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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1394
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 1021-1026
Copyright © 2006 by The Endocrine Society

Influence of Nutritional Recovery on the Leptin Axis in Severely Malnourished Children

Katja Stein, Edgar Vasquez-Garibay, Juergen Kratzsch, Enrique Romero-Velarde and Gerhard Jahreis

Institute of Human Nutrition (K.S., E.V.-G., E.R.-V.), University of Guadalajara and Research Ward for Infant Nutrition, Hospital Civil of Guadalajara Dr. Juan I. Menchaca, 44340 S.L. Guadalajara, Jalisco, Mexico; Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnosis (J.K.), University Hospital, D-04103 Leipzig, Germany; and Institute of Nutrition, Department of Nutritional Physiology (K.S., G.J.), Friedrich Schiller University, D-07743 Jena, Germany

Address all correspondence and requests for reprints to: Dr. Gerhard Jahreis, Institute of Nutrition, Friedrich Schiller University, Dornburger Strasse 24, D-07743 Jena, Germany. E-mail: b6jage{at}uni-jena.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Leptin might be more important as a starvation hormone than as a satiety signal. The role of the soluble leptin receptor (sOB-R) and its regulation in children with protein energy malnutrition (PEM) is poorly understood.

Design: We elucidated the effect of intensive nutritional support on the leptin axis in 26 severely malnourished toddlers who received infant milk-based formula for 2 wk via continuous enteral tube feeding followed by 2 wk ad libitum feeding. Serum levels of leptin, sOB-R, IGF-I, and IGF-binding protein-3 as well as anthropometric measurements were determined at the beginning of the study and at 2-wk intervals. The control group consisted of 13 well-nourished children.

Results: The following were changes in the PEM toddlers after the nutritional support. Leptin increased significantly (P < 0.001), reaching 166% of levels observed in control group. sOB-R decreased significantly (P < 0.001), and a 142-fold molar excess of sOB-R over leptin was found. There were significant correlations between leptin and IGF-I after 2 wk and IGF-binding protein-3 during the whole study. sOB-R was not correlated with any anthropometric data, whereas IGF-I was a predictor of sOB-R variance in the PEM toddlers (19.9%, P = 0.022).

Conclusion: It can be concluded that sOB-R has a modulatory effect on leptin in PEM children during nutritional recovery and participates in their adaptive survival mechanisms. Leptin and the molar excess of sOB-R over leptin are better biomarkers of nutritional status than IGF-I in PEM children during nutritional recovery.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE ADIPOCYTE-DERIVED hormone leptin was initially believed to function in the prevention of obesity (1). However, studies have demonstrated profound effects of this pleiotropic hormone in the response to fasting, regulation of reproduction, neuroendocrine and immune functions, hematopoiesis, angionesis, blood pressure control, and bone development (2, 3, 4, 5, 6). Prentice et al. (7) have suggested that leptin acts as a starvation hormone, which signals an energy deficit state in the human body and might be even more important in its absence than in its presence. The soluble leptin receptor (sOB-R), a major leptin-binding protein in human blood (8), facilitates the transport of leptin from its peripheral site of production to its central site of neuroactions (9) as well as to many leptin-sensitive peripheral tissues (10, 11).

The nutritional status has profound effects at all levels of the GH/IGF-I axis, especially on IGF-I and IGF-binding protein (IGFBP)-1 and -3 (12, 13).

Malnutrition causes a decrease in serum levels of leptin, IGF-I, and IGFBP-3, but the regulation of these biomarkers and their roles in children with severe protein energy malnutrition (PEM) during nutritional recovery are poorly understood. LaPaglia et al. (14) have hypothesized from an animal model that leptin may function as a neuromodulator of the GHRF-GH-IGF axis communicating the nutritional status to this hormonal system. In a study of undernourished children, Palacio et al. (15) observed a significantly positive correlation between IGF-I and leptin occurring after a weight gain of 10%. Other investigators have stressed the concept that IGF-I plays a role in the control of leptin secretion (16, 17). However, the majority of studies performed in children with PEM have focused on leptin without considering the potential effects of its soluble receptor. Kratzsch et al. (18) have suggested that there might be an indirect relationship between leptin and sOB-R and that IGF-I, as a permissive factor for growth and an indicator of nutritional status, could act as a mediator of sOB-R.

The aim of this study was to investigate the interrelationship between the leptin axis inclusive of its soluble receptor and both the nutritional anthropometric indicators and IGF-I and IGFBP-3 of children with severe PEM during a 4-wk nutritional recovery period.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
The 26 patients between the ages of 3 and 48 months with severe primary PEM and weight/age or weight/height indices of less than –3 SD from the median using the National Center for Health Statistics/World Health Organization reference standard (19, 20) or less than –2 SD from the median in the presence of edema and a clinical picture of kwashiorkor or marasmus-kwashiorkor were the subjects of a clinical intervention study during a 4-wk period of nutritional recovery in a metabolic ward. All these patients were full-term babies with a normal birth weight (>2500 g), no known causes of growth failure, or any diseases that might alter their nutritional recovery. They were clinically free of any acute or chronic diseases. The control group consisted of 13 well-nourished healthy children of the same age group with weight/age or weight/height more than –1 SD and less than 1 SD from the median. The Ethics Committee of the Hospital Civil Dr. Juan I. Menchaca and the University of Guadalajara, Mexico approved the protocol of the study, and an informed consent was obtained from the parents of children involved in this study.

The patients were fed an infant milk-based formula without lactose (Nestle, Mexico City, Mexico), and corn syrup was added to increase energy density from 2.8 to about 3.35 kJ/ml. The formula diet from Nestle contained 2129 kJ, 12.6 g protein, 56.8 g carbohydrates, and 25 g fat/100 g powder. As of the third week of nutritional recovery treatment, children older than 12 months were offered the following complementary cereal and/or vegetable pap foods (Nestle) prepared with the same formula: peas with potato, garden vegetables, mixed vegetables, dessert vanilla, dessert chocolate, and five cereals. These pap foods contained 1493–1753 kJ, 8.7–15.5 g protein, 69.1–80.8 g carbohydrates, and 1.0–9.0 g fat/100 g powder. During the initial 2 wk of continuous enteral tube feeding (ETF), the PEM subjects received a mean intake of 736.4 kJ/kg·d and 4.2 g protein/kg·d. The ETF treatment was followed by 2 wk of ad libitum feeding (ALF), which provided these patients with a mean intake of 686.2 kJ/kg·d and 3.9 g protein/kg·d. The total amount of formula and complementary food fed to the test subjects were administered and documented by well-trained nurses.

Anthropometric measurements [weight, length, height, upper arm circumference (UAC), head circumference, triceps, subscapular, and abdominal and suprailiac skinfold thickness] were performed on all test subjects at admission to the study and after that once a week by two trained persons. Weight measurements were documented to the nearest 5 g, and length and height were measured with a precision of 1 mm as described by Fomon (21). In the malnourished study group, the length was obtained in recumbent position even in those children older than 24 months of age considering the small size and the severity of PEM at admission. UAC was obtained using a metallic tape to the nearest 0.1 cm, and skinfold measurements were performed by the use of a Lange skinfold caliper (Cambridge Scientific Industries, Inc., Cambridge, MD).

Blood samples were taken by antecubital venopuncture between 0700 and 0900 h at the admission to the study, after 2 wk of ETF, and at the end of the study after 2 wk more of ALF. The serum was separated and kept frozen at –80 C until analyzed.

Laboratory methods

Determination of IGF-I was performed by RIA (Mediagnostic, Reutlingen, Germany) with a sensitivity of 0.02 ng/ml and intra- and interassay coefficient of variation less than 8% on the basis of serum acidification for dissociation of IGF-IGFBP complexes and adding IGF-II excess for saturation of IGF-binding sites; IGFBP-3 by ELISA (DSL, Sinsheim, Germany), with a sensitivity of 4 ng/ml and intra- and interassay coefficient of variation less than 12%. Leptin was measured by ELISA (R&D Systems, Wiesbaden, Germany), with a sensitivity less than 7.8 pg/ml and intra- and interassay coefficient of variation less than 6%. The concentration of sOB-R was determined by an in-house ligand-immunofunctional assay that featured minimal interference from leptin and possessed intra- and interassay coefficients of variation lower than 11.7% (18).

Data and statistical analysis

The Z scores of the anthropometric indices of weight/age, height/age, and weight/height were calculated using the EPI Info 2000 program, version 1.0 relative to the National Center for Health Statistics growth charts. Body mass index (BMI) was calculated as weight (kilograms) divided by height squared (meters squared), and the percentage of body fat (BF) was determined using the Slaughter equations (22): girls, BF = 1.33 (sum of triceps and subscapular skinfolds) – 0.013 (sum of triceps and subscapular skinfolds)2 – 2.5; and boys, BF = 1.21 (sum of triceps and subscapular skinfolds) – 0.008 (sum of triceps and subscapular skinfolds)2 – 1.7.

The midarm cross-sectional upper arm fat area (UAFA) was calculated according the equation of Frisancho (23): UAFA = (UAC2/4{pi}) – [(UAC – triceps skinfold x {pi})2/4{pi}].

The molar excess of sOB-R over leptin was calculated as sOB-R divided by leptin multiplied by 0.13.

Statistical analysis was performed using SPSS 10.0 for Windows (SPSS Inc., Chicago, IL). For the evaluation of the intragroup changes of the data during the periods of the study (start, after ETF treatment, after ALF treatment), a repeated measures ANOVA model was applied. Large SD values of the endocrinological biomarkers were observed throughout the nutritional recovery treatments of the PEM children. The nonparametric Spearman correlation test was used to investigate the relationships among endocrinological biomarkers as well as between the biomarkers and the anthropometric data at the beginning and after the ETF and ALF treatments of nutritional recovery. To determine which of the anthropometric and endocrinological variables predicted changes in the dependent endocrinological biomarkers, a multiple linear regression model (step-wise method) was performed with P < 0.05 for entry and P > 0.10 for removal. Null hypothesis was rejected with P ≤ 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The means ± SEM of anthropometric data of the PEM (n = 26) and control (n = 13) groups children are given in Table 1Go. In the first 2 wk of ETF leptin increased (P ≤ 0.001), whereas sOB-R and the molar excess of sOB-R over leptin decreased significantly (P ≤ 0.001) (Fig. 1Go). Also, IGF-I and IGFBP-3 showed significant increases within this period (P ≤ 0.001). During ALF, only leptin and IGFBP-3 still demonstrated a significant increase with P ≤ 0.001 and P ≤ 0.05, respectively, and the molar excess of sOB-R over leptin a significant decrease (P ≤ 0.01).


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  		TABLE 1. Anthropometric characteristics of malnourished children and controls in the course of the study (mean ± SEM)

 

Figure 1
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  		FIG. 1. Changes of the leptin axis (means ± SEM) during the 4 wk of nutritional recovery (repeated measures ANOVA). A, Leptin; B, sOB-R; C, molar excess of sOB-R over leptin. The control group level derived from a single measurement. {uparrow}, Change from continuous tube feeding to ALF.

 
Correlation analysis between parameters of the leptin axis with IGF-I, IGFBP-3, and anthropometric data

Leptin. At start of the study in the PEM group, serum leptin had a strong significantly positive correlation with the indicators of fat accumulation, namely BMI, UAC, and IGFBP-3, and a negative correlation with the molar excess of sOB-R over leptin (Table 2Go). After the first 2 wk of ETF, serum leptin also demonstrated a positive correlation with IGF-I and the index of weight/height (data not shown, r = 0.460, P ≤ 0.05). At this stage, an improvement of all correlations of leptin with the concentration of IGFBP-3 and the indicators of fat incorporation were observed when these samples were compared with that of the start period with the exceptions of BMI and UAC. After ALF, the correlations of serum leptin with the indicators previously mentioned were less closed. No correlation between leptin and its soluble receptor in any stage of nutritional recovery could be identified. In the control group, leptin was positively correlated with IGFBP-3 and UAC and negatively correlated with the molar excess of sOB-R over leptin.


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  		TABLE 2. Correlations between endocrinological biomarkers and anthropometric data (Spearman test)

 
sOB-R. At the beginning of PEM, a negative correlation of sOB-R with IGF-I and IGFBP-3 was found. sOB-R showed no correlation with any of the other anthropometric data (Table 2Go). After 2 wk of ETF, sOB-R was positively correlated with the average protein intake (r = 0.421, P = 0.032). At the end of the nutritional recovery, after ALF treatment, no significant correlation with sOB-R was observed. Surprisingly, in the control group, the serum sOB-R correlated with the molar excess of sOB-R over leptin, IGF-I, and IGFBP-3 as well as with index of height/age (data not shown, r = –0.786, P ≤ 0.001).

Molar excess of sOB-R over leptin. In the malnourished children, significantly negative correlations between the molar excess of sOB-R over leptin to leptin, IGFBP-3, BMI, UAC, and all the indicators of fat accumulation were observed at the beginning (P ≤ 0.01–0.001) (Table 2Go). After 2 wk of ETF, a closer negative correlation between the molar excess of sOB-R over leptin and all the parameters mentioned above was found (except for BMI and UAC). In addition, a significantly negative correlation between the molar excess of sOB-R over leptin and IGF-I appeared after ETF treatment. In the control group, the molar excess of sOB-R over leptin showed negative correlations with IGF-I, IGFBP-3, and UAC and a positive correlation with sOB-R.

Prediction for the variations of parameters of the leptin axis by IGF-I, IGFBP-3, and anthropometric parameters

Leptin. At the beginning of the study, no independent predictor of leptin could be identified with step-wise regression analysis in the PEM toddlers. After the 2 wk of continuously nutritional support, the variation of leptin could be related to UAFA (54.6%, P = 0.001) and IGFBP-3 (9.1%, P = 0.025). At the end of the study, the BF accounted for 26.1% (P = 0.008) of the variation of leptin. Regarding the control group, UAC (40.9%, P = 0.019) was an independent predictor for leptin.

sOB-R. At the beginning of the study, serum IGF-I (19.9%, P = 0.022) was an independent predictor of sOB-R in the PEM group.

After the ETF and ALF treatments, no independent predictor for sOB-R was observed. In the control group, 74.2% of the variation of sOB-R was explained by IGF-I (56.9%, P = 0.016) and the index of height/age (17.3%, P = 0.027).

Molar excess of sOB-R over leptin. At the beginning of the study, the serum level of IGFBP-3 (24.0%, P = 0.011) was an independent predictor of the molar excess of sOB-R over leptin in PEM children, and after ETF, the sum of the four skinfolds measurements explained 36.2% (P = 0.001) of the variation of the molar excess of sOB-R over leptin. After ALF, the BF (43.5%, P = 0.000) and the age (10.3%, P = 0.033) were found to be independent predictors of the molar excess of sOB-R over leptin and explained nearly 54% of its variation. In the control group, IGF-I was found to be a predictor for the molar excess of sOB-R over leptin (31.9%, P = 0.044).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
To our best knowledge, this study demonstrates for the first time that sOB-R is involved in the regulation of active serum leptin in children suffering from PEM. We hypothesize that the soluble receptor participated to ensure their survival.

Implication of PEM and nutritional recovery on the leptin axis

After ETF treatment the initial step of the nutritional recovery, a body weight gain of 23% was accompanied by a significant increase in serum leptin concentrations 31.4% higher than those detected in the healthy control group. Interestingly, this outcome was obtained even though both weight and BMI mean values were still below of those demonstrated in the control group. At the end of the nutritional recovery, after ALF treatment, the serum leptin levels in the PEM children were dramatically higher (165.7%) than those of the control children. In studies of patients with anorexia nervosa, significant elevations of serum leptin concentrations have been found after the period of nutritional recovery accompanied by an increase in BMI and body weight. However, the leptin levels still remained significantly below those detected in the control group (24, 25, 26). In contrast, Holtkamp et al. (27) observed hyperleptinemia in serum in the anorexia nervosa patients after 14.3 wk of nutritional recovery. In a group of malnourished children, the leptin values were similar to those in the control group after 1 month of nutritional recovery with 10% of weight gain (15). We propose that these findings may reflect a different leptin set point for a given fat mass at the hypothalamic level in severely undernourished children as a form of adaptation to the state of energy deficiency. The sudden excessive energy supply by continuous ETF might cause an uncoupling of this balance. Leptin seems to provide a remarkable measure of adipose tissue volume, but acute variations in energy balance could cause such short-term modulations as seen in the present study. As expected, leptin, being an adipocyte-derived hormone, showed strong significant correlations with all anthropometric indicators of fat accumulation during the whole study. In athletes, a significant correlation between BF and serum leptin as well as between BF mass and serum leptin levels has also been reported (28). It should be noted that the most significantly independent variables predicting the variation of leptin after 2 wk of ETF were IGFBP-3 and UAFA. However, after the 2 wk of ALF, the most significantly independent variable predicting the variation of leptin changes to the BF. There was a stronger correlation between leptin and BMI at the beginning of the study in the PEM children, and this relationship declined as the nutritional recovery treatment regime continued. In contrast, no relationship was found in the control group. However, there are a number of factors other than changes of BF that could influence the serum leptin concentration, such as glucose and/or insulin levels, proinflammatory cytokines, progesterone, corticosteroids, and GH (24, 25, 29, 30).

Leptin circulates mainly bound to the sOB-R (18, 31). A notable excess of the sOB-R inhibits the bioactivity of leptin through its competition with the membrane receptor (32) and may restrict the availability of free leptin for transport to the cerebrospinal fluid (33).

The apparently compensatory mechanism of up-regulation of the sOB-R during starvation supports the hypothesis that this receptor isoform may act to maintain low levels of free bioactive leptin, signaling an exigent body state that requires decreased energy expenditures and to increase appetite and food intake (16). Thus, the high molar excess of sOB-R over leptin found in the PEM toddlers at the start of the study could suppress the leptin action in central and peripheral tissues and suggests the possibility that the sOB-R as a potential reservoir of bioactive leptin prevents it from degradation and clearance by complexing free leptin, resulting in an increased half life of this hormone (31, 34).

Zastrow et al. (32) reported in a study including 529 healthy children and adolescents that during the first years of life, an up to 8-fold excess of sOB-R in boys and a 3-fold excess in girls were observed. Surprisingly, in our undernourished children, a 142-fold sOB-R excess was observed. The well-nourished children showed a molar excess of sOB-R in the range reported by Zastrow et al. (32). It is possible that in situations of insufficient energy and protein supply, the elevated molar excess of sOB-R over leptin also prevents leptin-mediated actions (32), such as stimulation of glucose uptake, glycogen synthesis, lactate formation (35), the reduction of glucagon-stimulated glucose production, and glucose production from different gluconeogenic precursors (35, 36). It is important to mention that intensively nutritional support in the severely undernourished children seems to induce a compensatory down-regulation of sOB-R. At the end of the nutritional recovery, the values of the molar excess of sOB-R over leptin were even lower than control group values but without reaching an equimolar ratio. These results also confirmed the assumption from Kratzsch et al. (18) that sOB-R levels are not directly related to changes in leptin and body fatness. In all our subjects, there was no correlation between the concentrations of leptin and sOB-R as well as between the concentrations of sOB-R and the anthropometric indicators of BF mass. However, the anthropometric indicators of BF mass highly correlated with leptin concentration in all these test subjects. Unlike the results in a cohort of healthy children and adolescents (18), both our control and PEM subjects demonstrated no significant correlation between sOB-R and BMI throughout the study.

IGF-I, as a nutritional indicator (37), was an independent predictor of sOB-R concentration in both severely malnourished and healthy children. The low levels of IGF-I during prolonged PEM may induce an up-regulation of the sOB-R at the level of the cell membrane (18). This finding supports the hypothesis of a possible influence of nutritional status on sOB-R concentration.

Relationship between leptin and the growth/IGF-I axis

How could the leptin axis be connected with the GH/IGF-I-axis in undernourished children? Even though IGF-I and leptin were clearly decreased, we could not confirm a significant correlation between these endocrinological parameters in both PEM and control groups as described by others (15, 16, 17). This result might be explained by analytical problems due to the low basal levels of these biomarkers and due to the relatively small number of subjects recruited for this study. Taken together, the severely undernourished and well-nourished children of our study (n = 39), a highly significant correlation between the serum concentrations of IGF-I and leptin (data not shown) was found. Llopis et al. (38) suggest that the low leptin levels observed in undernourished states probably suppress the production of IGF-I and GH binding protein/receptor and result in increased GH production through a negative feedback loop. Thus, the low levels of leptin might trigger the hypothalamic-pituitary-adrenal axis and the catabolic actions of GH in terms of increased lipolysis and glucose sparing, which are enhanced to ensure fuel supply for vitally important functions instead of growth (16, 38). In the present study, leptin and IGF-I levels positively correlated only after completing the ETF treatment. At the end of the study, after ALF treatment, unlike the leptin concentration, the IGF-I levels did not correlate with any anthropometric indicators, including those of fat incorporation. In contrast to IGF-I, leptin still increased significantly during the last 2 wk of nutritional recovery, which might have led to an uncoupling of the relation of these two axes. Therefore, it can be hypothesized that leptin seems to be a more sensitive indicator of the nutritional status in PEM children during these phases of nutritional recovery. Although the physiological pathway remains unclear, these results suggest that increased leptin levels during the nutritional recovery of undernourished children potentially induce an indirect IGF-I-stimulated catch-up growth. Thus, our findings are not in agreement with LaPaglia et al. (14) and Palacio et al. (15), who suggest a direct effect of leptin on IGF-I synthesis. In a mice model, leptin induced longitudinal growth and might therefore link nutritional status with bone growth (39).

We conclude that the decreased level of leptin as well as a high molar excess of sOB-R over leptin during PEM seem to ensure metabolic homeostasis and survival of severely malnourished toddlers. Intensive nutritional support during recovery resulted in a remarkable up-regulation of leptin and down-regulation of serum sOB-R concentrations. Therefore, leptin and the molar excess of sOB-R over leptin can be used as better markers of nutritional recovery than IGF-I, at least in children less than 4 yr with severe PEM.


   Acknowledgments
 
We thank R. Troyo-Sanroman and Dr. R. Schubert for excellent assistance with statistical analysis, Zaira Olguin Maciel and Alma Chavira Lomeli for help in the data input, José Guadalaupe Alviso Mora for support in the blood withdrawal, and all the nurses who took care of our patients. We are grateful to the children and families for their participation and understanding.


   Footnotes
 
First Published Online December 13, 2005

Abbreviations: ALF, Ad libitum feeding; BF, body fat; BMI, body mass index; ETF, enteral tube feeding; IGFBP, IGF-binding protein; PEM, protein energy malnutrition; sOB-R, soluble leptin receptor; UAC, upper arm circumference; UAFA, upper arm fat area.

This work was supported by a grant from the National Council of Science and Technology (Consejo Nacional de Ciencia y Tecnologia-Sistema de Investigación José Maria Morelos), Mexico; by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst); by the Secretary of Foreign Relations of Mexico; and by the Nestle Company of Mexico SA de CV.

Received June 23, 2005.

Accepted December 7, 2005.


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 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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J Kratzsch, I Knerr, A Galler, T Kapellen, K Raile, A Korner, J Thiery, J Dotsch, and W Kiess
Metabolic decompensation in children with type 1 diabetes mellitus associated with increased serum levels of the soluble leptin receptor.
Eur. J. Endocrinol., October 1, 2006; 155(4): 609 - 614.
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