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Department of Animal Science, Cornell University, Ithaca, New York 14853-4801
3To whom correspondence should be addressed. E-mail: yrb1{at}cornell.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • leptin • fat • neonatal • sheep • nutrition • insulin
Leptin is a protein hormone of 16 kDa secreted predominantly by white adipose tissue (1–3). An important function of leptin is to provide the central nervous system (CNS)3 with a readout of the energy status of the periphery (2). Consistent with this role, regions of the CNS involved in the regulation of energy metabolism, such as the arcuate, ventromedial and dorsomedial nuclei of the hypothalamus, have a high concentration of Ob-Rb, the fully competent signaling form of the leptin receptor (2,3). In adult animals, neural pathways responsible for the stimulation of appetite and metabolic efficiency are activated when the concentration of plasma leptin is low, whereas pathways stimulating nonessential functions such as reproduction are inhibited (2,3).
In view of its critical role in informing the CNS of the energy status of the periphery, the identification of factors regulating the plasma concentration of leptin has been a major research focus. In adult animals, leptin synthesis is stimulated by adiposity, energy supply, insulin and glucocorticoid, and inhibited by ß-adrenergic signaling (1,2). In contrast, far less is known about the regulation of plasma leptin in growing animals, particularly in the period following birth. This is somewhat surprising given the critical role played by nutrition and adiposity in regulating important developmental processes. For example, suboptimal nutrition leads to a delayed onset of puberty in many species, and it has been postulated that leptin mediates at least a portion of these effects (4,5).
Our first objective was to determine the relative importance of adiposity and nutrition in regulating plasma leptin synthesis during the postnatal growth period. A second objective was to identify the phase of postnatal growth in which these effects are initiated. For these studies, we used sheep, an animal model in which these objectives can be examined with minimal confounding effects of preexisting fetal nutrition or fatness because they are born with very little fat and maternal nutrition has no impact on fetal plasma leptin concentrations (6–8).
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All experimental procedures were conducted with the guidance and approval of the Cornell University Institutional Animal Care and Use Committee. All experimental lambs were male Suffolk x (Finn x Dorset) genotype and were a subset from a previously described experiment (9).
Lambs were obtained from the Cornell University Mt. Pleasant Sheep Farm managed under the STAR accelerated lambing system (10). Ewes managed under this system produce litters that vary in size from one to five fetuses. Ewes were fed throughout pregnancy according to estimated nutrient requirements for energy and protein (11). Despite adequate maternal nutrition, small neonates were frequently found with normal-sized littermates, especially in ewes carrying triplets or quadruplets. The growth deficit of the small lambs is attributable mostly to the inability of their placentae to provide adequate nutrient supply during late pregnancy (12). Newborn lambs weighing <2.9 kg were classified as small birth size (Small) whereas those weighing >4.5 kg were classified as large birth size (Large).
Blood samples were obtained within 2 h of birth by jugular venipuncture from six Large and four Small lambs. They were then killed by intravascular injection of sodium pentobarbital (Schering-Plough, Kenilworth, NJ) and their carcasses analyzed for fat content. Within 8 h of birth, a second group of Small and Large lambs were randomly assigned to either a Low or High plane of nutrition (eight lambs per birth size x nutrition category). Planes of nutrition were achieved by a single milk replacer (265 g crude protein, 272 g fat and 22.6 MJ gross energy per kg dry matter; Grober, Lehigh Valley, PA) either ate ad libitum (High plane) or in amounts sustaining a growth rate of 
150 g/d (Low plane). The milk replacer was provided daily at 0830 h and available throughout the day (High plane) or fed as two equal portions at 0830 h and 1600 h (Low plane). Lambs were individually housed in a controlled environment (30°C, 16 h light:8 h dark). Two lambs from each birth size x nutrition category were killed by jugular injection of sodium pentobarbital at 7.5, 10, 15 and 20 kg live weight.
Blood samples were obtained every 2 d throughout the experiment. Sampling was performed immediately before feeding at 0830 h by jugular venipuncture. In addition, on the day before slaughter, blood samples were taken at 15-min intervals for 6 h commencing 30 min after completion of the morning feeding. Blood samples were mixed with heparin (20 kU/L) and plasma was prepared and stored at -20°C.
Analysis of body fat content.
The body was prepared by removing the gastrointestinal tract contents. The empty body was ground and analyzed for fat content in duplicate by ether extraction (9). The rate of fat accretion in the empty body was calculated between the 10- and 15-kg and the 15- and 20-kg slaughter weights. Total accreted fat was calculated as the difference between fat present in each lamb at 15 or 20 kg, and the average fat present at the previous slaughter weight. Daily rates of fat accretion were obtained for each lamb by dividing accreted fat by the number of days required to grow from 10 to 15 kg or 15 to 20 kg.
Hormone assays.
Hormone assays were performed on individual samples collected between birth and d 20. After d 20, assays were performed on pooled samples. The samples were prepared for each animal by pooling plasma collected during each week or during the frequent sampling period preceding slaughter. Plasma leptin was assayed in triplicate by a double antibody bovine RIA previously validated in ovine plasma (13). The inter- and intraassay CV for the leptin RIA were <7 and <5%, respectively. Plasma insulin concentrations were measured on duplicate samples by a commercial RIA (Linco Research, St. Louis, MO) utilizing bovine insulin as iodinated hormone and the standard in the assay (14). Plasma growth hormone (GH) was measured in duplicate by a specific RIA using antiovine GH serum as the primary antibody (NIDDK-anti-oGh-2; NIDDK National Hormone and Peptide Program and A. F. Parlow, Torrance, CA) and bovine GH as iodinated hormone and the standard (15). For the determination of insulin-like growth factor (IGF)-1, plasma was subjected to acid-gel permeation chromatography and the fraction corresponding to free IGF was neutralized and analyzed by RIA (15). The inter- and intraassay CV for insulin, GH and IGF-1 assays were <10 and <7.5%, respectively.
Statistical analysis.
One-way ANOVA was used to analyze the effect of size at birth on plasma leptin. The ontogeny of plasma leptin was analyzed by a repeated measures model accounting for the plane of nutrition and time as fixed effects and animal as the random effect. Post hoc comparisons (e.g., timing of nutritional regulation of plasma leptin) were made using the conservative Scheffe cutoff values. Body fat content at slaughter was analyzed by a two-way ANOVA to account for the effects of nutrition and slaughter weight. To evaluate the relationship between plasma leptin and other variables at slaughter (body fat concentration, fat accretion rate, insulin, IGF-1 and GH), a regression model accounting for each level of nutrition was initially tested. When this model indicated treatment specific relationships, simple regression analysis was performed at each level of nutrition. Otherwise, a single regression was used across all data. In all analyses 
was set at 0.05. All statistical procedures were performed using the Statistical Analysis System (SAS Institute Inc., Cary, NC).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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At birth the Large lambs were twice as heavy as the Small lambs (4.9 ± 0.2 versus 2.2 ± 0.3 kg, P < 0.001). However, the two groups had similar body fat concentrations (Small versus Large, 2.0 ± 0.1 versus 2.2 ± 0.2 g/100 g empty body weight) and plasma leptin concentration (238 ± 19 versus 256 ± 20 pmol/L). Small lambs eating ad libitum grew more slowly than the Large lambs only during the first 11 d (248 ± 19 versus 353 ± 24 g/d, P < 0.05); no such size effects were detected in the Low plane lambs (9). Overall, lambs offered the Low and High planes of nutrition grew at 148 ± 2 and 337 ± 14 g/d, respectively (P < 0.001). More importantly, birth size did not affect plasma leptin concentrations at birth or at any subsequent time in early postnatal life (results not shown). Therefore, subsequent analyses were performed on leptin data pooled across birth size.
The developmental profile of plasma leptin was examined in the lambs slaughtered at 15 and 20 kg. The concentration of plasma leptin did not change from birth until 120 d of age in the Low plane lambs but increased rapidly after birth in the High plane lambs (Nutrition x Time, P < 0.001; Fig. 1). From d 6 of life, the plasma leptin concentrations were higher in the High than in the Low plane lambs (P < 0.05).
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The relationships between the plasma concentrations of leptin and adiposity at 7.5, 10, 15 and 20 kg live weight were examined. As expected, High plane lambs were younger at each slaughter weight than Low plane lambs (15 versus 29 d, 20 versus 43 d, 38 versus 79 d and 50 versus 115 d at 7.5, 10, 15 and 20 kg, respectively; P < 0.001). The High plane of nutrition increased body fat concentrations by 30%, regardless of weight at slaughter (Fig. 2; P < 0.001). In addition, body fat concentrations increased with slaughter weight (P < 0.001) regardless of the plane of nutrition. Therefore, the failure to observe a rise in plasma leptin concentrations in Low plane lambs cannot be attributed simply to a lack of fat accretion.
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42% of the variation in plasma leptin (P < 0.01). However, an additional 26% of the overall variation was accounted for when a model fitting a relationship to each level of nutrition was used (P < 0.001). Similarly, the slope of the relationship between body fat concentrations and plasma leptin was >3 times higher in the High plane than in the Low plane lambs (Fig. 3). This indicates that adiposity is not the only factor regulating the rate of leptin synthesis in growing lambs.
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The positive effects of nutrition were first detected on d 5 for plasma insulin (106 ± 18 versus 359 ± 32 pmol/L, Low versus High Plane lambs, P < 0.05) and on d 7 for plasma IGF-1 (22 ± 1 versus 32 ± 2 nmol/L, Low versus High Plane lambs, P < 0.05) (15). Plasma leptin is positively correlated with insulin and IGF-1 in growing and lactating dairy cattle (16). To determine when such relationships might develop, plasma samples collected within 2 h of birth and during postnatal growth were analyzed. At birth and on d 3 of postnatal life, plasma leptin was not associated with insulin and IGF-1 (results not shown and Fig. 5). Positive associations were first detected across the nutritional treatment on d 5 for leptin and insulin (Fig. 5), and on d 9 for leptin and IGF-1 (Table 1). From d 11 and beyond, both associations were not evident in the Low plane lambs but increased over time in the High plane lambs. (Fig. 5 and Table 1). It has been shown that plasma leptin is negatively correlated with GH in early lactating dairy cows (17). However, plasma leptin was not associated with GH at birth or at any time thereafter in growing lambs (results not shown).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In juvenile and adult animals, including ruminants, plasma leptin concentrations are increased by the plane of nutrition (1,13,21). The exact timing of this regulation has not been described in sheep. Others have reported static or even decreasing plasma concentrations after the 1st wk of life in naturally reared lambs, but have not reported nutrient inputs or growth rates (22,23). In this study Low plane lambs achieved a daily growth rate (148 g/d) that is within the range observed with conventional feeding programs during the 1st wk of life (9). Under these conditions, plasma leptin concentrations remained unchanged over the first 120 d of postnatal life. Interestingly, the rate of growth achieved by the Low plane lambs is similar to that observed in the sheep fetus during the last few weeks of pregnancy when plasma leptin concentrations also remain static (6,24). In contrast, plasma leptin concentrations were elevated within 6 d of birth in the High plane lambs, and increased until the end of the study. Therefore, in newborn lambs leptin synthesis increases in response to nutrition, but most feeding programs do not allow the expression of this potential.
A more important factor regulating plasma leptin concentrations during adulthood is adiposity (1,2,25). In fully grown sheep and cattle, adiposity and plane of nutrition have been estimated to account for 35 and 17% of the variation in plasma leptin concentrations, respectively (26,27). Similarly, adiposity accounted for 30% of the variation in plasma leptin concentrations in both the Low and High plane lambs. However, our data also suggest that the predominant factor in growing preruminant lambs is nutrition, not adiposity. This is illustrated by comparing the High plane lambs slaughtered at 15 kg with the Low plane lambs slaughtered at 20 kg. Despite having identical adiposity and being younger (38 versus 115 d), High plane lambs had plasma leptin concentrations almost double that of Low plane lambs (Figs. 1and 2). The predominant effect of nutrition is also suggested by the greater relationship between plasma leptin and fatness in the High plane than in the Low plane lambs (Fig 3). To better account for the effect of nutrition, plasma leptin was related to the rate of lipid accretion. Lipid accretion provides a dynamic measure of energy availability and is, under many circumstances, independent of existing adiposity (9). Lipid accretion rate did not account for any variation in plasma leptin concentrations in the Low plane lambs, but accounted for >75% of the variation in the High plane lambs. Again, these two contrasting patterns occurred despite High and Low plane lambs differing by only 30% in adiposity. These data suggest that, in growing lambs, leptin synthesis in adipose tissue will increase only when a threshold level of available energy has been reached. Because the lambs were milk-fed, they remained in a nonruminant state in which glucose is the major carbon source for lipid synthesis (28). Glucose uptake is a primary determinant of leptin synthesis in rat and human adipose tissue (29,30). We speculate that the limited availability of glucose may be the factor restricting both lipid and leptin synthesis in the Low plane lambs.
In addition, leptin synthesis in adipose tissue is regulated by the CNS via sympathetic signals, by adipocyte cell size and by metabolic hormones (1–3). Among the latter, insulin is known to mediate many of the pleiotropic effects of nutrition on adipose tissue, including stimulation of leptin synthesis in rodents and humans (2,31,32). Interestingly, plasma leptin and insulin were positively related as early as d 5 of life, a time that nearly coincides with the detection of nutritional effects. More importantly, this relationship was greater over time in the High plane lambs, and was not seen in the Low plane lambs. This suggests that plasma insulin could account for much of the difference in plasma leptin concentrations between High and Low plane lambs. In support of this, we and others have shown that hyperinsulinemic-euglycemia stimulates plasma leptin synthesis in lactating and nonlactating ruminants (16,33). These effects are likely direct because insulin alone stimulates leptin synthesis in the adipose tissues of various species, including ruminants (32,34). This could be tested by using the euglycemic insulin clamp to raise the plasma insulin concentrations of 20-kg Low plane lambs to that of the High plane lambs at equivalent adiposity (e.g., 15-kg High plane lambs). If this hypothesis is correct, the difference in plasma leptin concentrations between these two groups of animals should be eliminated.
A positive association was also detected between plasma concentrations of leptin and IGF-I. This relationship was first identified across treatments on postnatal d 9, and as for the relationship between insulin and leptin, persisted only in the High plane lambs. We do not consider this association to be causal because adipose tissue is devoid of IGF-I receptors (35), negating any direct effects of IGF-I. Rather, this association is more likely to reflect the developmental regulation of plasma IGF-I. Plasma IGF-I is produced predominantly in the liver where synthesis depends on adequate levels of GH and the induction of the hepatic GH receptor (GHR) (36). In neonatal animals, induction of the growth hormone receptor appears to be the limiting step in hepatic IGF-I synthesis, and occurs 1 wk after birth in sheep (37–40). After induction hepatic GHR abundance is positively regulated by nutrition and insulin (41–43). Therefore, the positive relationship between leptin and IGF-I likely reflects coregulation by energy availability. Finally, GH attenuates many of the effects of insulin on adipose tissue, including insulin-mediated leptin synthesis in cattle adipose explants (34). Despite this evidence, GH and leptin were never correlated in our study. Similarly, GH administration to mature lactating dairy cattle fails to alter plasma leptin (16). Overall, these observations do not support any major role for either IGF-I or GH in the regulation of plasma leptin in early postnatal lambs.
In conclusion, nutrition does not affect plasma leptin concentrations in fetal sheep, but exerts stimulatory effects within days following birth, with insulin being a likely mediator. Both nutrition and adiposity regulate plasma leptin in early postnatal life, with nutrition exerting a more prominent role than in adulthood. In other species, leptin has been shown to stimulate immunity and hasten the attainment of sexual maturity (1,4). Both functions are important determinants of productivity in ruminants, but whether either can be stimulated in sheep by increased plasma leptin in early postnatal life remains to be demonstrated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Recipient of Junior Research Fellowship from Meat Research Corporation (Australia). Present Address: NSW Agriculture Beef Industry Centre, University of New England, Armidale NSW 2351, Australia.
4 Abbreviations used: ADG, average daily gain; CNS, central nervous system; GH, growth hormone; GHR, growth hormone receptor; High plane, nutrition sustaining gain of 337 g/d; Large, newborn lambs weighing >4.5 kg; Low plane, nutrition sustaining gain of 148 g/d; IGF-1=insulin like growth factor 1; Small, newborn lambs weighing <2.9 kg.
Manuscript received 21 July 2003. Initial review completed 11 August 2003. Revision accepted 12 September 2003.
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