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From the Metabolism Section, Department of Veterans Affairs Medical Center, University of California, San Francisco, California
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and no
differences in interleukin-1ß in fasted compared to fed animals;
leptin had no effect on those cytokines. Furthermore, fasting
increased sensitivity to the lethal effect of TNF itself, which
was also reversed by leptin treatment. Thus, leptin seems to be
protective by both inhibiting TNF induction by LPS and by reducing TNF
toxicity.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Malnutrition is known to induce a state of immunodeficiency and to predispose to death from infectious diseases.7 Starvation suppresses immunity, particularly T-lymphocyte responses, and decreases resistance to infection.8,9 Leptin has been shown to have a direct effect on T lymphocytes, enhancing T-helper (Th) alloproliferative response, polarizing Th cells toward a Th1 phenotype.10 Exogenous leptin administration has also been shown to reverse the inhibitory effect of starvation on the development of a delayed-type hypersensitivity reaction.10 It has recently been shown that exogenous administration of leptin during fasting protects mice from the lymphoid atrophy associated with starvation, indicating a role for leptin in the immune dysfunction of starvation.11
Leptin levels are acutely increased by inflammatory stimuli such as lipopolysaccharide (LPS) and turpentine and by cytokines, indicating that leptin induction is part of the acute phase response to inflammation.12-14 Furthermore, the increase in leptin production during local and systemic inflammation is absent in interleukin (IL)-1ß-deficient mice.14 Thus, during inflammation leptin expression is regulated in a manner similar to the cytokine response to infection and injury. In addition, both the structure of leptin and that of its receptor suggest that leptin might be classified as a cytokine. The leptin receptor is homologous to the gp-130 signal-transducing subunit of the IL-6-type cytokine receptors,15-17 and the secondary structure of leptin itself has similarities to the long-chain helical cytokine family, which includes IL-6, IL-11, ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF).18 Moreover, in obese, leptin-deficient ob/ob mice there is increased susceptibility to LPS- and tumor necrosis factor (TNF)-induced lethality,19,20 suggesting that a functional leptin system may represent a protective component of the host response to inflammation.
Based on these observations, we hypothesized that the decrease in leptin levels that accompanies starvation may contribute to the increased susceptibility to lethal infections that occurs during starvation. Here we demonstrate that starvation increases the mortality induced by LPS and TNF and that this increase can be prevented by treatment with exogenous leptin.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five- to 6-week-old female C57Bl/6 mice, weighing approximately 20 g, were purchased from Jackson Laboratory (Bar Harbor, ME). Mice were fed, fasted, or fasted and treated with leptin for 48 hours. Body weight and water intake were recorded daily at 9:00 a.m. Water intake was evaluated per cage with each cage containing five mice. Murine leptin (Amgen, Thousand Oaks, CA) was given intraperitoneally (i.p.) twice a day (9:00 a.m. and 6:00 p.m.) at the dose of 1 µg/g body weight. This dose of leptin has been shown to produce a concentration of leptin 6 and 12 hours after injection similar to fed controls.4 This protocol has previously been used to study the role of leptin in the physiology of starvation.4 After 48 hours, at 9:00 a.m., mice were administered LPS (Difco Laboratories, Detroit, MI), i.p. at 7.5, 15, or 25 mg/kg or recombinant murine TNF (Genentech Inc., So. San Francisco, CA), intravenously (i.v.) at 0.5 mg/kg. Control mice received i.p. or i.v. saline. Survival was monitored for up to 6 days. For TNF and corticosterone determination blood was collected from the retroorbital plexus under halothane anesthesia 2 hours after LPS. For leptin determination, blood was collected 8 hours after LPS. Control mice received saline. The Animal Studies Committee of the Veterans Affairs Medical Center, San Francisco, approved these studies.
Cytokine Measurements
TNF-
, IL-1ß, and interferon (IFN)- were measured using
DuoSet enzyme-linked immunosorbent assay kits specific for murine
cytokines (Genzyme Diagnostic, Cambridge, MA) following the
manufacturer’s instructions.
Other Assays
Serum leptin levels were measured using an enzyme-linked immunosorbent assay kit specific for mouse leptin (Linco Research, Inc., St. Charles, MO). Serum corticosterone was measured using a kit from ICN Pharmaceuticals, Inc. (Costa Mesa, CA). Serum glucose was measured using a kit from Sigma Chemical Co. (St. Louis, MO).
Statistical Analysis
Data are expressed as the mean ± SEM. Analysis of variance with Bonferroni as post hoc test was used for comparison among three groups. Student’s t-test was used for comparison between two groups. Statistical significance for lethality rates was determined by Fisher’s exact test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The effect of acute starvation (48 hours) with or without
exogenous leptin administration on body weight and water intake is
shown in Table 1
. Depriving mice of food
for 48 hours caused a fall in body weight (17%) and dramatically
reduced water intake (61% and 68% between 0 to 24 and 24 to 48 hours,
respectively). Serum leptin levels decrease during
fasting.4
To increase the leptin levels in fasted mice, we
administered exogenous leptin following a protocol previously used to
study the role of leptin in the physiology of starvation (1 µg/g body
weight, i.p. twice a day for 2 days).4
Leptin treatment of
fasted mice did not affect the decreases in either body weight or in
water intake (Table 1)
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, fasting marked
increases the sensitivity to LPS toxicity. A dose of LPS of 7.5 mg/kg
that did not cause lethality in fed mice induced 60% mortality in
fasted mice. A dose of 15 mg/kg of LPS caused 100% lethality in fasted
mice compared to 20% mortality in fed mice. Because mice injected with
LPS (15 mg/kg) became anorectic, to exclude the possibility that fasted
mice subsequently treated with LPS died of starvation, a fasted group
of mice were treated with saline and kept fasted. No deaths were
observed in the fasted group during a period of up to 6 days of
fasting.
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Food deprivation for 48 hours reduced serum leptin levels from
6.3 ± 0.8 to 1.3 ± 0.3 ng/ml (Table 2)
. A single i.p. injection of 1 µg/g
body weight of leptin has been previously shown to produce
concentrations of leptin at 6 and 12 hours after injection similar to
fed controls.4
We measured leptin levels in the serum of
fasted mice treated with leptin 23 hours after the last leptin
injection and leptin levels were still higher than in fasted mice
(1.3 ± 0.3 versus 2.7 ± 0.4 ng/ml).
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. In contrast, 73% of the fed mice
survived. Exogenous leptin replacement during the period of food
deprivation was protective, increasing survival (31% survival). Thus,
decreasing the fasting-induced fall in leptin with exogenous leptin
administration substantially blunts the increase in sensitivity to LPS
toxicity.
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, despite the different basal levels due to different
nutritional status, leptin levels were induced by LPS to similar levels
in fasted, leptin-replaced fasted, or fed mice (Table 2)
. These data
suggest that, in mice, basal leptin levels, rather than the levels
induced by LPS, are crucial in determining sensitivity to LPS. Serum Glucose and Corticosterone Levels after LPS Administration
Endotoxemia and fasting are both conditions characterized by
reduced serum glucose levels. To evaluate the possibility that a more
profound hypoglycemia might occur in fasted mice treated with LPS, we
measured serum glucose levels before and after LPS in the different
nutritional conditions. As expected, depriving mice of food for 48
hours caused a decrease in basal glucose levels from 138 to 63 mg/dl
(Table 3)
. As previously
reported,4
leptin treatment of fasted mice did not alter
the basal levels of glucose. After LPS administration, a profound
decrease in blood glucose was observed in fed mice; glucose levels
after LPS were somewhat lower in fasted mice. Leptin treatment gave
intermediate levels of glucose after LPS (Table 3)
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. After LPS
administration, a marked increase in serum corticosterone was observed
in fed mice, which resulted in a difference between basal and induced
levels (
, the difference between two sets of mice, fed and
fed-treated with LPS) of 378 ng/ml. Less induction of corticosterone
was observed in fasted mice (= 191 ng/ml), suggesting that fasting
affects the responsiveness of the HPA axis to LPS. When animals
were treated with leptin during fasting, there was a more marked
increase in corticosterone after LPS administration, resulting in a
of 438 ng/ml, comparable to that which occurred in fed mice. Circulating Cytokine Levels after LPS Administration
The systemic release of cytokines mediates the endotoxic shock
syndrome. We therefore assessed whether the increased sensitivity to
LPS lethality due to fasting was associated with increases in TNF,
IFN-, or IL-1ß induction. As shown in Figure 3
, TNF induction by LPS was found to be
approximately fivefold higher in fasted than in fed mice. Moreover,
endogenous leptin replacement inhibited this marked rise in TNF levels
after LPS administration in fasted mice. In contrast, LPS induced lower
levels of IFN- in both fasted and fasted leptin-treated mice
compared to fed mice (Table 4)
. No
significant differences were observed in IL-1ß levels among the three
groups (Table 4)
. TNF, IFN-, and IL-1ß were undetectable in the
serum of mice that were fed, fasted, or fasted and treated with leptin
injected with saline.
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The increase in TNF production during fasting may contribute to
the greater LPS toxicity seen in fasted animals. Significantly, this
increase in the induction of TNF during fasting seems to be, at least
in part, prevented by leptin replacement (Figure 3)
. Because genetic
leptin deficiency has previously been shown to increase sensitivity to
the lethal effect of TNF,20
we therefore next assessed
whether fasting would exacerbate TNF toxicity. A dose of mTNF of 500
µg/kg caused 55% lethality when administered to fed mice (Figure 4)
. This same dose resulted in 100%
lethality in mice fasted for 48 hours. Most importantly, leptin
replacement reversed the increase in TNF toxicity induced by fasting,
reducing the lethality to levels comparable to fed mice (Figure 4)
.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The generation of an acute phase response by LPS requires the induction
of cytokines, such as TNF, IL-1, and IFN-, which are the mediators
of the pathophysiological changes which occur during infections and
inflammation.23
We found that starvation causes a
dysregulation in the pattern of induction by LPS of some cytokines. In
fact, LPS induced a fivefold higher serum TNF level in fasted compared
to fed mice, whereas lower levels of IFN- were detected in fasted
compared to fed mice. In contrast, no differences were observed in
IL-1ß induction. The higher levels of TNF in fasted mice might, at
least in part, explain their increased susceptibility to LPS lethality.
This hypothesis is reinforced by the finding that leptin treatment
conferred protection against LPS lethality and concomitantly
significantly reduced the exaggerated TNF response observed in fasted
mice. On the other hand, a direct effect of leptin on TNF production is
unlikely, because leptin administration to fed animals has been
previously shown to be ineffective in inhibiting TNF induction by
LPS.24
However, it is likely that leptin administration
during fasting prevents changes in circulating as well tissue-specific
cytokine-producing leukocyte subsets, such as monocytes-macrophages and
lymphocytes, rather than affecting TNF production directly. For
example, thymic and splenic atrophy and decreased T-lymphocyte
responses, such as delayed-type hypersensitivity reaction, are
well-known features of starvation.10,11
The reduction in
circulating leptin levels has been shown to be responsible for the
lymphoid atrophy associated with starvation and leptin can reverse the
inhibitory effect of starvation on the development of delayed-type
hypersensitivity reaction as a consequence of its effect on
lymphocytes.10,11
Furthermore, in ob/ob mice
thymus atrophy and alterations in the number of circulating lymphocytes
and monocytes lead to reduced sensitivity to T-cell activating stimuli
and enhanced responses to monocyte-macrophage
activators.11,19,20,25
Leptin replacement restores
circulating leukocyte populations by increasing lymphocytes and
decreasing monocyte numbers, which result in the reconstitution of the
responses to T-cell activating stimuli as well as in the protection
from monocyte-activating stimuli.19,25
It is
therefore possible that in fasted mice leptin treatment normalizes TNF
induction as a consequence of restoration of leukocyte populations.
Likewise, the lower levels of IFN- measured in fasted mice might
also reflect alterations in lymphocyte populations because T
lymphocytes are an important source of IFN- and are depleted during
fasting. Interestingly, it has recently been shown that prevention of
lymphocyte apoptosis is associated with improved survival in a murine
model of sepsis, suggesting a critical role of the lymphocyte in
resolving severe infection.26
It has been suggested that
the significant decrease in the number of lymphocytes which occurs in
septic and endotoxic shock, will impact multiple facets of the
immunological response and may lead to uncontrolled inflammatory
response and death. The profound lymphopenia of fasted mice might
therefore substantially contribute to their increased susceptibility to
infection and inflammation and leptin could confer protection by
preventing fasting-induced lymphopenia.
A decrease in serum glucose is among the metabolic changes occurring during starvation and is also a component of the acute phase response. LPS further reduced glucose levels in fasted mice and the levels were lower than those in LPS-treated fed animals. However, leptin treatment during fasting did not affect either the basal glucose levels, as previously reported, or significantly reverse the further decrease in the glucose levels after LPS. It seems therefore that the protective effect of leptin on LPS lethality is not mediated by the hypoglycemic response.
During the acute phase response, the activation of the HPA axis results in an increase in glucocorticoids, which attenuates the inflammatory reaction by exerting a negative feedback on TNF production after LPS and also protects against TNF toxicity.21,27 Several lines of evidence suggest a regulatory loop between HPA axis and circulating leptin. Leptin deficiency, as observed in ob/ob mice, results in chronic HPA axis activation, which is reversed by leptin treatment.28 In addition, leptin administration substantially prevents the activation of the HPA axis in response to stress or fasting.4,29 Furthermore, in mice, adrenalectomy decreases basal leptin levels and corticosterone replacement therapy restores circulating leptin to physiological levels.30 Here we show that fasted mice have an impaired HPA axis activation after LPS administration, suggesting that fasting might affect the responsiveness of the HPA axis to LPS. As previously reported,4 leptin administration during fasting reduced the basal serum corticosterone levels in fasted mice; in addition we now show that leptin restores the HPA axis activation in response to LPS in fasted mice to levels comparable to that observed in fed animals. It is possible that the restored HPA axis response contributes to the protective effect of leptin in fasted animals.
Interestingly, -MSH, a pro-opiomelanocortin-derived peptide, is an
anti-inflammatory agent31
which, like leptin, is
down-regulated by fasting.32
A link between leptin and the
melanocortin system has been suggested and leptin has been demonstrated
to stimulate pro-opiomelanocortin expression.33,34
Therefore the protective effect of leptin during starvation, might, at
least to some extent, be mediated by -MSH.
We also have shown that fasting increases sensitivity to TNF lethality, indicating that the effect of fasting on LPS toxicity also occurs downstream to TNF production. Importantly, leptin replacement reversed the increase in TNF toxicity secondary to fasting. Therefore, the protective effect of leptin on LPS toxicity is also likely to be downstream to TNF suggesting that leptin exerts its anti-inflammatory effects both by decreasing TNF induction by LPS and also by protecting against the TNF-induced inflammatory cascade. The protective effect of leptin on TNF toxicity in starved mice might involve TNF-induced cytokine production. For example, IL-1 contributes to TNF lethality35 and cross-regulation exists between leptin and IL-1. Leptin levels are acutely increased by IL-112 and IL-1 mediates the induction of leptin during local and systemic inflammation caused by injection of turpentine or LPS in mice.14 Conversely, leptin actions in the brain seem to depend on IL-1. Luheshi et al36 showed that leptin increases levels of IL-1 in the hypothalamus of normal rats. The effect of leptin on fever and food intake is abolished by the IL-1 receptor antagonist and is absent in mice lacking the main IL-1 receptor (80 kd, R1) responsible for IL-1 actions. On the other hand, IL-1 does not seem to be involved in increased susceptibility to LPS in fasted mice, because we observed comparable levels of IL-1ß in fed, fasted, and leptin-treated fasted mice. Although this does not completely rule out the possible involvement of IL-1 in the protective effect of leptin on TNF toxicity in fasted mice, it is likely that other mediators and cytokines are involved.
The major focus of research on leptin action has been on metabolism and nutritional homeostasis.1 However, leptin has been shown to have pleiotropic activity, including roles in hematopoiesis37-39 and reproductive physiology.4,40 Leptin can also be classified as a cytokine because of its secondary structure and the leptin receptor is homologous to the gp-130, the signal-transducing subunit of the IL-6 receptor family.15-18 Leptin levels are increased by cytokines and inflammatory stimuli.12-14 Importantly, the absence of functional leptin, as observed in ob/ob mice or in normal mice treated with a leptin antagonist, sensitizes mice to LPS and TNF toxicity,19,20 suggesting that leptin is a protective component of the acute phase response. In agreement with these data, we show here that the low leptin levels, which occur during fasting, play an important role in increasing the susceptibility to LPS.
A role for leptin in the physiology of the immune system is emerging.
Leptin has been shown to enhance the alloproliferative response of
peripheral blood lymphocytes by provoking a strong proliferative
response by both naïve and memory T cells.10
Leptin has been proposed to induce a switch in T-cell responses toward
a Th-1 phenotype, because it has been shown to increase IL-2 and
IFN- while inhibiting IL-4 production by T cells.10
Exogenous leptin administration has been shown to reverse the
inhibitory effect of starvation on the development of a delayed-type
hypersensitivity reaction and to protect from starvation-induced
lymphoid atrophy, indicating a role for leptin in the immune
dysfunction of starvation.10,11
The data presented in this
article further support the hypothesis that the absence of leptin plays
a role in the immune dysfunction of starvation, providing a potential
mechanism for the increased susceptibility to infection secondary to
malnutrition.
In summary, we have shown that fasting increases susceptibility to LPS and leptin administration can inhibit this increase. The ability of leptin to inhibit TNF production and TNF toxicity could partially account for the protective effect of leptin on LPS toxicity in fasted mice. These data indicate that leptin represents a link between nutritional status and immune response. Our findings suggest that the decrease in leptin that occurs during food deprivation could contribute to the increased morbidity and mortality of infections in malnourished patients and raises the possibility that leptin treatment may be beneficial in malnourished patients at high risk for sepsis.
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Footnotes |
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Supported by National Institutes of Health grant DK49448 (to C. G.), and by the Research Service of the Department of Veterans (to C. G. and K. R. F.).
Accepted for publication January 24, 2000.
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) for 48 hours and
then injected i.p. with 7.5, 15, or 25 mg/kg of LPS
(n = 5 mice per
group). Mortality was assessed daily for 6
days.
). Leptin was
administered i.p., 1 µg/g body weight, twice a day for 2 days to
fasted mice. Fasted or fed mice received saline. Mice were then
challenged with LPS (15
mg/kg). Mortality was assessed daily for 6 days.
*P < 0.05, **P < 0.01,
***P < 0.001 versus fed by
Fisher’s exact test.
