| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Neonatology (A.W., C.F.) and Research Laboratory (C.M., R.S.), Department of Pediatrics, Ernst Moritz Arndt University, D-17487 Greifswald; Lilly Research Laboratories (W.F.B.), D-61350 Bad Homburg; and the Department of Pediatrics, Justus Liebig University, D-35394 Giessen, Germany
Address all correspondence and requests for reprints to: Christoph Fusch, M.D., Department of Pediatrics, Ernst Moritz Arndt University, Soldtmannstrasse 15, D-17487 Greifswald, Germany. E-mail: fusch{at}rz.uni-greifswald.de
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In healthy children, CSF leptin levels account for approximately 5% of plasma levels. CSF/plasma ratios in girls are lower than those in boys, explaining why calorie intake and energy expenditure are not grossly different despite large differences in circulating plasma leptin concentrations. CSF/plasma ratios of lean children are higher than those in obese children. The dynamic changes in the CSF/plasma ratios are more pronounced in lean children, i.e. the nonlinear transport characteristics of the leptin system amplifies the information about changes in body energy stores in this population, indicating that leptin is part of a mechanism to protect the body from critical weight loss rather than to avoid obesity.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In adult subjects, it has been shown that leptin levels in cerebrospinal fluid (CSF) correlate positively with leptin levels in plasma (8). However, the CSF/plasma ratios of leptin measured in obese subjects are lower compared with those in lean subjects (9, 10, 11), suggesting that leptin enters the CNS compartment at different rates. The choroid plexus, as part of the blood-brain barrier, is responsible for the generation of CSF, and, in fact, leptin-specific binding has been observed in the choroid plexus (12, 13). In mice and rabbits, a saturable transport system for leptin across the blood-brain barrier has been reported (14, 15). It has therefore been hypothesized that in obesity insufficient leptin concentrations are reached in the CNS and that this failure to fully feed back to the hypothalamus may be involved in further accumulation of fat mass. To date, no data have been published about this mechanism in children. It was therefore the aim of the present study to assess leptin concentration in plasma and CSF in relation to body constitution in healthy children.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The clinical record charts of all children were carefully reviewed, and the following parameters were extracted: age, height, weight, body temperature, diagnosis, white and red blood cell count, C-reactive protein, CSF cell count, and CSF protein and glucose content. For analysis, only patients free from CNS infection or blood-brain barrier dysfunction were included. The inclusion criteria were defined as follows: body temperature less than 38.5 C, C-reactive protein below 10 mg/L, CSF leukocyte count below 107/L, no need for neurosurgical or oncological treatment, and no history of trauma.
To correlate leptin levels with body constitution, subjects were grouped into four categories of body mass index (BMI; group, 1, <10th percentile; group 2, 10–50th percentile; group 3, 50–90th percentile; group 4, >90th percentile), using age- and sex-related percentiles for BMI (16).
Leptin was measured in 100 µL CSF or plasma using a commercially available RIA (Mediagnost, Tübingen, Germany). The method has been described previously (4). The study was approved by the local ethical committee.
Statistics
Data were analyzed using nonparametric methods whenever
possible. Descriptive statistics were determined using median and
interquartile ranges; correlation analysis was performed using
Spearman’s 
test; comparison between groups was made using
Fisher’s exact test (for frequencies); ANOVA (one-way) followed by
Scheffe’s test were used to localize the exact difference between the
groups.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
shows leptin concentrations in
plasma and CSF. Although plasma levels in girls were significantly
higher than those in boys (7.4 vs. 2.6 ng/mL;
P < 0.05), leptin levels in CSF were not different
between girls and boys (0.273 vs. 0.204 ng/mL). Overall, CSF
levels were 5.7% of serum levels. The CSF/plasma ratios were
approximately 50% lower in girls (ratio of 0.045) compared to those in
boys (ratio of 0.071).
|
depicts all individual data of
CSF/plasma ratio vs. plasma leptin levels. The
inset shows CSF vs. plasma levels. Ratios are
high at low plasma leptin levels (lean subjects) and low at high plasma
leptin levels (obese subjects), suggesting that leptin enters the CNS
of lean subjects more easily than the CNS of obese subjects.
|
) revealed
that CSF and plasma leptin levels, but not CSF/plasma ratios, were
weakly correlated with age. CSF leptin levels were significantly
correlated with plasma leptin levels (r = 0.61). The CSF/plasma
ratio correlated with plasma leptin (r = -0.73) and body
composition (BMI, group, r = -0.48), but not with CSF leptin
(Tables 1
and 2).
|
depicts data for leptin levels (plasma, CSF, ratio) when
grouped in the four BMI categories. Plasma leptin levels increased with
increasing BMI percentile: plasma leptin levels of subjects with BMI
less than the 10th percentile accounted for only 30% of the level in
patients with a BMI above the 90th percentile. CSF/plasma ratio
decreased with increasing degree of obesity. The observed effect was
not caused by age- or sex-related differences. ANOVA revealed no
differences between groups for age and gender, but differences were
found for plasma and CSF levels as well as for CSF/plasma ratios.
Significant differences between groups 1 and 4 were identified for
plasma and CSF leptin as well as for the ratio (P <
0.009, 0.021, and 0.028, respectively). Differences for plasma leptin
levels and the CSF/plasma ratio were statistically significant also
between groups 2 and 4 (P < 0.002, and 0.007,
respectively). |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Despite considerably higher peripheral leptin production and plasma levels, girls have CSF levels that exceed those of boys only marginally. It must be concluded that the transport of leptin across the blood-brain barrier differs between sexes with respect to rate and/or capacity. The finding may explain why calorie intake and energy expenditure are not grossly different between males and females despite large differences in circulating leptin concentrations (4).
Interindividual variations in leptin transport across the blood-brain barrier may distort the information about body energy stores at the CNS level. The inverse correlation of leptin ratios with obesity suggests that leptin enters the brain of obese children at lower rates compared to those in lean children. Hence, the brain in obese children tends to underestimate true body fat and may therefore not be able to counteract adequately, resulting in obesity.
The data of this study do not prove that leptin is transported across the blood-brain barrier by a saturable carrier, because such a system should show an asymptotic approach of CSF leptin to a limiting level. It is more likely that there is a nonlinear relation, because data show that CSF leptin still tends to increase at high plasma levels and also in obese subjects.
However, the dynamic changes in CSF/plasma ratios in lean subjects are at least as remarkable as the impaired leptin transport observed in obese subjects. We hypothesize that, teleologically, this nonlinear transport of leptin may, rather, be a mechanism to protect the body from a critical loss of fat mass than to avoid obesity, because the dynamic response is much more pronounced in lean subjects. The nonlinear leptin transport may therefore stimulate food intake more effectively in subjects with reduced energy stores than in obese ones. This hypothesis is supported by others investigating leptin levels during weight changes (17, 18, 19): 1) fasting in normal weight subjects induced a rapid and marked decrease in plasma leptin, which rose immediately after the administration of sufficient energy (17); 2) a reduction of leptin levels was found to be disproportionate to the loss of fat mass (18); and 3) falling leptin levels in mice were a critical signal to adapt the organism to starvation by initiating the neuroendocrine response (19). These findings support the hypothesis that leptin acts more to protect the body from critical weight loss than to prevent from obesity.
The leptin system reacts quite quickly to an acute changes in energy supply. The study of Kolaczynski et al. (22) demonstrates a rise in serum leptin levels (40%) in humans within 5 h after start of acute overfeeding (lasting 12 h) that persisted even after an overnight fast compared to prolonged overfeeding (10% weight gain), which resulted in a 3-fold elevation of serum leptin. Harris et al. (23) described in rodents a 3-fold ob messenger ribonucleic acid expression after a 2-day overfeeding without significant changes in body fat content, but with increased filling of the adipocytes.
In summary, the excessive supply of calories that is now present in western societies is a relatively new situation during evolution. The fact that obesity develops in an epidemic manner in these countries despite the postulated leptin weight control mechanism may be explained by the fact that the leptin feedback loop was designed to react not against chronic overfeeding but against an inadequate or low calorie supply.
|
Acknowledgments |
|---|
Received March 22, 1999.
Revised May 7, 1999.
Accepted June 1, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. Kos, A. L. Harte, N. F. da Silva, A. Tonchev, G. Chaldakov, S. James, D. R. Snead, B. Hoggart, J. P. O'Hare, P. G. McTernan, et al. Adiponectin and Resistin in Human Cerebrospinal Fluid and Expression of Adiponectin Receptors in the Human Hypothalamus J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 1129 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S E Moore, G Morgan, A C Collinson, J A Swain, M A O'Connell, and A M Prentice Leptin, malnutrition, and immune response in rural Gambian children Arch. Dis. Child., September 1, 2002; 87(3): 192 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Rodrigues, R. B. Radominski, H. d. L. Suplicy, S. M. De Almeida, P. A. Niclewicz, and C. L. Boguszewski The Cerebrospinal Fluid/Serum Leptin Ratio during Pharmacological Therapy for Obesity J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1621 - 1626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Landt, C. A. Parvin, and M. Wong Leptin in Cerebrospinal Fluid from Children: Correlation with Plasma Leptin, Sexual Dimorphism, and Lack of Protein Binding Clin. Chem., June 1, 2000; 46(6): 854 - 858. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
