Study of leptin and its regulation has demonstrated its importance as an integral part of homeostatic mechanism in the regulation of body weight [1
]. However, it is not known whether this is applicable to all life stages and what changes it may have during growth in which weight gain and tissue accretion rather than maintenance of body weight is the physiologic norm.
To our knowledge, this is the first report of the relationship of the circulating leptin and sOB-R concentrations to various physiological variables of growth and body composition specifically, bone, fat and lean masses, during infancy. Age appears to be a major physiologic determinant of plasma leptin concentrations. It is decreased during infancy in those with normal age and gender specific weight and length Z scores as indicated by our data, and is also decreased in infants with poor postnatal growth during longitudinal measurement of plasma leptin from cord blood and at 8, 16 and 52 weeks [9
]. In this study, the initial measurement of circulating leptin and its soluble receptor at 2 months likely eliminated the confounding factors of placental leptin [23
], the initial physiologic adaptation that occurs commonly with other endocrine systems [24
], and the apparent transient increase in plasma leptin during the first weeks after birth observed by some [25
] but not by other [9
] investigators. In the two reports on postnatal increase in plasma leptin concentration, one reported an increase in plasma leptin at 30 days which was significantly correlated with interval weight gain [25
] but no data was available beyond 30 days. In the other report, plasma leptin concentration was higher in term versus preterm infants up to 30 days but there was no significant difference between groups at 90 days. The increase in plasma leptin was correlated with weight gain and increase in subcutaneous tissue [26
]. Whether this transient increase in plasma leptin is related to changes in leptin transport, metabolism or clearance is not known.
Plasma sampling in our study tend to correspond to ages when milk intake is the exclusive or dominant source of nutrient, namely at 2 and 4 months, and when mixed diet becomes increasingly established at 8 and 12 months respectively. Our preliminary data suggest that usual dietary intake in healthy and normally grown infants probably does not affect plasma leptin or its soluble receptor concentrations, although determination of the relationship between leptin and its receptor with details of nutritional intake was not the primary goal of this study and further studies are needed.
Anthropometric and body composition measurements are related to and predictive of plasma leptin. This is consistent with other reports that plasma leptin is correlated with actual [26
] or gain [25
] in body weight, and actual [8
] and changes [9
] in body mass index, and with indirect indicators of body fat such as subcutaneous skinfold thicknesses [7
]. Plasma leptin was also found to discriminate both the long term and changes in energy status based on skinfold thickness [9
The consistent relation between the plasma leptin particularly with fat mass is supportive of adipose tissue being the major source of circulating leptin. The negative correlation of percent bone mass and percent lean mass with plasma leptin is not surprising since an increase in the proportion of fat mass is generally correlated with decreased proportion of lean and bone mass. However, a direct relation between plasma leptin and other tissue mass may be possible since increasing numbers of non-adipose tissues including skeletal muscle [27
], chondrocyte [28
] and human osteoblast [29
] are reported to synthesize leptin and may have cellular leptin receptor forms with physiological activity in experimental models. In any case, the exact role of leptin in the changes in skeletal muscle and bone in humans remain to be defined.
Our data show elevated sOB-R concentrations throughout infancy. Other investigators have reported persistently elevated sOB-R concentrations during early childhood [30
]. The positive relation between plasma sOB-R and fat mass may be indicative of the increased membrane-bound leptin receptor forms, the source of sOB-R. The negative correlation of percent lean mass with plasma sOB-R is consistent with the generally inverse relation between percent lean and fat mass.
The correlation between these plasma variables with anthropometric or body composition measurements were better with the use of Z scores rather than absolute measurements, with fat percent rather than absolute fat mass, and generally better with body composition, specifically fat mass, rather than anthropometric measurements. Thus the use of standardized rather than absolute measurements of anthropometry and body composition is indicated in future studies on the interplay of leptin and its receptor with different nutrition support in growing subjects. Furthermore, body composition measurements are probably more sensitive indicators of leptin production and bioactivity.
It is interesting that even with the limited sample size, our findings of higher leptin concentration in African American infants independent of fat mass is consistent with the report on adult males and females that non-Hispanic blacks have slightly higher values compared to non-Hispanic whites or Mexican Americans [31
]. Our data of higher plasma leptin concentration in female infants also are consistent with the presence of sexual dimorphism [9
]. Furthermore, our data show that race and gender effects were eliminated in the presence of body composition measurements, presumably body composition measurements more specifically reflect the source of leptin and its receptors. Our data indicate that variations in plasma sOB-R are independent of race, gender or age but are predicted by body composition measurements.
Complexes of leptin with sOB-R reflect a molecular ratio of 1:1 [33
] and reached a median value of >10 as early as 3 days after birth because of a decrease in circulating leptin with an accompanied increase in sOB-R [7
]. Our data indicated that plasma sOB-R:leptin ratios remained >10 throughout infancy. Limited data indicate the high plasma sOB-R:leptin ratios may persist until 2 to 3 years [30
]. It is possible that high circulating concentrations of sOB-R may block leptin function by its competition with the membrane receptor for the ligand, which in turn may be an important stimulus for energy uptake in the rapidly growing infant or in other conditions with a high energy demand. However, the decreasing sOB-R:leptin ratio during later infancy is presumably associated with increasing bioavailable leptin, and is consistent with slowing of growth [19
] and tissue accretion [20
Our report represents an exploratory step to determine the developmental variations of plasma leptin and its soluble receptor during the period of most rapid postnatal growth when the body weight and tissue accretion triples over a one year period. These data when coupled with the body composition measurements are critical to the design of future studies to determine the interplay of leptin and its receptors with nutrition support and the regulation of growth and tissue accretion.