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secretion cause
resistance of db/db mice to endotoxin
Department of Foods and Nutrition, University of Georgia, Athens, Georgia 30602
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Leptin deficiency in ob/ob mice
increases susceptibility to endotoxic shock, whereas leptin
pretreatment protects them against LPS-induced lethality. Lack of the
long-form leptin receptor (Ob-Rb) in db/db mice causes
resistance. We tested the effects of LPS in C57BL/6J
db3J/db3J (BL/3J) mice, which
express only the circulating leptin receptors, compared with C57BL/6J
db/db (BL/6J) mice, which express all short-form and
circulating isoforms of the leptin receptor. Intraperitoneal injections
of LPS significantly decreased rectal temperature and increased leptin,
corticosterone, and free TNF-
in fed and fasted BL/3J and BL/6J
mice. TNF- was increased three- and fourfold in BL/3J and BL/6J,
respectively. LPS (100 µg) caused 50% mortality of fasted BL/6J mice
but caused no mortality in fasted BL/3J mice. Pretreatment of fasted
BL/3J mice with 30 µg leptin prevented the drop in rectal
temperature, blunted the increase in corticosterone, but had no effect
on TNF- induced by 100 µg LPS. Taken together, these data provide
evidence that fasted BL/3J mice are more resistant than BL/6J mice to
LPS toxicity, presumably due to the absence of leptin receptors in
BL/3J mice. This resistance may be due to high levels of free leptin
cross-reacting with other cytokine receptors.
tumor necrosis factor-; leptin receptor; lipopolysaccharides
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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LOSS OF BODY WEIGHT
and lack of appetite are serious complications associated with acute
and chronic infections due to increased levels of inflammatory
mediators and cytokines needed for killing pathogens (24,
25). A severe inflammatory response can, therefore, cause
deleterious changes in nutrition that adversely affect growth, reproduction, and the immune system (3). LPS, a
gram-negative bacterial endotoxin, has been extensively used for
experimental induction of an inflammatory response; its administration
results in anorexia, fever, and increased cytokine production in
rodents (27, 33). The anorexia and host responses to LPS
infection are mediated by IL-1
and TNF- (7). The
involvement of leptin in the immune response to LPS has been
demonstrated by hypersensitivity of ob/ob mice to endotoxin
administration. Leptin-deficient (ob/ob) mice are
hypersensitive to the lethal effects of LPS and TNF-, but C57BL/6J
db/db mice are resistant to LPS-induced anorexia and
lethality (10, 12, 36). Leptin administration to
ob/ob mice blunts the increased sensitivity to LPS and
TNF- (36).
Flier (16) hypothesized that leptin signals a shift
between adequate and inadequate stores of energy, whereby a fall in leptin may lead to a series of physiological and metabolic adaptations that improve survival during times of energy insufficiency. One potential adaptation could be in the interaction between leptin and the
immune system. Malnutrition is known to compromise immune function by
reducing resistance to infection (31). The susceptibility to LPS-induced lethality is increased in fasted, but not fed, wild-type
mice (13). Leptin protected against LPS-induced lethality in ob/ob mice but did not mediate the anorexia of
inflammation in starved wild-type mice (12). Leptin has
been shown to directly stimulate phagocytic activity of macrophages
(18, 28) and to enhance endotoxin-induced production of
TNF-, IL-6, and IL-12 (28). Furthermore, leptin
prevents the increased susceptibility to endotoxic shock in mice that
have been fasted for 48 h (11) and reverses
starvation-induced suppression of cellular immune responses
(29). The latter suggests that leptin may provide a
critical link between malnutrition and immunosuppression (11, 31).
Leptin mRNA expression and circulating protein concentrations are
stimulated within hours of LPS administration in fasted animals
(14, 19, 35). TNF- and IL-1 have been shown to be
involved in LPS-induced leptin expression and secretion (9, 15). It was initially thought that cytokine-induced
hyperleptinemia might be involved in the anorexia that accompanies
infection. However, leptin was recently shown not to be essential in
LPS-induced anorexia (12) but was suggested to participate
in the host response to inflammation by modulating the immune and
cytokine response after LPS treatment (10). Furthermore,
administration of exogenous leptin did not affect either
proinflammatory or anti-inflammatory cytokine responses during
LPS-induced acute inflammation (6).
Leptin plays an important role not only in the regulation of appetite, body weight, and energy expenditure but also in the immune response (8). Leptin performs these functions by binding to its receptor, Ob-R (37). There are five isoforms of the receptor (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re) produced by alternative mRNA splicing (26). Spontaneous mutations in the leptin receptor lead to the development of obesity in mice (26). A mutation in C57BL/6J db/db (BL/6J) mice produces short-form receptors (Ob-Ra, Ob-Rc, Ob-Rd) and the circulating receptor (Ob-Re) but no long-form receptor (Ob-Rb). A mutation in C57BL/3J db3J/db3J (BL/3J) mice produces only the truncated Ob-Re (26). Both genotypes are hyperleptinemic but do not respond to leptin by reducing food intake or body weight due to lack of functional Ob-Rb (37). These experiments were, therefore, carried out to test the hypothesis that mice that lack membrane-bound Ob-R will, like ob/ob mice, be hypersensitive to LPS due to the absence of leptin signaling.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal housing. Mice were obtained from a colony maintained at the University of Georgia. They were housed individually in shoebox cages with free access to rodent chow (Purina Mills, St. Louis, MO) and water in a room maintained at 75°F, with a 12:12-h light-dark cycle starting from 7 AM, and were handled daily during the 1-wk acclimation period for measurement of body weights. Experimental protocols used were approved by the Institutional Animal Care and Use Committee of the University of Georgia and were conducted in conformity with the Guiding Principles for Research Involving Animals and Human Beings of the American Physiological Society (2).
Experiment 1: effects of LPS on fed BL/3J db/db mice. The objective of this study was to determine whether the absence of leptin signaling in BL/3J db/db mice causes them to be hypersensitive to LPS similar to ob/ob mice.
On the day of experiment, starting at 7:30 AM, 12 11-wk-old female BL/3J mice were divided into two weight-matched groups (6 mice/group). Rectal temperature of each mouse was recorded, and a 100-µl blood sample was collected by tail bleeding at 0 h. One group received intraperitoneal injections of 0.1 ml saline, and the other group was injected with 10 µg LPS in 0.1 ml saline (low-dose LPS). This low dose was chosen based on the lethal effects of LPS in ob/ob mice (10). Fifty-microliter blood samples were collected by tail bleeding 1, 3, and 6 h after injection. Rectal temperatures were recorded 6 h after injection. All mice were decapitated after 6 h.Experiment 2: effects of LPS on fed BL/6J db/db mice. Because our hypothesis was that BL/3J mice would be as susceptible to LPS toxicity as ob/ob mice, the objective of this experiment was to use BL/6J mice as controls for resistance to high doses of LPS.
Nine female BL/6J mice, aged 11 wk, were housed and handled as described above. On the day of experiment, starting at 7:30 AM, rectal temperature of each mouse was recorded and a 100-µl blood sample was collected by tail bleeding. Mice were allowed free access to chow and water during the experiment. Each animal received an intraperitoneal injection of either 0.1 ml saline (4 mice/group) or 50 µg LPS (5 mice/group) in 0.1 ml saline. Fed BL/6J mice are resistant to low doses of LPS (12), therefore a dose of 50 µg LPS/mouse was used. Experimental design was the same as for experiment 1.Experiment 3: effects of LPS and LPS plus leptin on fasted BL/3J db/db mice. Leptin has been shown to protect fasted wild-type mice from LPS-induced lethality (13). Experiment 1 showed that the low dose LPS was not toxic to fed BL/3J mice. Therefore, the objective of this study was to test whether high doses of LPS were lethal in fasted BL/3J mice and whether pretreatment with leptin protected fasted BL/3J mice against LPS.
Twenty-seven 11-wk-old female BL/3J mice were housed and handled for 1 wk as described above. On the day of experiment, a baseline 100-µl blood sample was collected by tail bleeding, starting at 7:30 AM, and mice were fasted for 24 h. The next day, a 100-µl blood sample was collected by tail bleeding before injections (0 h). One group of six mice received an intraperitoneal injection of 30 µg leptin in 0.1 ml PBS and were tail bled 1 h after leptin injection. Mice were then injected with either saline (8 mice/group) or 50 µg (8 mice/group) or 100 µg (5 mice/group) LPS in 0.1 ml saline. The leptin-pretreated group was injected with 100 µg LPS. Blood samples (50 µl) were collected by tail bleeding at 1, 3, and 6 h postinjection. Rectal temperatures were recorded at 6 h, and mice were killed by decapitation 24 h after injection.Experiment 4: effects of LPS on fasted BL/6J db/db mice. Sixteen female BL/6J db/db mice, aged 11 wk, were housed and handled as described above. On the day of experiment, a baseline 100-µl blood sample was collected by tail bleeding, starting at 7:30 AM, and mice were fasted for 24 h. The next day, a 100-µl blood sample was collected by tail bleeding at 0 h. Mice were injected with saline (4 mice/group), 50 µg LPS (6 mice/group), or 100 µg LPS (6 mice/group) in 0.1 ml saline. Because leptin pretreatment has been shown to confer resistance to LPS in BL/6J mice, it was omitted in this experiment. Experimental design was the same as for experiment 3.
Blood and tissue samples.
Trunk blood was collected for measurement of serum leptin,
corticosterone, and TNF- concentrations. Serum was prepared by centrifugation and stored at 
80°C until analysis for leptin, corticosterone, and TNF-, as described below. Spleen, liver, inguinal, retroperitoneal, and uterine fat pads were dissected and weighed.
Hormone analysis.
For each hormone assay, samples from all experiments were analyzed
together in duplicate to avoid interassay variations. Corticosterone was measured by RIA (rat RIA kit: ICN Diagnostics, Costa Mesa, CA) in
serum from the 0-, 1-, and 6-h time points. Free TNF- was measured
by ELISA (murine TNF- quantikine kit; R&D Systems, Minneapolis, MN)
in both 0- and 1-h serum samples, diluted 1:25 in saline. Leptin was
measured by RIA (murine leptin RIA kit, Linco Research, St. Charles,
MO) in the 0-, 1-, 3-, 6-, and 24-h samples with serum from LPS- and
leptin-injected mice diluted 1:100 in assay buffer, and the serum from
saline-treated mice diluted 1:20.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment 1.
Treatment of fed BL/3J mice with 10 µg LPS had no effect on serum
leptin levels 1 h postinjection (Fig.
1); however, at 3 and 6 h, leptin
levels were significantly higher in LPS-injected mice compared with
saline controls. LPS did not affect corticosterone levels 1 h
postinjection, but caused a significant increase in corticosterone
6 h postinjection. Serum TNF- was higher in LPS- than
saline-injected mice 1 h postinjection (Fig. 1). Treatment of fed
BL/3J mice with 10 µg LPS caused a significant decrease in rectal
temperature compared with saline controls (2.7 ± 0.4 vs.
0.6 ± 0.2°C, P < 0.01).
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Experiment 2.
LPS treatment did not affect serum leptin levels in fed BL/6J mice
1 h postinjection, but caused a 1.5- and 4-fold increase in serum
leptin levels at 3 and 6 h, respectively (Fig.
2). LPS treatment did not affect
corticosterone levels at 1 h postinjection, but significantly
increased corticosterone levels after 6 h (Fig. 2,
P < 0.05). Serum TNF- was significantly increased
by LPS treatment 1 h postinjection (Fig. 2, P < 0.05). Treatment of mice with 50 µg LPS caused a significant decrease
in rectal temperature (2.0 ± 0.1 vs. 0.2 ± 0.2°C,
P < 0.005).
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Experiment 3.
Fasting decreased body weight of saline- and LPS-treated BL/3J mice,
and treatment with 50 or 100 µg LPS after fasting did not cause
further weight loss (Fig. 3).
Pretreatment of BL/3J mice with 30 µg leptin, 1 h before
injection of 100 µg LPS, partially prevented the loss of body weight
(Fig. 3, P < 0.05). There were no differences in
rectal temperatures of fasted BL/3J mice at 0 h, but temperature
was significantly lower in LPS than control animals 6 h after
injection (Fig. 3, P < 0.0001). Leptin partially prevented the hypothermia caused by LPS treatment (Fig. 3,
P < 0.0001).
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levels
measured before injections (Fig. 4), but LPS caused a significant
dose-dependent increase in serum TNF- levels (P < 0.001) 1 h after injection. Leptin pretreatment had no effect on
LPS-induced TNF- levels in BL/3J mice.
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Experiment 4.
Fasting for 24 h decreased body weight of saline- and LPS-injected
BL/6J mice (Fig. 5). Treatment of mice
with 50 or 100 µg LPS after fasting caused a significant
dose-dependent weight loss compared with saline (50 µg,
P < 0.05; 100 µg, P < 0.001) and three of the six mice injected with 100 µg LPS died within less than
24 h of injection. There were no differences in rectal
temperatures at 0 h, but LPS caused a substantial, dose-dependent
decrease in rectal temperature after 6 h (50 µg,
P < 0.01; 100 µg, P < 0.001).
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levels 1 h after injection (50 µg, P < 0.05;
100 µg, P < 0.005).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study show that fed and fasted BL/3J mice are
resistant to LPS and that leptin inhibits LPS-induced corticosterone secretion in the absence of membrane-bound leptin receptors. We had
hypothesized that because BL/3J db/db mice lack
membrane-bound leptin receptors, they would be as sensitive to LPS as
leptin-deficient ob/ob mice. The heightened sensitivity of
ob/ob mice to LPS has been attributed to the absence of
leptin necessary for signaling, and LPS resistance in BL/6J
db/db mice has been attributed to the absence of Ob-Rb
(10, 12). This study shows that the absence of leptin
signaling in BL/3J mice did not cause increased susceptibility to high
doses of LPS, which suggests that LPS resistance of BL/3J mice is due
to absence of membrane-bound receptors and the increased circulating
levels of leptin rather than the absence of leptin signaling. This
observation is supported by other studies showing that pretreatment of
ob/ob mice with leptin does not exacerbate the anorexic
effects of LPS, but rather protects against LPS-induced toxicity
(13). Likewise, pretreatment of starved wild-type mice with leptin protects them against the lethal effects of TNF- (36). The resistance to LPS may also be due to increased
free leptin in BL/3J mice who might have lost the functionality of the
Ob-Re due to a premature stop codon that produces a truncated receptor
(20). This truncated receptor may have lost the tertiary structure required for leptin binding.
LPS caused robust increases in serum leptin in fed and fasted BL/6J and BL/3J mice, and pretreatment of BL/3J mice with leptin inhibited the increase in serum leptin levels caused by 100 µg LPS. These results are consistent with other studies showing that LPS increases serum leptin levels (4, 19, 35). Berkowitz et al. (4) gave fasted mice increasing doses of LPS and found sevenfold increases in circulating leptin and leptin expression 16 h after injection. Grunfeld et al. (19) also found that LPS stimulated leptin mRNA expression and increased serum leptin levels in fasted hamsters. Moreover, an increase in leptin expression 5 h after an LPS injection has been reported in mice that had been fasted for 7 h before LPS treatment (35). This increase in leptin secretion by LPS was abolished when animals were fed (19, 35).
The LPS-induced stimulation of leptin secretion is not a direct effect
of LPS on adipose tissue, because the response can be initiated by
central administration of LPS (15), and also because LPS
does not stimulate leptin secretion from primary adipocytes. In
contrast, TNF- causes a dose-dependent increase in leptin secretion
(15). This indicates that LPS induces synthesis of the
proinflammatory cytokine TNF-, which subsequently increases leptin
secretion. Our studies are consistent with a report that leptin
administration protects mice from becoming hypersensitive to TNF- or
to endotoxic shock (13, 36). The protective effect of
leptin was thought to be limited to animals that were hypoleptinemic, such as ob/ob mice or mice starved for 48 h
(13). In this study, we found that, even in mice deficient
in membrane-bound Ob-R, exogenous leptin blunts the LPS-induced rise in
corticosterone with no effect on the levels of the proinflammatory
cytokine TNF-. The hyperleptinemia present in BL/3J mice may also
provide protection against high LPS doses that are lethal to fasted
wild-type and ob/ob mice and BL/6J mice. We hypothesize
that, in the absence of membrane-bound leptin receptors, especially
Ob-Rb, the excess leptin may cross-react with other class I cytokine
receptors to modulate the anti-inflammatory response. Furthermore, the
presence of high leptin levels may also induce secretion of
anti-inflammatory cytokines, such as the endogenous inhibitor of IL-1,
the IL-1 receptor antagonist.
Pretreatment with leptin did not influence LPS-induced serum TNF-
levels in fasted BL/3J mice. This is consistent with, and could
potentially explain, the resistance to LPS observed in fed BL/6J
db/db mice compared with fasted lean and leptin-deficient ob/ob mice (12). Leptin has been shown to
inhibit the activation of the hypothalamic-pituitary-adrenal (HPA) axis
by exerting a direct, dose-dependent inhibition of stimulated cortisol
secretion by normal human and rat adrenal cells in vitro
(17) and by lowering ACTH secretion (1).
Inasmuch as no effect of leptin was observed on adrenal cells obtained
from db/db mice, these effects of leptin were suggested to
be mediated by the Ob-Rb, which is expressed in the adrenal gland
(1, 17). In contrast to the lack of activity in vitro,
this study shows that the inhibition of corticosterone secretion occurs
in the absence of membrane-bound leptin receptor, suggesting that it is
not an Ob-Rb-dependent process in vivo, or that the process is not
exclusively dependent on Ob-Rb.
In this study, LPS increased corticosterone levels compared with saline
controls in BL/3J and BL/6J mice, and exogenous leptin administration
significantly blunted the LPS-induced rise in serum corticosterone in
fasted BL/3J mice, consistent with glucocorticoids having
anti-inflammatory functions in response to LPS injection (20). The synthesis of glucocorticoids and proinflammatory
cytokines is connected by feedback loops through the HPA axis
(5). That is, corticosterone downregulates the synthesis
and activities of proinflammatory cytokines, such as TNF-, whereas
proinflammatory cytokines, especially TNF- and IL-1, stimulate
release of ACTH from the pituitary gland to increase corticosterone
levels (5, 36). Glucocorticoids have also been shown to
increase leptin gene expression and secretion, and removal of adrenal
steroids decrease serum leptin levels (30). Adrenalectomy
also increases the sensitivity to LPS lethality, an effect that is
prevented by pretreatment with dexamethasone (32),
potentially by increasing serum leptin levels. The inhibition of
LPS-induced corticosterone release by leptin treatment is consistent
with reports that leptin inhibits stress-induced release of
glucocorticoids in food-deprived and immobilized mice (1,
21). Moreover, the rise in serum leptin in pretreated mice could
potentially downregulate corticosterone levels in an attempt to
decrease the corticosterone-induced rise in leptin.
LPS injection caused three- and fourfold increases in TNF- secretion
of fasted BL/3J and BL/6J mice, respectively, and exogenous leptin
administration had no effect on LPS-induced TNF- levels in fasted
BL/3J mice. LPS treatment in vivo increases serum TNF- levels, which
subsequently increase leptin secretion (9, 15). Leptin has
recently been demonstrated to correct the hypersensitivity of
ob/ob mice to LPS (9) and TNF- challenges
(13, 36) and to promote phagocytic activity of macrophages
isolated from ob/ob mice and not those from db/db
mice (28). This suggests that Ob-Rb is involved at some
level in the cellular immune response (28). The reduced
TNF- secretion found in BL/3J compared with BL/6J mice could
represent a significant effect of the absence of membrane-bound Ob-R,
providing an environment with increased nonspecific release of
anti-inflammatory cytokines and decreased proinflammatory cytokines due
to high leptin levels. This observation is consistent with decreased
TNF- levels observed in LPS-resistant BL/6J db/db mice
(12).
In conclusion, this study provides evidence that hyperleptinemia
present in BL/3J mice, combined with reduced LPS-induced serum TNF-
secretion, increases resistance to LPS-induced toxicity.
Perspectives
Obese humans and genetically obese animals have decreased T cell function and increased leptin levels, but the precise role of leptin on immune function in obesity is still unclear. The link between inflammation, obesity, and diabetes is beginning to unravel, with evidence of this relationship coming from observations that various factors (TNF-, IL-2, -4, -6, interferon-
) are modulated similarly
in these human conditions. TNF- and leptin are overexpressed in
white adipose tissue of obese rodents and humans (23) and TNF- plays an important role in the obesity-linked insulin
resistance (22). Data presented in this study using Ob-R
mutant mice indicate that leptin administration, even in the absence of
Ob-Rb, can offer protection against inflammation. Considering that
obesity and diabetes are low-grade inflammatory diseases, leptin may be used in certain situations to reduce the inflammatory response.
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ACKNOWLEDGEMENTS |
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This work was supported by a National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-53903 to R. B. S. Harris.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. B. S. Harris, Dept. of Foods and Nutrition, Dawson Hall, Univ. of Georgia, Athens, GA 30602 (E-mail: harrisrb{at}arches.uga.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpregu.00610.2002
Received 4 October 2002; accepted in final form 4 November 2002.
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RESULTS
DISCUSSION
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