaffected by the inclusion
of leptin concentrations in the models.
Discussion
This is one of the ®rst studies to examine the relation-
ship between birthsize and leptin concentrations in
adults in a population-based study. In accordance with
previous studies, we found that leptin concentrations
correlated strongly with measures of obesity in both
men and women.
22,23
These observations are consis-
tent with leptin concentrations being directly related
to the mass of adipose tissue. We also found that
leptin concentrations were higher in women than men.
However, the novel ®nding in our study was that, at
any level of adult obesity, people with low birth
weight tended to have higher concentrations of
leptin than people who were larger at birth.
As recent studies have suggested that leptin may
play a part in modulating insulin action and because
small size at birth is associated with insulin resis-
tance,
6,24
it is possible that the high leptin concentra-
tions in people who were small at birth may contribute
to the impairment of insulin action. Although we did
not have direct measurements of insulin resistance in
this study, we found that insulin but not glucose
concentrations, during the glucose tolerance test
were strongly and consistently associated with leptin
concentrations even after adjustment for obesity. This
is consistent with other studies
23
and suggests an
association between leptin and insulin resistance.
However, in multiple regression models examining
the association between birthsize and glucose toler-
ance or birthsize and insulin concentrations, we found
Table 4 Multiple linear regression models for variables
predicting 2 h plasma glucose in the 309 men and 193 women
born in Hertfordshire before and after the inclusion of leptin
concentration
Va ri a b l e Be t a s. e . P-v a lu e
Model 1
Body mass index (kg=m
2
) 0.017 0.004 <0.001
Age (y) 0.012 0.005 0.013
Sex 0.053 0.029 0.07
Birthweight (lb) 70.044 0.012 <0.001
Model 2
Body mass index (kg=m
2
) 0.015 0.005 0.002
Age (y) 0.012 0.005 0.015
Sex 0.024 0.05 0.6
Birthweight (lb) 70.043 0.012 <0.001
Leptin (ng=ml) 0.025 0.03 0.42
Table 3 Mean plasma leptin concentrations (ng=ml) in 193
women born in Hertfordshire between 1923 and 1930 according
to birthweight and current body mass index (BMI)
Birthweight (lb)
Adult BMI
(kg =m
2
)<7. 2 5 78.25 >8.25 Total
<25 14.7 13.5 13.6 14.1
(29) (24) (12) (65)
25 ± 30 24.2 23.3 22.4 23.2
(33) (26) (29) (88)
>30 45.0 38.9 30.5 38.9
(15) (14) (11) (40)
Total 24.7 23.1 22.1 23.4
(77) (64) (52) (193)
Table 2 Mean plasma leptin concentrations (ng=ml) in 309 men
born in Hertfordshire between 1920 and 1930 according to
birthweight and current body mass index (BMI)
Birthweight (lb)
Adult BMI
(kg =m
2
)<7. 2 5 78.25 >8.25 Total
<25 4.4 3.8 4.0 4.1
(29) (31) (33) (93)
25 ± 30 7.7 7.3 6.9 7.3
(53) (60) (59) (72)
>30 14.3 14.1 11.4 13.0
(13) (13) (18) (44)
Total 7.6 7.1 6.7 7.1
(95) (104) (110) (309)
Foetal and infant growth and adult leptin
DIW Phillips
et al
1027

that inclusion of leptin concentration in the models did
not reduce the strength of these associations. This
argues against a causative role for leptin in the
programming of insulin resistance and glucose intol-
erance during foetal life.
It is possible that the association between birthsize
and leptin concentration re¯ects altered body compo-
sition or other physiological changes associated with
small size at birth. Because the methods of measuring
fat mass in ®eld studies are necessarily imprecise, we
may have underestimated the overall fat mass and fat
distribution in our subjects. Most studies show that
people who were small babies tend to have a lower
weight for height (BMI) in adult life than people who
were larger at birth, and that BMI increases with
increasing birthsize.
2,25,26
Limited data, however, sug-
gest that people who were small babies tend to have a
more truncal distribution of obesity and signi®cantly
reduced muscle mass, raising the possibility that the
body fat content of people who were small at birth is
high despite their lower BMI.
27 ± 29
The results we
have obtained may therefore be explained by a rela-
tively greater fat mass in people who were small at
birth. A further possibility is that the elevated leptin
concentrations in adults who were small babies are a
consequence of altered hormonal control of ob gene
expression. There is increasing evidence that cAMP
and b-adrenoceptor agonists inhibit leptin expression,
while glucocorticoids and insulin up-regulate it.
30
Low birthweight is associated with adult hyperinsuli-
naemia.
1
Moreover, there is now evidence from
animal studies and human data that growth retardation
during foetal life resets the hypothalamic ± pituitary ±
adrenal axis resulting in hypercortisolaemia.
31,32,9
Raised leptin concentrations in people who were
small at birth may therefore re¯ect the combination
of hyperinsulinaemia and hypercortisolaemia.
Our data imply that babies of low weight or
ponderal index at birth who are known to have low
cord blood leptin concentrations subsequently go on
to have high plasma leptin concentrations. The reason
for or the timing of this switch is not known. Because
leptin concentrations signal energy homeostasis, the
low leptin concentrations in growth-retarded newborn
infants are consistent with low energy reserves and
reduced fat deposits.
18,19
Recent evidence suggests
that catch-up growth in these babies is strongly related
to cord blood leptin concentrations and suggests that
leptin may be one of the mediators of the neuroendo-
crine response to in utero undernutrition.
19
After this
catch-up period, it is likely that the altered neuro-
endocrine function resulting from growth retardation
together with relative overnutrition leads to fat deposi-
tion and elevated leptin concentrations.
In summary, we have shown that people who had
low birthweight have higher leptin concentrations in
adult life than would be expected from their BMI. The
higher leptin concentrations do not appear to explain
the greater glucose intolerance associated with small
size at birth. They may however, be a consequence of
the altered body composition or other physiological
changes, which are known to be a consequence of
reduced foetal growth.
Acknowledgements
We are grateful to all the men and women in Hert-
fordshire who gave us their time. The ®eldwork was
carried out by P Harwood, S Haynes, P Howell, R
Rosenthal and S Wolfe. The study was funded by The
Medical Research Council, The Wessex Medical
Trust and The British Diabetic Association.
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