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induces leptin production
through the p55 TNF receptor
Laboratory of Integrative Biology, Department of Animal Sciences, University of Illinois, Urbana, Illinois 61801
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Tumor necrosis factor (TNF)-
acts directly on
adipocytes to increase production of the lipostatic factor, leptin.
However, which TNF receptor (TNFR) mediates this response is not known. To answer this question, leptin was measured in plasma of wild-type (WT), p55, and p75 TNFR knockout (KO) mice injected intraperitoneally with murine TNF- and in supernatants from cultured WT, p55, and p75
TNFR KO adipocytes incubated with TNF-. Leptin also was measured in
supernatants from C3H/HeOuJ mouse adipocytes cultured with blocking
antibodies to each TNFR and TNF- as well as in supernatants from
adipocytes incubated with either human or murine TNF-, which activate either one or both TNFR, respectively. The results using all
four strategies show that the induction of leptin production by TNF-
requires activation of the p55 TNFR and that although activation of the
p75 TNFR alone cannot cause leptin production, its presence affects the
capability of TNF- to induce leptin production through the p55 TNFR.
These results provide new information on the interplay between cells of
the immune system and adipocytes.
tumor necrosis factor receptor; ob gene; cytokine; adipocytes
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TUMOR NECROSIS FACTOR (TNF)- induces adipocytes to
secrete the lipostatic hormone leptin (11, 14, 17, 26). Because leptin
reduces food intake (4, 15, 21) and increases energy expenditure (21),
the increased production of leptin in response to TNF- may be
involved in the negative energy balance that is common to infectious,
autoimmune, and neoplastic diseases. However, the induction of leptin
by cytokines may also serve some other purpose. For example, mice
lacking the secreted form of leptin (ob/ob), in addition to
being obese, have severe deficits in T lymphocyte maturation and
cytotoxicity (6). These deficiencies may be the result of the absence
of leptin, because culturing T cells from ob/ob mice with
recombinant leptin induced memory T cell proliferation and cytokine
production (19). Recent findings also suggest that low plasma leptin
levels explain the immunoinsufficiencies of malnourished individuals,
because leptin administration corrected starvation-induced deficits in
the immune response in mice (19). Thus the induction of leptin by
TNF- may be an important immunological response. Despite the
potential significance of this immune-endocrine interaction, the
cellular signaling pathways involved in the induction of leptin by
TNF- are not yet known.
Two distinct receptors in the TNF/nerve growth factor receptor
superfamily mediate the diverse biological actions of TNF- (7).
These two receptors, the murine p55 and p75 TNFR, share sequence
homology in their ligand-binding domains, but their intracellular domains are dissimilar and thus discrete intracellular signaling pathways are activated by each (7). Accordingly, activation of the p55
receptor elicits biological responses that are distinct from those
induced by activation of the p75 TNFR (2, 3). Unfortunately, the TNFR
on adipocytes that stimulates leptin gene expression has not yet been
defined, which is a necessary first step to understanding the alliance
between TNFR signaling and leptin gene transcription. Therefore, to
determine the TNFR activated by TNF- to induce leptin production,
TNFR knockout (KO) mice, antagonistic antibodies to each of the TNFR,
and human TNF-, which binds only the murine p55 TNFR, were employed
in a series of in vivo and in vitro experiments. The results of this
study suggest that the p55 TNFR is critical for the induction of leptin by TNF-.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental Animals
Adult female C57BL/6-TNFR1tm1Mak (p55 TNFR KO), C57BL/6-TNFR2tm1Mwm (p75 TNFR KO), and C57BL/6J (WT) mice (22-25 g) were purchased from Jackson Laboratories. Adult male C3H/HeOuJ (OuJ) mice (26-32 g) were obtained from a breeding colony maintained at the University of Illinois. All mice were housed in groups of three or four in polypropylene cages under a reverse 12:12-h light-dark cycle (lights on at 2100) with ad libitum access to water and rodent chow. All housing conditions and procedures were approved by the University of Illinois Laboratory Animal Care Advisory Committee.Reagents
Recombinant murine and human TNF- were purchased from Pharmingen
(San Diego, CA). Whereas murine TNF- had a biological activity of 1 × 108, human TNF- had a biological activity of 1 × 107 as measured by the murine L929 cell bioassay.
The fact that human TNF- binds only to the murine p55 receptor (31)
may explain the difference in the activity of these two species of
TNF- in the murine bioassay. Each species of TNF- was certified
by Pharmingen to contain <0.1 ng endotoxin/1 µg TNF- as assessed
by Limulus amoebocyte assay. Bovine insulin was purchased from Sigma
Chemical (St. Louis, MO). For injection, murine TNF- was dissolved
in sterile PBS (Sigma) containing 0.2% BSA. Insulin, murine, and human
TNF- were dissolved in sterile Krebs-Ringer phosphate (KRP) for use
in cell culture experiments.
Antagonistic hamster anti-mouse antibodies specific for the p55 or p75
receptor (30) were purchased from Genzyme (Cambridge, MA). Each was
certified by the manufacturer to bind specifically to either the p55 or
p75 TNFR, and no cross-reactivity between TNFRs or TNF- was
reported. An isotype matched control antibody raised against
Schistosoma japonicum glutathione S-transferase was also
purchased from the same source. Antibodies were provided in
preservative-free solutions, which were diluted in sterile KRP for use
in cell culture systems.
Measurements
Leptin. Cell supernatant leptin concentration was measured using a commercially available RIA specific for murine leptin (Linco Research, St. Charles, MO). The assay was conducted as specified by the manufacturer except that all reagents were used at one-half recommended volume as previously described (11). The sensitivity of the assay was <0.2 ng/ml. The intrassay variation was 5.7% and interassay variation <6.0%.RNase protection assay. Total cellular RNA was isolated by the TRI-REAGENT (Sigma) method, except an additional centrifugation step was necessary to remove excessive lipid. RNA integrity was confirmed by denaturing agarose gel electrophoresis and RNA concentration determined by spectrophometric absorbency at two dilutions.
Radiolabeled RNA probes were generated by in vitro transcription using
the MAXIscript protocol (Ambion, Austin, TX). The cDNAs for the murine
leptin gene (the generous gift of Amgen, Thousand Oaks, CA) or 18S rRNA
(Ambion) were used as templates to produce UTP--32P-labeled anti-sense probes. The full-length
leptin and 18S probes were 560 and 155 bp in length, and protected
fragments were 515 and 80 bp, respectively.
RNase protection assays (RPA) were performed using the RPA III (Ambion)
protocol with minor modification. After gel purification, ~1 × 104 counts/min of each probe were hybridized to 15 µg of
total cellular RNA from ovarian fat pads in an overnight incubation at
42°C. RNase digestion was performed at 37°C for 30 min and
fragments precipitated using RNase inactivation/precipitation solution
(Ambion). Protected fragments were then separated using an 8 M urea-5%
acrylamide gel. Gels were exposed to Kodak Biomax MR film at
80°C using an intensifying screen.
Adipocyte Isolation
Adipocytes were isolated as previously described (11). Briefly, mice were euthanized by CO2 gas asphyxiation at the onset of the dark phase, when leptin production was anticipated to be at its nadir (12, 26). Gonadal fat pads were excised and minced into small pieces, and adipocytes were dissociated by a 35-min collagenase (1 mg/ml; Sigma) digestion in a 37°C shaking water bath. The resulting cell suspension was filtered through a 140-µm mesh screen to remove any remaining tissue. Cells were then washed four times by centrifugation (500 g) in KRP containing 2 mg/ml dextrose (Sigma) and 33 mg/ml BSA (Fraction V; cell culture grade; Sigma) to remove contaminating cells. Adipocytes were counted, adjusted to 2 × 106 cells/ml, and then plated in 0.5 ml of KRP in 24-well plates.Experimental Procedure
Effect of murine TNF- on leptin in TNFR KO mice. At the
onset of the dark phase, after fasting 12 h to reduce circulating leptin levels, adult WT, p55, and p75 KO mice were injected
intraperitoneally with 0.25 ml vehicle (PBS with 0.2% BSA) or vehicle
containing 500 ng recombinant murine TNF-. At 8 h postinjection,
mice were euthanized by CO2 gas asphyxiation, and ovarian
fat pads were removed and quickly frozen in liquid nitrogen for later
measurement of leptin mRNA. A blood sample from the inferior vena cava
of each mouse was collected into an EDTA-coated syringe, and plasma leptin content was later determined by RIA. A total of 36 mice was used
in two separate but identical trials (n = 6).
Effect of TNF- on leptin production by adipocytes from TNFR KO
mice. Adipocytes isolated from WT, p55, or p75 receptor KO mice
were cultured in the presence of insulin (300 ng/ml) or murine TNF-
(0, 1, 10, 100 ng/ml; n = 8). After 8 h of culture in the presence of TNF- or insulin, cell-free supernatants were removed and
stored frozen (80°C) until assayed for leptin concentration.
Effect of antagonistic anti-TNFR antibodies on TNF--induced
leptin production. Adipocytes were isolated from OuJ mice as above.
The OuJ mouse strain was used in this study because they possess large
fat stores at maturity and have previously been used to determine the
effects of TNF- on leptin production (11). Adipocytes were cultured
in KRP alone or in KRP containing anti-p55 antibody (10 µg/ml),
anti-p75 antibody (10 µg/ml), or isotypic control antibody (10 µg/ml) in the presence or absence of murine TNF- (100 ng/ml;
n = 6) for 8 h. In a separate experiment, insulin (300 ng/ml;
n = 6) was used in place of TNF-. Supernatants were removed
after 8 h and assayed for leptin concentration. The dose of antibody
employed in this study was in accordance to Genzyme's recommended
concentration for inhibition of ligand binding.
Comparison of murine and human TNF-. Adipocytes isolated
from OuJ mice were cultured in the presence of murine or human TNF- (0, 1, 10, 100 ng/ml; n = 12). As assessed by Pharmingen using the murine L929 cell-line bioassay, there was a 10-fold difference in
the activity of these two species of cytokine. Because the relative
difference in activity of these two species of TNF- could be
explained by the use of the murine bioassay to determine bioactivity,
they were employed in equimolar concentrations for comparison of effect
on leptin production. Supernatants were collected after 8 h of culture
and stored at 80°C until assayed for leptin content.
Statistical Analysis
All data were analyzed using general linear model procedures (27). Data were subjected to one- or two-way ANOVA to determine the significance of main factors and main factor interactions. When ANOVA revealed a significant effect of a main factor or an interaction between main factors, differences between treatment means were tested using least squares difference. All data are presented as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF- induces leptin production in p75 but not p55 TNFR KO
mice. Intraperitoneal injection of TNF- in WT mice has been
shown to increase leptin mRNA in adipose tissue (14, 26) and increase circulating leptin levels (11, 14, 17, 26). To determine which TNFR is
involved, following an overnight fast, WT, p55, and p75 KO mice were
injected with vehicle or 500 ng of recombinant murine TNF-. Eight
hours later, fat pads and blood plasma were collected for determination
of leptin mRNA and protein, respectively. As expected, TNF-
significantly increased plasma leptin and leptin mRNA levels in WT mice
(Fig. 1). However, p55 KO mice were
completely resistant to this effect of TNF-, suggesting that TNF-
induces leptin by activating the p55 receptor. Consistent with this
hypothesis, TNF- significantly increased plasma leptin and leptin
mRNA levels in p75 KO mice. In fact, mice that lacked the p75 receptor
were hypersensitive to the induction of leptin by TNF-, possibly
because they had less circulating soluble TNFR (22) to neutralize
TNF-.
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Adipocytes from p55 TNFR KO mice do not secrete leptin in response
to TNF-. The previous experiment suggested that TNF- activated the p55 receptor to induce leptin production. To more carefully evaluate this, adipocytes from WT, p55, or p75 KO mice were
isolated and cultured in the presence of increasing concentrations of
murine TNF-. Consistent with a previous report (11), TNF- increased supernatant leptin content in a dose-dependent fashion in
cultures of adipocytes from WT mice (Fig.
2). Conversely, adipocytes from p55 KO mice
did not secrete higher amounts of leptin in response to TNF-. Murine
TNF- increased supernatant leptin levels in cultures from p75 KO
mice, but the magnitude of increase was less than that of cultures from
WT mice.
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As a positive control, adipocytes of each genotype were also cultured
in the presence of insulin (300 ng/ml). A twofold increase in
supernatant leptin concentration was induced by insulin in all three
strains of adipocytes (Fig. 2). The fact that the absence of either
TNFR did not affect insulin-induced leptin production indicates that
adipocytes from KO mice have retained the ability to synthesize and
secrete leptin and that the lack of sensitivity to TNF- is more
likely due to the absence of the TNFR, not a nonspecific cellular defect.
Antagonistic antibodies to either TNFR attenuate TNF--induced
leptin production. Adipocytes from OuJ mice were cultured in medium
alone, medium containing anti-p55 antibody, anti-p75 antibody, or an
isotypic control antibody in the presence or absence of murine TNF-
or insulin for 8 h. Supernatants were then removed and assayed for
leptin concentration. As expected, TNF- alone dramatically increased
supernatant leptin concentration. However, culturing adipocytes with
antagonistic anti-p55 TNFR antibodies completely prevented this effect
of TNF- (Fig. 3). Treatment with the
isotype control antibody had no effect on TNF--induced leptin
production. Furthermore, the p55 antibody did not blunt production of
leptin in response to insulin (Table 1).
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As evident in Fig. 4, culture with p75
antibody partially blocked the induction of leptin by TNF-.
Supernatant leptin concentrations in cultures exposed to p75 antibody
and TNF-, though higher than levels in control cultures, were lower
than those subjected to TNF- alone. Culturing cells in the presence
of the isotype control antibody again did not inhibit TNF--induced
leptin production. In addition, the use of p75 antibodies did not
interfere with insulin-induced leptin production (Table 1).
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Murine TNF- is more potent at inducing leptin production than
human TNF-. To evaluate further the role of each TNFR in the induction of leptin by TNF-, primary adipocytes from OuJ mice were
cultured in the presence of human TNF-, which selectively binds the
p55 TNFR (31), and murine TNF-, which binds both receptors. Although
both species of TNF- increased supernatant leptin content in a
dose-dependent manner, murine TNF- was significantly more potent at
inducing leptin production (Table 2). This
again is consistent with the idea that the p55 receptor is critical to
the induction of leptin by TNF-, but also that p75 costimulation somehow enhances this effect.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TNF- has been shown to act directly on adipocytes to induce the
production of leptin (11, 14, 17, 26), but until now the TNFR that
mediates this response was not known. In the present study, we measured
leptin in 1) plasma of WT, p55, and p75 TNFR KO mice after
intraperitoneal injection of murine TNF-; 2) supernatants
from cultured WT, p55, and p75 TNFR KO adipocytes that had been
incubated with TNF-; 3) supernatants from cultured OuJ mouse adipocytes that had been incubated with blocking antibodies to the p55 and p75 TNFR and with TNF-; and 4) supernatants
from cultured OuJ adipocytes incubated with either human or murine TNF- that bind either one or both TNFR, respectively. The results using all four strategies show that the induction of leptin gene expression and production by TNF- requires activation of the p55
receptor and that although activation of the p75 TNFR alone cannot
cause leptin production, its presence affects the capability of TNF-
to induce leptin production through the p55 receptor.
The fact that the p55 TNFR was essential for TNF- to stimulate
leptin production was evident in the first study where WT, p55, and p75
KO mice were injected intraperitoneally with TNF-. Whereas WT mice
showed a marked elevation in plasma leptin and leptin mRNA accumulation
after injection of TNF-, mice lacking the p55 TNFR were entirely
refractory to these effects of TNF-. It should be noted that in the
present study, leptin was measured at 8 h only. This point in time was
chosen because previous work of this lab found that plasma leptin was
still maximally elevated 8 h after inflammatory challenge
(11). Nonetheless, it is possible in the present study that the absence
of the p55 TNFR altered the kinetics of leptin production. Because
leptin was only measured 8 h postinjection, it may be that leptin
production was elevated early on, but had already declined. However,
adipocytes from p55 KO were completely refractory to TNF--induced
increases in the accumulation of leptin in the culture medium, arguing
against that possibility.
In contrast to p55 TNF KO mice, mice lacking p75 TNFR were
hyperresponsive to the effects of TNF- on leptin production and leptin mRNA expression compared with WT controls. The finding that p75
KO mice exhibited an exacerbated response to TNF- is comparable with
other studies (22) and may be explained by the absence of soluble p75
TNFR (sTNFR). On TNF- treatment, a significant number of p55 and p75
TNFR are shed from the cell membrane of leukocytes to become soluble
receptors that compete with membrane-bound TNFR for available ligand
(1). Although both types of soluble TNFR can inhibit the effects of
TNF-, p75 sTNFR appears to be the major form of this receptor in
circulation (1, 23). Because TNF- levels had most likely returned to
baseline by 8 h postinjection (22), plasma cytokine concentration was
not assessed in the current study. However, there is at least one
previous report that lipopolysaccharide (LPS)-stimulated plasma TNF-
levels are significantly greater in TNFR KO mice than in WT controls
(22). Thus in the present study, the hypersensitivity of p75 KO mice to
the induction of leptin could be due to high levels of bioactive TNF- that act through intact p55 receptors found on adipocytes.
To eliminate potentially confounding factors such as the presence or
absence of sTNFR, which are reportedly liberated from leukocytes (1,
23), an adipocyte primary culture system was used in subsequent
studies. Consistent with what was observed in vivo, studies employing
blocking antibodies or primary cultures of adipocytes from p55 TNFR KO
mice showed that the p55 TNFR is necessary for the increased leptin
production induced by TNF-. However, whereas the absence of the p75
TNFR resulted in hypersensitivity to this effect of TNF- in vivo,
all three in vitro approaches (i.e., blocking antibodies, adipocytes
from KO mice, and human TNF-) revealed that the induction of leptin
by TNF- was partially abrogated by the absence or blockade of the
p75 receptor. This suggests that the p75 TNFR somehow cooperates with
the p55 TNFR to enhance TNF--induced leptin production. This concept
of TNFR cooperativity has been reported for several other biological
effects of TNF-. For instance, whereas p55 TNFR KOs failed to
produce IL-6 in response to TNF- (2, 20), the absence of p75
receptor costimulation markedly reduced the production of IL-6.
Likewise, concomitant stimulation of the p75 receptor enhanced
p55-mediated cytotoxicity (3, 32), apoptosis (8), and nitric oxide production (24).
It is not yet clear how TNF receptors interact to enhance the actions
of TNF-. In some cases, a putative ligand passing mechanism between
the two receptors may exist. In that model, the p75 receptor binds
circulating TNF- and acts as a sink to prevent extracellular degradation (30). Subsequently, soluble TNF- bound to the p75 receptor cross-links or is passed over to the p55 receptor, through which the cytokine induces its effects.
In other cases, because the p75 receptor possesses signaling capabilities (16, 25), cross-talk between certain intracellularly located TNFR-associated elements seems to be responsible for the amplification of p55 TNFR-mediated responses (32). This is possible because the p55 and p75 TNFRs share several receptor-associated proteins (7). The results of the current study could be explained by either the ligand passing or receptor cross-talk model.
Grunfeld and colleagues (14) were the first to report that endotoxin or
cytokines could increase leptin mRNA expression. It was proposed that
leptin contributed to anorexia and cachexia in sick people and animals,
because, like the proinflammatory cytokines, leptin is a potent
anorectic agent. However, ob/ob mice, which fail to secrete
leptin, are hypersensitive to the anorectic properties of LPS (10).
Furthermore, plasma leptin levels in cachectic tumor-bearing rats (5)
and acquired immune deficiency syndrome patients (13) were not
inappropriately increased as would be expected if leptin were a key
mediator of cachexia. Long-term exposure to TNF-, which occurs in
cachexia, may actually decrease leptin production by a p55
TNFR-mediated mechanism (33). In fact, in a study by Yamaguchi and
colleagues (33), it was found that culturing parametrial adipocytes
from pregnant mice with TNF- for >48 h significantly reduced
leptin production. Collectively, this suggests that the induction of
leptin secretion by TNF- may serve some other purpose.
For example, several lines of evidence suggest that leptin is necessary for complete immunocompetence. In accordance with the idea that leptin improves immunocompetency, protein/energy malnutrition not only depletes body fat stores and reduces leptin levels, but also leaves the individual severely immunocompromised and prone to opportunistic infections (28). More importantly, leptin administration reversed starvation-induced suppression of the immune response in mice (19). This may be mediated by leptin acting directly on functional receptors found on cells of the immune system, because leptin also enhanced T cell proliferation, macrophage phagocytosis, and cytokine production in vitro (18, 19). Collectively, there is now sufficient evidence to conclude that leptin is itself a cytokine and an important regulator of the immune system.
More recent evidence suggests that leptin is also a necessary negative
feedback signal that prevents cytokine toxicity. Two studies have shown
that ob/ob mice are significantly more sensitive to TNF--
and LPS-induced lethality (9, 29) and that the heightened sensitivity
can be alleviated by the administration of exogenous leptin. The
mechanism by which leptin exerts its anti-inflammatory effects is still
unclear, but further demonstrates the importance for a better
understanding of the induction of this hormone by cytokines such as
TNF-.
Implications
Seemingly disparate systems of the body are actually closely linked by commonality of the communication pathways that they use. For instance, interplay between cells of the immune system and adipocytes such as that demonstrated in this study is potentially important when the ability of leptin to modulate immune function is considered. What is known hints that the induction of leptin by cytokines such as TNF-
is an adaptive response that aids the clearance of invading pathogenic
microorganisms and is important to the anti-inflammatory response to
potentially toxic stimuli. The studies presented here provide an
important first step to better understanding the TNFR signaling
pathways involved in this immune-endocrine interaction.
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ACKNOWLEDGEMENTS |
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This research was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-51576 and DK-49311 and the Illinois Council on Food and Agricultural Research. B. N. Finck is supported by a National Institute of General Medical Sciences fellowship (GM-007143).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. W. Johnson, Univ. of Illinois, Urbana/Champaign, 390 Animal Sciences Laboratory, 1207 W. Gregory Dr., Urbana, IL 61801.
Received 2 June 1999; accepted in final form 17 September 1999.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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