| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Metabolism Section, Department of Veterans Affairs Medical Center, University of California, San Francisco, California 94121; and Divisions of 2 Infectious Diseases and 3 Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Leptin is
induced by lipopolysaccharide (LPS) and cytokines. We investigated the
role of leptin in LPS-induced toxicity using leptin-deficient
(ob/ob)
and leptin receptor-deficient
(db/db) mice. Sensitivity to LPS-induced mortality is significantly greater in
ob/ob
mice compared with their own lean littermates but not in
db/db
mice. LPS reduced serum glucose in both
ob/ob
and
db/db mice but induced corticosterone only in
db/db
mice. Despite the very high basal levels of serum leptin in
db/db
mice, a twofold increase in serum leptin levels was observed after LPS
in both db/db
mice and their lean littermates. No differences were detected in
LPS-induced serum levels of interleukin (IL)-1
, tumor necrosis factor, macrophage inflammatory protein-1
, and interferon-
in ob/ob
mice compared with their own littermates. In contrast, a blunted
induction of IL-10 and IL-1 receptor antagonist (IL-1Ra) was observed
in
ob/ob
mice compared with their littermates. In vitro, leptin induced IL-1Ra
production and upregulated the IL-1Ra induction by LPS in macrophages.
Moreover, treatment with leptin reversed the increased sensitivity to
LPS-induced lethality found in
ob/ob
mice. These results suggest that leptin participates in the host
response to inflammation by modulating the host immune and cytokine
responses after LPS.
lipopolysaccharide; bacterial product; OB protein; leptin receptor; interleukin; tumor necrosis factor; macrophage inflammatory protein; cytokine
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
LEPTIN REGULATES ENERGY balance by decreasing energy intake and increasing energy expenditure (5, 18, 24). Defects in leptin production (ob/ob mice) or a deletion in the long isoform of the leptin receptor (Ob-R; db/db mice) causes severe hereditary obesity, characterized by increased food intake and body weight plus decreased energy expenditure (7, 20, 22, 34). Administration of leptin decreases food intake in normal mice and reverses the obese phenotype in ob/ob mice. The db/db mice are resistant to the weight-reducing effects of leptin (5, 18, 24).
It is becoming increasingly clear that leptin has other physiological functions in addition to regulating food intake and energy expenditure. Several reports have shown an important role for leptin in reproductive physiology (1, 6, 8). Moreover, leptin has been shown to modulate phagocytosis and cytokine production by macrophages and to stimulate hematopoiesis (15, 21, 29). The weight-regulating effects of leptin are mediated through the Ob-Rb form in the hypothalamus (16, 30). However, several alternatively spliced isoforms of the leptin receptor have been cloned (13). Constitutive levels of mRNA for leptin receptors (predominantly the short isoform Ob-Ra) are highly expressed in several peripheral tissues and cells, including kidney, lung, liver, spleen, and macrophages (28). Therefore, the expression pattern of leptin receptor mRNAs is consistent with multiple targets for leptin's action, well beyond the hypothalamus.
Increased leptin levels are observed after lipopolysaccharide (LPS) or
turpentine administration in rodents and occur after proinflammatory
cytokine administration in rodents and humans, suggesting that leptin
might also participate in the acute phase response to inflammation (17,
26). Furthermore, leptin induction during local and systemic
inflammation is absent in interleukin (IL)-1-deficient mice (10).
Therefore, it appears that leptin induction is regulated in a manner
similar to the cytokine response to infection and injury. Both the
structure of leptin and that of its receptor suggest that leptin might
be classified as a cytokine. For example, leptin has recently been
shown to have structural similarities to the long-chain helical
cytokine family, which includes IL-6, IL-11, ciliary neurotrophic
factor (CNTF), and leukemia inhibitory factor (LIF; see Ref. 33). The
leptin receptor is homologous to gp-130, the signal transducing subunit
for IL-6, IL-11, CNTF, and LIF receptors (28).
Surprisingly, despite its role in the control of food intake, leptin does not mediate the anorexia of inflammation. In fact, ob/ob mice, which are leptin deficient, are more susceptible to LPS-induced anorexia than their lean littermates (11). We now report that ob/ob mice are more susceptible to LPS-induced death than lean littermates. Hypothalamic receptor-deficient (db/db) mice do not show comparable increased sensitivity. Furthermore, we investigated the role of leptin in the hypoglycemia, activation of hypothalamus-pituitary-adrenal (HPA) axis, and cytokine response that occurs after systemic administration of LPS comparing ob/ob mice with their lean littermates. In addition, we studied the in vitro effect of leptin on the response of macrophages to LPS.
| |
MATERIALS AND METHODS |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Animals and treatments. Female
C57BL/6J
ob/ob,
C57BL/KsJ
db/db
(both weighing ~40 g), and their respective lean littermates (+/?;
weighing ~20 g) mice (5 wk) were purchased from Jackson Laboratory
(Bar Harbor, ME). Lean littermate control mice were not separated by
genotype (either +/+ and +/ob or +/+
and +/db) and are therefore referred
to as +/?ob for the
ob/ob
littermates and +/?db for the
db/db
littermates. For analysis of serum cytokine, glucose, and
corticosterone levels, LPS (Escherichia
coli 055:B5; Difco Laboratories, Detroit, MI) was
administered intraperitoneally at 5 µg/g. Control mice received
intraperitoneal saline. Blood was collected from the retroorbital
plexus under halothane anesthesia at 0, 2, and 6 h after LPS
administration. For lethality studies, LPS was injected
intraperitoneally at doses of 10, 30, 100, 300, and 1,000 µg/mouse,
as indicated in the text. The
ob/ob
mice were given five injections (
40, 16, 1, +8,
and +32 h) of 100 µg of murine leptin (Amgen, Thousand Oaks, CA) or
saline surrounding challenge with 150 µg (5 µg/g) of LPS
(time 0). These studies were
approved by the Animal Studies Committee of the San Francisco Veterans
Affairs Medical Center.
Cell culture. The RAW 264.7 murine macrophage cells, obtained from American Type Tissue Collection (Rockville, MD), were seeded (105/well) in 24-well plates in RPMI 1640 (Mediatech, Herndon, VA) supplemented with penicillin, streptomycin, and 10% of FCS (Summit Biotechnology, Greeley, CO). After 4 h of culture, the medium was replaced by fresh RPMI 1640 media supplemented with 2.5% FCS, and stimulants were added. The culture supernatants were collected after 24 h and kept frozen until assayed for their IL-1 receptor antagonist (IL-1Ra) content. The leptin used in the RAW 264.7 cells experiments was from R&D Systems (Minneapolis, MN).
Cytokine measurement. IL-1,
interferon- (IFN-), IL-10, and IL-6 levels were measured with
ELISA kits specific for murine cytokines, obtained from Endogen
(Cambridge, MA). Tumor necrosis factor- (TNF-) was measured using
an electrochemiluminescence method using the ORIGEN apparatus (Ingen,
Gaithersburg, MD), as previously described (12). Macrophage
inflammatory protein-1 (MIP-1) was measured with the same
technique using anti-MIP-1 antibodies and standards from R&D
Systems. A previously described sandwich ELISA was used to determine
IL-1Ra concentration (14).
Other assays. Serum leptin levels were measured using a radioimmunoassay kit specific for mouse leptin (Linco Research, St. Charles, MO). Serum glucose was measured using a kit from Sigma Chemical. Serum corticosterone was measured using a kit from ICN Pharmaceuticals (Costa Mesa, CA).
Statistical analysis. Analysis of variance with Bonferroni as post hoc test was used. Data are expressed as means ± SE. Statistical significance for lethality rates was determined by Fisher's exact test.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
LPS-induced lethality in ob/ob and db/db mice and leptin induction in db/db mice. The ob/ob and db/db mice and their own lean littermates (+/?, designated respectively, +/?ob and +/?db) were injected with increasing doses of LPS. As shown in Fig. 1A, the sensitivity to the lethal effect of LPS was significantly enhanced in ob/ob mice compared with +/?ob mice, with an LPS half-maximal lethal dose (LD50) of 50 µg for ob/ob and 600 µg for +/?ob mice. When the difference in the body weight between ob/ob and +/?ob mice is taken into account, the LD50 values for LPS are 1.25 mg/kg for the ob/ob and 30 mg/kg for the +/?ob mice, a 24-fold increase in sensitivity. Mice died between 24 and 48 h after treatment for both groups.
|
As shown in Fig. 1B, doses of LPS between 100 and 1,000 µg caused similar dose-dependent lethality in db/db and +/?db mice, with an LPS LD50 of 200 µg for both db/db and +/?db mice. When adjusted per body weight, the LD50 was 5 mg/kg for db/db and 10 mg/kg for the +/?db mice, showing only a two-fold increased sensitivity between db/db and +/?db mice compared with the 24-fold difference observed between ob/ob and +/?ob mice.
Administration of LPS increases leptin levels in lean mice. The ob/ob mice do not have circulating leptin, whereas db/db mice have very high levels of leptin. As shown in Fig. 2, despite the very high levels of serum leptin in db/db mice, a twofold induction of leptin levels after LPS was observed in both db/db and +/?db mice.
|
Glucose and corticosterone levels in ob/ob and db/db mice after LPS administration. As expected, ob/ob and db/db mice display basal hyperglycemia (Fig. 3) and high serum corticosterone levels (Fig. 4) compared with their littermates, with the ob/ob having lower basal glucose levels and higher corticosterone levels than those of the db/db mice. After LPS administration (5 µg/g), significant reductions in serum glucose levels were observed in ob/ob and db/db mice and their lean littermates. These data indicate that both ob/ob and db/db mice are sensitive to the hypoglycemic effects of LPS.
|
|
Basal corticosterone levels were higher in both ob/ob and db/db mice compared with lean littermates. As shown in Fig. 4A, the already high basal corticosterone levels in ob/ob mice were not increased further by LPS administration. In contrast, in db/db mice, serum corticosterone levels were increased by LPS and reached similar levels as those induced in +/?db mice (Fig. 4B).
The failure of LPS to increase serum corticosterone levels in ob/ob mice raised the possibility that an absence of corticosterone feedback inhibition of proinflammatory cytokine production in ob/ob mice could account for the increased sensitivity to LPS. Therefore, we next determined whether circulating cytokine levels were higher after LPS administration in ob/ob mice compared with +/?ob mice.
Circulating cytokine levels in ob/ob
mice after LPS administration. The
ob/ob
mice and their littermates were administered 5 µg/g of LPS, and blood
was collected at 0, 2, and 6 h for cytokine measurements. As shown in
Table 1, comparable increases
in serum levels of the proinflammatory cytokines IL-1, TNF-,
IFN-, and MIP-1 were observed in
ob/ob
and +/?ob mice. Serum IL-6 levels measured 2 h after LPS were significantly lower in
ob/ob
than in +/?ob mice
(P < 0.05 by
t-test). However, 6 h after LPS, the levels of serum IL-6 were increased to a similar degree in both groups
of mice.
|
We next measured the levels in the serum of the anti-inflammatory IL-10 and IL-1Ra. Significantly lower levels of IL-10 (Fig. 5A) and IL-1Ra (Fig. 5B) were induced by LPS in ob/ob compared with +/?ob mice.
|
In vitro effect of leptin on IL-1Ra production in macrophages. RAW 264.7 murine macrophage cells were stimulated in vitro for 24 h with 10 ng/ml of LPS, 1 µg/ml of leptin, or the combination, and then IL-1Ra secretion was measured. The leptin dose is comparable to that used to show in vitro effects of leptin on hematopoietic cells, on proinflammatory cytokine production, and on mitogen-activated protein kinase (21, 27, 29). As shown in Fig. 6, leptin induced an increase in IL-1Ra secretion from macrophages and potentiated the production of IL-1Ra after LPS stimulation, indicating that leptin can directly modulate the IL-1Ra production by macrophages.
|
Effect of leptin treatment on LPS-induced lethality in
ob/ob mice. Because there is no
circulating leptin in
ob/ob
mice, we next assessed the possibility that the absence of leptin
enhanced sensitivity to LPS-induced lethality. The
ob/ob
mice were treated with five injections (40, 16, 1,
+8, and +32 h) of 100 µg of leptin or saline surrounding challenge
with 150 µg (5 µg/g) of LPS (administered at time
0). The 2-day pretreatment with leptin caused a 40%
decrease in food intake but did not induce a significant loss of body
mass in that time period (initial body weight 38.6 ± 0.5; body
weight after 2 days pretreatment 37.0 ± 0.5). As shown in Fig.
7, survival was prolonged in leptin-treated
ob/ob
mice compared with saline-treated controls. At 2 and 3 days after LPS administration, leptin treatment resulted in a statistically
significant protection against LPS-induced lethality compared with the
saline treatment.
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
In this report, we have studied the role of leptin in the inflammatory and toxic responses elicited by LPS administration using leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Sensitivity to the lethal effect of LPS was markedly enhanced in ob/ob compared with +/?ob mice, in agreement with recent data showing increased sensitivity to LPS-induced anorexia and liver injury in ob/ob mice compared with +/?ob mice (11, 32). Short-term leptin treatment reverses the increased sensitivity to LPS observed in ob/ob mice before significant weight loss occurred, indicating that the increased sensitivity to LPS-induced lethality was due to the leptin deficiency.
In contrast to ob/ob mice, db/db mice and their lean littermates had a similar sensitivity to LPS-induced lethality. These data eliminate the possibility that the increased sensitivity to LPS-induced toxicity observed in ob/ob mice was due to obesity, because both ob/ob and db/db mice are equally obese. Moreover, db/db mice are even more diabetic than ob/ob mice (9); therefore, diabetes cannot account for the these differences. Furthermore, the profound decrease in serum glucose levels after LPS administration detected in both ob/ob and db/db mice indicates that the difference observed in terms of LPS-induced lethality was not due to a more generalized defect in the responses of ob/ob mice to LPS.
We further showed that leptin administration reverses the increased
sensitivity to LPS observed in
ob/ob
mice. These results, together with the previous observations that
inflammatory stimuli, like LPS, turpentine, or proinflammatory
cytokines, increase leptin production (10, 17, 19, 26) suggest that
leptin is involved in the acute phase response to tissue injury and
systemic inflammation. It is noteworthy that leptin has structural
similarities to the IL-6-like cytokine family, which also includes
IL-11, CNTF, and LIF (33). Additionally, the leptin receptor is a
member of the gp-130 family (28, 33). In vivo, protection against
lethal endotoxic-septic shock can be induced by prior administration of
CNTF or LIF (2, 31). However, all of these cytokines provide protection
against LPS-induced lethality by decreasing the induction of TNF. In
this study, we have shown that LPS induced comparable levels of
IL-1, TNF-, IFN-, MIP-1, and IL-6 in
ob/ob
and +/?ob mice. Interestingly, lower
levels of IL-10 and IL-1Ra were detected after LPS in
ob/ob
mice compared with +/?ob mice. In
addition, we have shown that leptin stimulates IL-1Ra secretion by
macrophages and potentiates the LPS-induced production of IL-1Ra,
indicating that leptin has direct effects on the immune system. The
blunted induction of IL-10 and IL-1Ra by LPS in
ob/ob
mice could contribute to the increased toxicity of LPS but is unlikely
to fully account for that increased sensitivity, and other cytokines
are probably also involved.
Interestingly, it has been reported recently that, in critically ill, septic patients, leptin levels were increased significantly and were higher in survivors than in nonsurvivors, suggesting that leptin might have a protective effect in patients with severe inflammatory disease (4).
The activation of the HPA axis is a component of the host response to inflammation and provides an important negative feedback to proinflammatory cytokine production and toxicity (3). A failure of LPS to increase the already high serum corticosterone levels was observed in ob/ob mice. It is therefore possible that the inability of ob/ob mice to adequately respond to LPS in terms of HPA axis activation might also contribute to the increased susceptibility to LPS-induced toxicity.
A direct effect of leptin on development and differentiation of hemopoietic lineages has been described (8). Leptin has also been shown to enhance phagocytosis by macrophages (15). Furthermore, we now present direct evidence that leptin modulates IL-1Ra secretion by macrophages both in basal and LPS-stimulated states. Our results show that a defect in leptin production is associated with an impaired host response to inflammation. The blunted production of IL-1Ra and IL-10 and the dysregulation in corticosterone induction in leptin-deficient mice are examples of immunological changes that could contribute to the increased susceptibility to LPS-induced lethality.
The ob/ob mice do not have leptin, whereas very high serum levels of leptin are detectable in db/db mice (5, 18, 24) and are further increased after LPS. The db/db mice are resistant to the weight-regulating effect of leptin because they have a defect in the Ob-Rb form of the leptin receptor (7, 20). However, the other forms of the leptin receptor, which are highly expressed in peripheral tissues, are normally expressed in db/db mice. The Ob-Ra form has recently been shown to be capable of transmitting signals and might mediate some of the extrahypothalamic activities of leptin (23). Our results raise the possibility that circulating leptin acting through the Ob-Ra contributes to the host response to inflammation, accounting for the difference in LPS sensitivity observed when ob/ob and db/db mice are compared with their respective lean littermates.
Leptin induction during inflammation appears to be part of the cytokine cascade, which is activated during the acute phase response to infection and injury. We have previously shown that leptin levels are increased by cytokines, such as IL-1, TNF, and IL-6. We now report that leptin deficiency is accompanied by increased susceptibility to LPS-induced lethality and decreased induction of anti-inflammatory cytokines, supporting the hypothesis that leptin is an important cytokine component of the acute phase response. Recognizing the ability of leptin to modulate cytokine production can also help in understanding the biological basis for the pleotropism of the activities of leptin (25). Given that leptin functions as a cytokine, we would speculate that disorders characterized by decreased leptin levels, such as cachexia and starvation, might result in an impaired host defense that would increase susceptibility to infection.
| |
ACKNOWLEDGEMENTS |
|---|
This work was supported by National Institues of Health Grants DK-40990, DK-49448, and AI-15614, the Research Service of the Department of Veterans Affairs, and the University of California San Francisco AIDS Clinical Research Center (CC98-5F-139). C. Gabay is a recipient of a postdoctoral fellowship grant from the Swiss National Foundation for Scientific Research and from "La Fondation Suisse de Bourse de Medecine et Biologie."
| |
FOOTNOTES |
|---|
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: C. Grunfeld, Metabolism Section (111F), Dept. of Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121.
Received 9 July 1998; accepted in final form 10 September 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
1.
Barash, I. A.,
C. C. Cheung,
D. S. Weigle,
H. Ren,
E. B. Kabigting,
J. L. Kuijper,
D. K. Clifton,
and
R. A. Steiner.
Leptin is a metabolic signal to the reproductive system.
Endocrinology
137:
3144-3147,
1996[Abstract].
2.
Benigni, F.,
P. Villa,
M. T. Demitri,
S. Sacco,
J. D. Sipe,
L. Lagunowich,
N. Panayotatos,
and
P. Ghezzi.
Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.
Mol. Med.
1:
568-575,
1995[Medline].
3.
Besedovsky, H.,
A. del Rey,
E. Sorkin,
and
C. A. Dinarello.
Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones.
Science
233:
652-654,
1986
4.
Bornstein, S. R.,
J. Licinio,
R. Tauchnitz,
L. Engelmann,
A. B. Negrao,
P. Gold,
and
G. P. Chrousos.
Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion.
J. Clin. Endocrinol. Metab.
83:
280-283,
1998
5.
Campfield, L. A.,
F. J. Smith,
Y. Guisez,
R. Devos,
and
P. Burn.
Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.
Science
269:
546-549,
1995
6.
Chehab, F. F.,
M. E. Lim,
and
R. Lu.
Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin.
Nat. Genet.
12:
318-320,
1996[Medline].
7.
Chen, H.,
O. Charlat,
L. A. Tartaglia,
E. A. Woolf,
X. Weng,
S. J. Ellis,
N. D. Lakey,
J. Culpepper,
K. J. Moore,
R. E. Breitbart,
G. M. Duyk,
R. I. Tepper,
and
J. P. Morgenstern.
Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice.
Cell
84:
491-495,
1996[Medline].
8.
Cioffi, J. A.,
A. W. Shafer,
T. J. Zupancic,
G. J. Smith,
A. Mikhail,
D. Platika,
and
H. R. Snodgrass.
Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction.
Nat. Med.
2:
585-589,
1996[Medline].
9.
Coleman, D. L.
Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.
Diabetologia
14:
141-148,
1978[Medline].
10.
Faggioni, R.,
G. Fantuzzi,
J. Fuller,
C. A. Dinarello,
K. R. Feingold,
and
C. Grunfeld.
IL-1 mediates leptin induction during inflammation.
Am. J. Physiol.
274 (Regulatory Integrative Comp. Physiol. 43):
R204-R208,
1998
11.
Faggioni, R.,
J. Fuller,
A. Moser,
K. R. Feingold,
and
C. Grunfeld.
LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R181-R186,
1997
12.
Fantuzzi, G.,
S. Sacco,
P. Ghezzi,
and
C. A. Dinarello.
Physiological and cytokine responses in IL-1-deficient mice after zymosan-induced inflammation.
Am. J. Physiol.
273 (Regulatory Integrative Comp. Physiol. 42):
R400-R406,
1997
13.
Fei, H.,
H. J. Okano,
C. Li,
G. H. Lee,
C. Zhao,
R. Darnell,
and
J. M. Friedman.
Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues.
Proc. Natl. Acad. Sci. USA
94:
7001-7005,
1997
14.
Gabay, C.,
B. Porter,
G. Fantuzzi,
and
W. P. Arend.
Mouse IL-1 receptor antagonist isoforms: complementary DNA cloning and protein expression of intracellular isoform and tissue distribution of secreted and intracellular IL-1 receptor antagonist in vivo.
J. Immunol.
159:
5905-5913,
1997[Abstract].
15.
Gainsford, T.,
T. A. Willson,
D. Metcalf,
E. Handman,
C. McFarlane,
A. Ng,
N. A. Nicola,
W. S. Alexander,
and
D. J. Hilton.
Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells.
Proc. Natl. Acad. Sci. USA
93:
14564-14568,
1996
16.
Ghilardi, N.,
S. Ziegler,
A. Wiestner,
R. Stoffel,
M. H. Heim,
and
R. C. Skoda.
Defective STAT signaling by the leptin receptor in diabetic mice.
Proc. Natl. Acad. Sci. USA
93:
6231-6235,
1996
17.
Grunfeld, C.,
C. Zhao,
J. Fuller,
A. Pollack,
A. Moser,
J. Friedman,
and
K. R. Feingold.
Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.
J. Clin. Invest.
97:
2152-2157,
1996[Medline].
18.
Halaas, J. L.,
K. S. Gajiwala,
M. Maffei,
S. L. Cohen,
B. T. Chait,
D. Rabinowitz,
R. L. Lallone,
S. K. Burley,
and
J. M. Friedman.
Weight-reducing effects of the plasma protein encoded by the obese gene.
Science
269:
543-547,
1995
19.
Janik, J. E.,
B. D. Curti,
R. V. Considine,
H. C. Rager,
G. C. Powers,
W. G. Alvord,
J. Smith,
B. L. Gause,
and
W. C. Kopp.
Interleukin 1 alpha increases serum leptin concentrations in humans.
J. Clin. Endocrinol. Metab.
82:
3084-3086,
1997
20.
Lee, G. H.,
R. Proenca,
J. M. Montez,
K. M. Carroll,
J. G. Darvishzadeh,
J. I. Lee,
and
J. M. Friedman.
Abnormal splicing of the leptin receptor in diabetic mice.
Nature
379:
632-635,
1996[Medline].
21.
Loffreda, S.,
S. Q. Yang,
H. Z. Lin,
C. L. Karp,
M. L. Brengman,
D. J. Wang,
A. S. Klein,
G. B. Bulkley,
C. Bao,
P. W. Noble,
M. D. Lane,
and
A. M. Diehl.
Leptin regulates proinflammatory immune responses.
FASEB J.
12:
57-65,
1998
22.
Montague, C. T.,
I. S. Farooqi,
J. P. Whitehead,
M. A. Soos,
H. Rau,
N. J. Wareham,
C. P. Sewter,
J. E. Digby,
S. N. Mohammed,
J. A. Hurst,
C. H. Cheetham,
A. R. Earley,
A. H. Barnett,
J. B. Prins,
and
S. O'Rahilly.
Congenital leptin deficiency is associated with severe early-onset obesity in humans.
Nature
387:
903-908,
1997[Medline].
23.
Murakami, T.,
T. Yamashita,
M. Iida,
M. Kuwajima,
and
K. Shima.
A short form of leptin receptor performs signal transduction.
Biochem. Biophys. Res. Commun.
231:
26-29,
1997[Medline].
24.
Pelleymounter, M. A.,
M. J. Cullen,
M. B. Baker,
R. Hecht,
D. Winters,
T. Boone,
and
F. Collins.
Effects of the obese gene product on body weight regulation in ob/ob mice.
Science
269:
540-543,
1995
25.
Plata-Salaman, C.
Leptin (OB protein), neuropeptide Y, and interleukin-1 interactions as interface mechanisms for the regulation of feeding in health and disease.
Nutrition
12:
718-719,
1996[Medline].
26.
Sarraf, P.,
R. C. Frederich,
E. M. Turner,
G. Ma,
N. T. Jaskowiak,
D. Rivet,
J. S. Flier,
B. B. Lowell,
D. L. Fraker,
and
H. R. Alexander.
Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia.
J. Exp. Med.
185:
171-175,
1997
27.
Takahashi, Y.,
Y. Okimura,
I. Mizuno,
K. Iida,
T. Takahashi,
H. Kaji,
H. Abe,
and
K. Chihara.
Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells.
J. Biol. Chem.
272:
12897-12900,
1997
28.
Tartaglia, L. A.,
M. Dembski,
X. Weng,
N. Deng,
J. Culpepper,
R. Devos,
G. J. Richards,
L. A. Campfield,
F. T. Clark,
J. Deeds,
Identification and expression cloning of a leptin receptor, OB-R.
Cell
83:
1263-1271,
1995[Medline].
29.
Umemoto, Y.,
K. Tsuji,
F. C. Yang,
Y. Ebihara,
A. Kaneko,
S. Furukawa,
and
T. Nakahata.
Leptin stimulates the proliferation of murine myelocytic and primitive hematopoietic progenitor cells.
Blood
90:
3438-3443,
1997
30.
Vaisse, C.,
J. L. Halaas,
C. M. Horvath,
J. J. Darnell,
M. Stoffel,
and
J. M. Friedman.
Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.
Nat. Genet.
14:
95-97,
1996[Medline].
31.
Waring, P. M.,
L. J. Waring,
T. Billington,
and
D. Metcalf.
Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.
Proc. Natl. Acad. Sci. USA
92:
1337-1341,
1995
32.
Yang, S. Q.,
H. Z. Lin,
M. D. Lane,
M. Clemens,
and
A. M. Diehl.
Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis.
Proc. Natl. Acad. Sci. USA
94:
2557-2562,
1997
33.
Zhang, F.,
M. B. Basinski,
J. M. Beals,
S. L. Briggs,
L. M. Churgay,
D. K. Clawson,
R. D. DiMarchi,
T. C. Furman,
J. E. Hale,
H. M. Hsiung,
B. E. Schoner,
D. P. Smith,
X. Y. Zhang,
J. P. Wery,
and
R. W. Schevitz.
Crystal structure of the obese protein leptin-E100.
Nature
387:
206-209,
1997[Medline].
34.
Zhang, Y.,
R. Proenca,
M. Maffei,
M. Barone,
L. Leopold,
and
J. M. Friedman.
Positional cloning of the mouse obese gene and its human homologue.
Nature
372:
425-432,
1994[Medline]. [Corrigenda. Nature 374, 1995, p. 479.]
This article has been cited by other articles:
|
|
 |
|
  R. W. Hick, A. L. Gruver, M. S. Ventevogel, B. F. Haynes, and G. D. Sempowski Leptin Selectively Augments Thymopoiesis in Leptin Deficiency and Lipopolysaccharide-Induced Thymic Atrophy J. Immunol., July 1, 2006; 177(1): 169 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Bullen Jr, M. Ziotopoulou, L. Ungsunan, J. Misra, I. Alevizos, E. Kokkotou, E. Maratos-Flier, G. Stephanopoulos, and C. S. Mantzoros Short-term resistance to diet-induced obesity in A/J mice is not associated with regulation of hypothalamic neuropeptides Am J Physiol Endocrinol Metab, October 1, 2004; 287(4): E662 - E670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Madiehe, T. D. Mitchell, and R. B. S. Harris Hyperleptinemia and reduced TNF-alpha secretion cause resistance of db/db mice to endotoxin Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2003; 284(3): R763 - R770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Holycross and M. J. Radin Cytokines in Heart Failure: Potential Interactions with Angiotensin II and Leptin Mol. Interv., November 1, 2002; 2(7): 424 - 427. [Abstract] [Full Text]
|
|
|
|
|
|
P. B. Persson What is written, read, and cited in AJP-Regulatory, Integrative and Comparative Physiology? Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1261 - R1263. [Full Text] [PDF]
|
|
|
|
|
|
P. Mancuso, A. Gottschalk, S. M. Phare, M. Peters-Golden, N. W. Lukacs, and G. B. Huffnagle Leptin-Deficient Mice Exhibit Impaired Host Defense in Gram-Negative Pneumonia J. Immunol., April 15, 2002; 168(8): 4018 - 4024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Busso, A. So, V. Chobaz-Peclat, C. Morard, E. Martinez-Soria, D. Talabot-Ayer, and C. Gabay Leptin Signaling Deficiency Impairs Humoral and Cellular Immune Responses and Attenuates Experimental Arthritis J. Immunol., January 15, 2002; 168(2): 875 - 882. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Diehl Nonalcoholic Steatosis and Steatohepatitis: IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G1 - G5. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. FAGGIONI, K. R. FEINGOLD, and C. GRUNFELD Leptin regulation of the immune response and the immunodeficiency of malnutrition FASEB J, December 1, 2001; 15(14): 2565 - 2571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Barazzone-Argiroffo, P. Muzzin, Y. R. Donati, C.-D. Kan, M. L. Aubert, and P.-F. Piguet Hyperoxia increases leptin production: a mechanism mediated through endogenous elevation of corticosterone Am J Physiol Lung Cell Mol Physiol, November 1, 2001; 281(5): L1150 - L1156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zarkesh-Esfahani, G. Pockley, R. A. Metcalfe, M. Bidlingmaier, Z. Wu, A. Ajami, A. P. Weetman, C. J. Strasburger, and R. J. M. Ross High-Dose Leptin Activates Human Leukocytes Via Receptor Expression on Monocytes J. Immunol., October 15, 2001; 167(8): 4593 - 4599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yang, H. Lin, and A. M. Diehl Fatty liver vulnerability to endotoxin-induced damage despite NF-{kappa}B induction and inhibited caspase 3 activation Am J Physiol Gastrointest Liver Physiol, August 1, 2001; 281(2): G382 - G392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tilg and A. M. Diehl Cytokines in Alcoholic and Nonalcoholic Steatohepatitis N. Engl. J. Med., November 16, 2000; 343(20): 1467 - 1476. [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
|
|
|
|
|
|
D. L. Drazen, L. J. Kriegsfeld, J. E. Schneider, and R. J. Nelson Leptin, but not immune function, is linked to reproductive responsiveness to photoperiod Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1401 - R1407. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fruhbeck, J. Salvador, B. Chandrasekar, D. H. Mitchell, J. T. Colston, and G. L. Freeman Is Leptin Involved in the Signaling Cascade After Myocardial Ischemia and Reperfusion? Response Circulation, May 9, 2000; 101 (18): e194 - e194. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Faggioni, A. Moser, K. R. Feingold, and C. Grunfeld Reduced Leptin Levels in Starvation Increase Susceptibility to Endotoxic Shock Am. J. Pathol., May 1, 2000; 156(5): 1781 - 1787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. Finck and R. W. Johnson Tumor necrosis factor (TNF)-alpha induces leptin production through the p55 TNF receptor Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2000; 278(2): R537 - R543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Thieringer, J. E. Fenyk-Melody, C. B. Le Grand, B. A. Shelton, P. A. Detmers, E. P. Somers, L. Carbin, D. E. Moller, S. D. Wright, and J. Berger Activation of Peroxisome Proliferator-Activated Receptor {gamma} Does Not Inhibit IL-6 or TNF-{alpha} Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo J. Immunol., January 15, 2000; 164(2): 1046 - 1054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Faggioni, J. Jones-Carson, D. A. Reed, C. A. Dinarello, K. R. Feingold, C. Grunfeld, and G. Fantuzzi Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: Role of tumor necrosis factor alpha and IL-18 PNAS, February 29, 2000; 97(5): 2367 - 2372. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||
