(Journal of Leukocyte Biology. 2000;68:437-446.)
© 2000
by Society for Leukocyte Biology
Leptin in the regulation of immunity, inflammation, and hematopoiesis
Giamila Fantuzzi* and
Raffaella Faggioni
* Department of Medicine, University of Colorado Health Sciences Center, Denver; and
Metabolism Section, Department of Veterans Affairs Medical Center, University of California, San Francisco
Correspondence: Giamila Fantuzzi, Ph.D., Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue B168, Denver, CO 80262. E-mail: Giamila.Fantuzzi{at}UCHSC.edu
 |
ABSTRACT
|
|---|
Leptin, the product of the ob gene, is a pleiotropic
molecule that regulates food intake as well as metabolic and endocrine
functions. Leptin also plays a regulatory role in immunity,
inflammation, and hematopoiesis. Alterations in immune and inflammatory
responses are present in leptin- or leptin-receptor-deficient animals,
as well as during starvation and malnutrition, two conditions
characterized by low levels of circulating leptin. Both leptin and its
receptor share structural and functional similarities with the
interleukin-6 family of cytokines. Leptin exerts proliferative and
anti-apoptotic activities in a variety of cell types, including T
lymphocytes, leukemia cells, and hematopoietic progenitors. Leptin also
affects cytokine production, the activation of monocytes/macrophages,
wound healing, angiogenesis, and hematopoiesis. Moreover, leptin
production is acutely increased during infection and inflammation. This
review focuses on the role of leptin in the modulation of the innate
immune response, inflammation, and hematopoiesis.
Key Words: lymphocytes • cytokines • angiogenesis • metabolism • endocrinology
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THE DISCOVERY OF LEPTIN AND ITS RECEPTOR
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In the late 1950s, a genetic defect that caused a severely obese
phenotype due to overeating and decreased energy expenditure was
identified in mice [1
]. The gene was named ob
and the obese mice carrying the mutation were called
ob/ob [2
]. Parabiotic animal
experiments suggested that ob/ob mice were unable
to produce a satiety factor, but could respond to such a factor from a
parabiotic mate. Similar experiments were performed in
db/db mice, which have a mutation in the
db gene and display a phenotype very similar to that of
ob/ob mice. Db/db mice
produced the factor missing in ob/ob mice, but
could not respond to it. It was therefore hypothesized that the
db gene encoded for the ob receptor. In 1994, the
molecular defect responsible for the obesity syndrome in
ob/ob mice was identified [3
]. The
16-kDa protein encoded by the ob gene was named leptin, from
the Greek leptos (
os), meaning thin. Leptin is
primarily produced by adipose tissue and circulating levels directly
correlate with adipose tissue mass. Leptin reverses the obesity
syndrome of ob/ob mice and results in decreased
food intake and increased activity when administered to normal mice
[4
5
6
]. The leptin receptor (OB-R) was identified
shortly after the discovery of leptin itself [7
]. The
OB-R was found to be the product of the db gene and
db/db mice were shown to be resistant to leptin
[8
]. The obese phenotype of Zucker
fa/fa rats is also due to a mutation of the OB-R
[9
].
|
LEPTIN IS A PLEIOTROPIC MOLECULE
|
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The most important role for leptin is considered to be its
inhibitory effect on appetite. However, both leptin-deficient
(ob/ob) and leptin-receptor-deficient
(db/db) mice are not only obese. They also
develop a complex syndrome characterized by abnormal reproductive
function, hormonal imbalances, and alterations in the
hematopoietic and immune system. Similar alterations have been
described in leptin-deficient humans [10
].
The syndrome of ob/ob and
db/db mice closely resembles the adaptive
response to starvation. In the fed state there is a direct relationship
between leptin levels and body fat mass. With the onset of starvation,
leptin levels fall rapidly, disproportionally to changes in adipose
tissue mass [11
]. This fall in leptin levels is a signal
for the brain to initiate the adaptive response to starvation.
Ob/ob and db/db mice exist
in a state of perceived starvation and, as a consequence, become obese
when given free access to food. Endocrine changes of starvation include
suppression of reproductive and thyroid function and stimulation of the
hypothalamus-pituitary-adrenal axis [11
]. Starvation is
also associated with marked abnormalities of the immune response
[12
]. When caloric intake is adequate and energy stores
are normal, leptin levels increase, allowing a permissive role on
metabolic, endocrine, and immune functions.
|
LEPTIN AND ITS RECEPTOR: STRUCTURE, TISSUE DISTRIBUTION, AND SIGNAL
TRANSDUCTION
|
|---|
Both the structure of leptin and that of its receptor suggest that
leptin should be classified as a cytokine [13
,
14
]. In fact, leptin and its receptor share structural
and functional similarities with members of the long-chain helical
cytokines, which include interleukin (IL)-6, IL-11, IL-12, leukemia
inhibitory factor (LIF), granulocyte-colony stimulating factor (G-CSF),
ciliary neurotrophic factor (CNTF), and oncostatin M (OSM). In
particular, despite the absence of sequence similarities, a four-helix
bundle structure is present both in leptin and in the members of the
long-chain helical cytokine family [14
].
Although white adipose tissue is the major site of leptin gene
expression [3
], constitutive leptin mRNA has been
detected in placenta trophoblasts and amnion cells, in the human
choriocarcinoma cell line BeWo, and in a number of tissues in the fetal
mouse, including bone and cartilage [15
,
16
]. Leptin mRNA is also selectively transcribed in
specific areas of the brain and pituitary in the rat and in a
glioblastoma cell line [17
]. It is interesting that
abnormalities in brain development are present in
ob/ob mice, suggesting that leptin is required
for normal neuronal and glial maturation [18
]. Finally,
leptin expression has been detected in rat gastric epithelium and in
the glands of the gastric fundic mucosa [19
].
The leptin receptor (OB-R) is related to class I cytokine receptors,
which includes gp-130, the common signal transducing component for the
IL-6-related family of cytokines [13
] (Fig. 1
). The 840-amino-acid extracellular domain of OB-R contains motifs
typical of the hemopoietin receptors, particularly a fibronectin type
III domain and two hemopoietin domains [20
]. Leptin
receptors form homodimers, both in the presence and absence of ligand
[21
]. Each leptin receptor binds one molecule of leptin,
resulting in a tetrameric complex composed of two receptors and two
leptin molecules. However, activation of the receptor is thought to
result from a ligand-induced conformational change rather than from
dimerization of the receptor [21
, 22
].
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Figure 1. Structural similarities between OB-R and the gp130-related family of
cytokine receptors. One molecule of leptin binds to one OB-R. The
formation of a tetrameric complex composed of two receptors and two
molecules of leptin is required for signaling. Filled boxes represent
conserved class 1 cytokine receptor family domains that are present in
each member of the gp130-related family of cytokine receptors. With the
sole exception of the short form of OB-R, every other member of the
family activates the JAK/STAT pathway of signal transduction.
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Several alternatively spliced isoforms of the OB-R have been cloned
[23
]. The weight-regulating effects of leptin are
mediated through the long form of the OB-R (OB-Rb) in the hypothalamus
[24
]. As indicated in Table 1
, OB-Rb is also present in several peripheral tissues. In
particular, endothelial cells, platelets, CD4+ and
CD8+ T lymphocytes, CD34+ cells, the yolk sac,
and the fetal liver express OB-Rb as do leukemia cells, particularly
those of patients with primary acute myeloid leukemia
[25
26
27
28
29
30
].
Different short isoforms of the OB-R exist. The OB-Ra is the
predominant OB-R found in most tissues and cells, including kidney,
lung, liver, spleen, and macrophages [7
]. Leptin is a
relatively large protein that would ordinarily be inaccessible to the
brain. However, it is transported through the blood-brain barrier via a
saturable transport system likely mediated by OB-Ra, which is highly
expressed in the choroid plexus [7
, 47
].
Although transfection experiments suggest that OB-Ra may have signaling
capabilities, no definitive demonstration of the signaling role of this
receptor has been reported. The OB-Ra may be either a signaling
receptor or function as a decoy receptor, similar to the IL-1R type II
[48
]. The internalization patterns of the short OB-R
suggest a role in the intracellular transport and degradation of leptin
inside lysosomes [49
].
Leptin circulates in both a bound and a free form [50
].
In lean persons, roughly 50% of leptin is present in the bound form,
whereas mostly free leptin is present in the circulation of obese
people [50
]. The OB-Re isoform is a soluble receptor
[51
]. The function of OB-Re has not been fully
characterized. Similar to the IL-6 receptor, OB-Re may act as a carrier
protein, delivering leptin to the membrane signaling receptor(s)
[52
]. Alternatively, similar to the soluble receptors
for IL-1 or tumor necrosis factor, it may function as an inhibitor of
leptin activity [53
, 54
].
The OB-Rb isoform contains a 302-amino-acid cytosolic domain that
includes binding motifs associated with the activation of the JAK/STAT
signaling pathways. OB-Rb has signaling activities similar to those of
the IL-6-type cytokine receptors [24
]. Leptin activates
STAT-1, -3, and -5 after engaging to the long, but not the short
receptor isoforms [55
, 56
]. In a variety of
in vitro systems, leptin activates the MAPK pathway
[40
, 57
] and induces expression of
suppressor of cytokine signaling (SOCS)-3 [58
]. SOCS-3
is a member of a family of cytokine-inducible signaling inhibitors
[59
]. Transfection data suggest that SOCS-3 acts as an
inhibitor of leptin signaling [58
].
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REGULATION OF LEPTIN PRODUCTION DURING INFECTION AND INFLAMMATION
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Leptin is constitutively produced by adipose tissue and is present
in nanogram concentrations in the systemic circulation; its levels are
regulated by a variety of factors, particularly food intake and the
endocrine system [for review see refs. 60
61
]. However, the innate
immune system also plays a major role in the regulation of leptin
production.
In experimental animals, leptin levels are acutely increased by
inflammatory stimuli, such as endotoxin [lipopolysaccharide (LPS)]
and turpentine, and by the administration of proinflammatory cytokines
such as tumor necrosis factor 
(TNF-) and IL-1
[62
63
64
]. Endogenous IL-1ß plays a critical role in
the induction of leptin by LPS or turpentine because the rise in leptin
after administration of LPS or turpentine is absent in
IL-1ß-deficient mice [64
]. Similar results have also
been reported in rats pretreated with soluble IL-1 receptors, which
inhibit IL-1 activity [65
]. Endogenous TNF-
contributes to the up-regulation of leptin production observed during
bacterial peritonitis in mice [66
]. In rats, elevated
leptin levels are present during infection with the nematode
Nippostrongylus brasiliensis and in the course of intestinal
inflammation [67
, 68
]. In each model
studied, the up-regulation of leptin is transient and occurs early
after administration of the inflammatory stimulus. The kinetics of
leptin production during infection and inflammation resembles that of
cytokine induction.
As outlined above, results obtained in animal experiments indicate an
acute up-regulation of leptin during infection or inflammation.
However, data obtained in human studies do not always agree with
results obtained in rodents. Although the administration of IL-1ß or
TNF- results in increased serum leptin levels in healthy volunteers
[69
, 70
], LPS injection to humans did not
lead to an increase in leptin as it did in mice and hamsters
[71
72
73
]. Results from studies conducted in septic
patients are also contradictory: either increases [74
,
75
] or no changes [76
] in leptin levels
during sepsis have been reported. In contrast, two different studies
demonstrated a positive correlation between leptin levels and survival
after sepsis [74
, 77
]. However, no
correlation between leptin levels and disease activity and no increase
in serum leptin levels have been found in patients affected by
rheumatoid arthritis, inflammatory bowel disease, or in HIV-infected
individuals [78
79
80
81
]. In chronic obstructive pulmonary
disease, circulating leptin levels have been reported to be either
physiologically regulated or related to the inflammatory status
[82
, 83
]. Furthermore, in patients affected
by chronic heart failure, either increased or inappropriately low
plasma leptin levels have been reported [84
,
85
]. More consistent data exist on the association of
circulating leptin levels with hypertension, particularly essential
hypertension, independent of body mass index [86
87
88
89
].
It should be noted that the studies reported above analyzed only
systemic circulating leptin levels. However, as with other regulators
of the inflammatory response, leptin function may be modulated by local
leptin concentration, the ratio between free and bound leptin, the
expression of different forms of the receptors, the ratio between
signaling and non-signaling receptors, and the presence of specific
inhibitors. These factors all have to be taken into account to evaluate
the possible role of leptin in human disease. For example, although
total circulating leptin levels increase significantly in pregnant
women, this is mostly due to a rise in bound leptin, with no
alterations in the levels of free leptin [90
].
Leptin and the anorexia of inflammation
Anorexia is commonly associated with local or systemic
inflammatory conditions [91
]. Leptin decreases food
intake and leptin levels are elevated in experimental models of
infection and inflammation. Therefore, it was quite obvious to
hypothesize that leptin could mediate the anorexia of inflammation.
However, leptin is not responsible for the anorexia induced by
administration of LPS, TNF-, or turpentine in mice. In fact, no
correlation between anorexia and leptin levels during inflammation has
been observed [64
, 66
]. Moreover,
ob/ob mice and fa/fa rats
are even more susceptible to LPS-, TNF--, or IL-1-induced anorexia
than their lean littermates [92
93
94
]. In addition,
leptin does not seem to be responsible for tumor-induced anorexia in
rat models of hepatoma and lung carcinoma [95
].
Therefore, in animals leptin is not responsible for the anorexia of
inflammation. In addition, no correlation between leptin and cachexia
has been reported in patients affected by chronic heart failure, AIDS,
or cancer [80
, 81
, 85
,
96
].
However, a link between leptin-induced anorexia and the cytokine system
exists. Luheshi and colleagues demonstrated that administration of
leptin increased levels of IL-1ß in the hypothalamus in the rat. The
effect of leptin on food intake and body temperature was abolished by
administration of the IL-1 inhibitory protein IL-1 receptor antagonist
(IL-1Ra) and was absent in IL-1 receptor-deficient mice
[97
]. It thus appears that some of the effects of leptin
in the central nervous system are mediated through activation of the
IL-1 system, a typical feature of the inflammatory response.
|
EFFECTS OF LEPTIN ON IMMUNITY, INFLAMMATION, AND HEMATOPOIESIS
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|---|
Regulation of cytokine production by leptin
Leptin directly regulates the production of several cytokines
in vitro. Lord and colleagues reported a major role for
leptin in the modulation of T cell-derived cytokines
[28
]. Leptin increased IL-2 and interferon-
(IFN-)
production while decreasing IL-4 levels, in the course of a mixed
lymphocyte reaction (MLR). Therefore, leptin may play an important role
in the regulation of the T helper (Th)1/Th2 balance. Leptin also
modulates cytokine production from monocytes/macrophages. An increase
in LPS-induced production of TNF-, IL-6, and IL-12 in murine
peritoneal macrophages and human monocytes has been reported
[98
, 99
]. In addition, leptin both induces
and up-regulates production of IL-1Ra in the murine macrophage cell
line RAW 264.7 [100
]. Furthermore, leptin induces mRNA
expression for transforming growth factor ß (TGF-ß) in rat
glomerular endothelial cells [32
]. In human umbilical
vein endothelial cells (HUVEC), leptin induces production of the
chemokine monocyte chemoattractant protein-1 (MCP-1)
[101
].
In vivo, the role of leptin in the regulation of cytokine
production has been studied primarily in leptin-deficient mice
(ob/ob) and in leptin receptor-deficient mice
(db/db) and rats (fa/fa)
injected with LPS. Either increased, decreased, or unchanged levels of
TNF- have been observed in ob/ob mice and
fa/fa rats compared to their lean littermates
[98
, 100
, 102
]. IL-6
production was slightly decreased in both ob/ob
mice and fa/fa rats, whereas levels of IL-1ß,
IFN-, and the chemokine macrophage inflammatory protein 1 were
not affected by leptin deficiency [98
, 100
,
102
]. Serum IL-10 and IL-1Ra levels were decreased in
ob/ob mice injected with LPS, as was the hepatic
expression of IL-10 and IL-12 in LPS-treated
fa/fa rats [100
,
102
]. In a study evaluating the hepatic response of
ob/ob mice to the administration of P.
acnes and LPS, increased hepatic expression of IL-12, IL-18, and
IFN- associated with reduced levels of IL-4 and IL-10 was reported
[103
]. The disparate results obtained in in
vivo experiments evaluating the role of leptin in the cytokine
response to LPS are likely due to differences in the models studied
(high- versus low-dose LPS, pre-sensitization models versus direct
administration, etc.). However, despite the lack of agreement on the
role of leptin in cytokine production after LPS administration in
vivo, it is clear that leptin deficiency is associated with an
increased sensitivity to LPS-induced toxicity (see below).
In ob/ob mice, administration of T
cell-activating stimuli leads to a markedly reduced production of
TNF- and IL-18, but not of IL-12 and IFN- [104
].
This decreased production of TNF- and IL-18 is associated with
protection from T cell-mediated liver toxicity and is probably due to
the T cell atrophy observed in ob/ob mice (see
below).
Despite its structural and signaling similarities with the IL-6 family
of cytokines, leptin does not induce an acute-phase response when
administered to mice. However, at the dose of 5 mg/kg, leptin augments
IL-1-induced corticosterone and IL-6 production, two effects typically
observed after administration of different members of the IL-6 family
[105
, 106
].
Effects on phagocytic function
Only a few studies report on the role of leptin in the regulation
of phagocytosis. In vitro, leptin enhances the phagocytic
activity of murine peritoneal and bone marrow-derived macrophages
against Leishmania major and Candida
parapsilopsis [31
, 98
]. Accordingly,
the phagocytic function of Kupffer cells is decreased in
fa/fa rats [102
]. However, a
different report demonstrated increased superoxide and hydrogen
peroxide production, as well as augmented cyclooxygenase-2-dependent
production of prostaglandin E2 in macrophages obtained from
ob/ob mice [107
]. These data
suggest that leptin may actually down-regulate the activation of
monocytes/macrophages.
Proliferative and anti-apoptotic activities
Leptin displays proliferative and anti-apoptotic effects in a
variety of cell types. In vitro, leptin enhances the
alloproliferative response of human peripheral blood lymphocytes by
acting on T lymphocytes [28
]. Naive and memory T cells
are differentially affected by leptin, which mainly regulates primary T
cell responses. For example, T cells from umbilical cord blood are
activated by leptin, whereas the presence of memory T cells in an MLR
reduces the enhancing effect of leptin on proliferation
[28
]. Leptin also enhances phytohemagglutinin- and
concanavalin A-induced proliferation of human T lymphocytes and
increases the expression of the activation markers CD69, CD25, and CD71
in both CD4+ and CD8+ cells
[29
]. Leptin exerts anti-apoptotic activities on murine
thymocytes cultured in the presence of dexamethasone
[108
], possibly through the maintenance of Bcl-2
expression [109
]. Similar to IL-6, a role for STAT-3
activation is likely in the proliferative and anti-apoptotic effects of
leptin [110
]. The role of leptin in the regulation of
proliferation and apoptosis of T lymphocytes is instrumental in the
development of the T cell atrophy of ob/ob and
db/db mice (see below).
Leptin stimulates proliferation of cultured tracheal epithelial cells,
lung squamous cells, and embryonic and pancreatic cell lines
[34
, 40
, 57
]. A role for
leptin in glomerulosclerosis is suggested by its stimulatory effect on
glomerular endothelial cell proliferation, particularly in the presence
of angiotensin II [32
].
Leptin has proliferative and anti-apoptotic activities in leukemic
cells, which express the long and short forms of OB-R
[30
, 111
]. In primary acute myeloid
leukemia cells, leptin induces low-level proliferation and increases
proliferation induced by GM-CSF, IL-3, and stem-cell factor (SCF),
while reducing apoptosis induced by cytokine withdrawal in MO7E and
TF-1 cells [30
].
Hematopoiesis
That leptin may participate in the regulation of hematopoiesis is
suggested by the alterations observed in ob/ob
and db/db mice. Colony-forming assays demonstrate
a deficit in lymphopoietic progenitors in db/db
mice, which are also unable to completely recover their lymphopoietic
populations after an irradiation insult [112
].
Db/db mice also have defective erythrocyte
production in the spleen, although the concentration of peripheral
blood erythrocytes is normal [112
]. A decrease in the
number of circulating lymphocytes and an increase in monocytes is
present in ob/ob mice [104
].
Furthermore, a correlation between leptin levels and leukocyte counts
in humans has been reported [113
, 114
].
A direct role for leptin in hematopoiesis has been suggested based on
the expression of OB-Rb in yolk sac, fetal liver, bone marrow, and
CD34+ cells, as well as lympho-hematopoietic, fetal
stromal, and megakaryocytic cell lines [27
,
30
, 31
, 112
]. However, data on
the role of leptin in the direct regulation of hematopoietic cell
proliferation are somewhat contradictory. Leptin has been reported to
induce granulocyte-macrophage colony formation from murine bone marrow
cells and to enhance the activity of SCF and erythropoietin
[115
]. In addition, a proliferative effect of leptin on
BAF-3 and on multilineage progenitor cells has been observed
[112
]. On the other hand, Gainsford and colleagues
[31
] were unable to demonstrate a proliferative role for
leptin in murine or human marrow cells, even when leptin was used in
combination with GM-CSF, G-CSF, M-CSF, IL-3, IL-6, Flk-ligand,
erythropoietin, SCF, or thrombopoietin.
In conclusion, the demonstration of a direct role for leptin on the
proliferation of hematopoietic progenitors is still controversial.
However, in vivo data strongly suggest a regulatory role,
possibly indirect, for leptin in hematopoiesis, particularly on the
lymphocytic lineage.
Angiogenesis and atherogenesis
Endothelial cells express the long form of the OB-R, which
mediates leptin-induced proliferation [25
,
33
]. Exposure of endothelial cells to leptin leads to
tyrosine phosphorylation of the OB-R and activation of STAT-3 and
Erk1/2 [25
, 33
]. Both in vitro
and in vivo assays demonstrate that leptin has angiogenic
activities, inducing neovascularization and formation of capillary-like
structures [25
, 33
]. However, leptin does
not increase angiogenesis in vivo in the skin of
ob/ob mice [116
].
In HUVEC, leptin increases the generation of reactive oxygen
intermediates and MCP-1 by activating JNK, AP-1, and NF-
B pathways,
therefore exerting potential atherogenic effects [101
].
Furthermore, leptin promotes aggregation of human platelets when used
at concentrations corresponding to those observed in obese individuals
[26
].
|
LEPTIN DEFICIENCY CAUSES A DYSREGULATION OF THE IMMUNE AND
INFLAMMATORY RESPONSE
|
|---|
As indicated above, a multifactorial syndrome characterized by
obesity, diabetes, infertility, and various hormonal imbalances is
present in ob/ob and db/db
mice and in fa/fa rats. Dysregulation of the
immune and inflammatory response is also observed in these animals and
is primarily characterized by reduced T cell numbers, altered
responsiveness of the monocyte/macrophage system, and impaired wound
healing (Fig. 2
).
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Figure 2. Immune alterations associated with leptin deficiency or low leptin
levels. Effect of exogenous leptin. Reduced numbers of T lymphocytes
and suppressed responsivity to T cell-activating stimuli are present in
both leptin-deficient (ob/ob) mice and in starved
mice, which have low leptin levels. Under the same conditions, a
hyperresponsiveness of the monocyte/macrophage system is observed.
Administration of exogenous leptin alone normalizes most of the
observed immunological abnormalities associated with leptin deficiency
or low leptin levels.
|
|
T lymphocytes
Consistent with the proliferative activity of leptin on T cells,
thymic atrophy is present in ob/ob and
db/db mice and in fa/fa
rats [108
, 117
118
119
120
121
]. A decrease in the
number of circulating lymphocytes and an increase in monocytes is also
present in ob/ob and db/db
mice [104
, 122
]. In addition, the number of
CD4+ NK T cells is selectively reduced in the liver of
ob/ob mice [103
]. The ability of
leptin to protect leptin-deficient animals from thymic atrophy probably
involves a direct anti-apoptotic mechanism [108
].
Ob/ob and db/db mice
exhibit defective T cell-mediated immunity, as demonstrated by an
impaired delayed-type hypersensitivity reaction (DTH), suppression of
skin allograft rejection, and inhibition of footpad swelling induced by
recall antigens [117
, 120
]. Furthermore,
ob/ob mice are protected from liver damage
induced by activation of T cells and production of TNF- and IL-18
[104
]. Exogenous leptin restores the responsiveness of
ob/ob mice to T cell-activating stimuli and
normalizes their lymphocyte and monocyte populations
[104
, 108
]. It is worth noting that obese
individuals receiving long-term (4 weeks) subcutaneous injections of
leptin at 0.3 mg/kg/day developed skin reactions characterized by
erythema, induration, pruritus, and rash at the injection site (the
reactions were milder or absent in subjects receiving lower doses of
leptin). The adverse effects were severe enough to convince the data
monitoring committee of the clinical trial to halt that part of the
study [123
]. Although not studied during the trial,
activation of cell-mediated immunity by leptin may have contributed to
skin reactions observed at the site of leptin administration.
Monocytes/macrophages
In contrast to the reduced responsiveness of
ob/ob and db/db mice to T
cell-activating stimuli, an increased sensitivity to
monocyte/macrophage-activating stimuli is observed in the absence of
leptin. In particular, ob/ob mice are more
susceptible to LPS- or TNF--induced lethality than their lean
littermates [93
, 100
].
Ob/ob mice and fa/fa rats
also display enhanced hepatotoxicity after administration of LPS
[102
, 104
]. Furthermore, an enhanced
pyrogenic response to IL-1 is present in fa/fa
rats [124
]. The mechanism responsible for the increased
sensitivity of ob/ob mice and
fa/fa rats to LPS, TNF-, and IL-1 remains
unclear. It should be noted that, in addition to reduced thymic and
circulating lymphocytes, a fourfold increase in the number of
circulating monocytes is present in ob/ob mice
[104
]. In addition, prevention of lymphocyte apoptosis
is associated with improved survival in a murine model of sepsis,
suggesting a critical role for lymphocytes in the regulation of
susceptibility to LPS [125
].
Wound healing
Ob/ob and, particularly,
db/db mice spontaneously develop a syndrome
resembling type 2 diabetes. One characteristic of this syndrome is
impaired wound healing. Both ob/ob and
db/db mice show a delayed dermal healing response
[126
, 127
]. Although the cause of this
impairment is not clear, cellular infiltration, formation of
granulation tissue, and neovascularization are reduced in
db/db mice compared with their wild-type
littermates [127
]. Administration of leptin, either
systemically or topically, accelerates wound healing in
ob/ob mice, without affecting angiogenesis
[116
]. Similar results are obtained by administration of
basic fibroblast growth factor to db/db mice
[127
].
|
LEPTIN AND THE IMMUNE SUPPRESSION OF STARVATION
|
|---|
The multifactorial syndrome observed in
ob/ob and db/db mice
closely resembles the neuroendocrine-immune response to starvation
[11
]. Leptin levels fall sharply with the onset of
starvation, and administration of leptin effectively prevents
neuroendocrine alterations, which include changes in gonadal, adrenal,
and thyroid hormones in male mice and delay in ovulation in female mice
[11
]. However, starvation also suppresses the immune
system, with a particularly marked effect on T cell-mediated responses
[128
129
130
] (Fig. 2)
. Reduced thymus weight and IL-2
production, associated with increased susceptibility to infections, are
characteristically observed in malnourished individuals
[129
, 131
, 132
]. Increased
susceptibility to infections has also been reported in leptin-deficient
individuals [10
]. Malnutrition also leads to wound
healing impairment and, possibly, to hyperactivation of the
monocyte/macrophage system [133
, 134
].
These features of malnutrition also occur in
ob/ob and db/db mice,
although the susceptibility to infection of these animals has not been
thoroughly studied as yet.
Most of the neuroendocrine and immune alterations associated with
fasting can be reversed by administration of leptin. In mice, exogenous
leptin prevents suppression of cell-mediated immunity, development of
thymic atrophy, and reverses the increased susceptibility to the lethal
effects of LPS or TNF- [28
, 108
,
135
].
|
CONCLUSIONS
|
|---|
Leptin, initially discovered as a regulator of food intake and
energy expenditure, is emerging as a pleiotropic molecule involved in a
variety of physiological and pathological conditions. The immune system
is one of the targets of leptin activity, as demonstrated by in
vitro experiments and by the immune alterations observed in
leptin- and leptin receptor-deficient animals (Fig. 3
). Starvation and malnutrition, two conditions characterized by low
leptin levels, are also associated with alterations of the immune
response, which in experimental studies can be reversed by
administration of leptin alone. Although recent important contributions
have been made to this field, future studies should address the
potential role of leptin in the regulation of autoimmune and/or
inflammatory conditions.
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Figure 3. Effects of leptin on the immune and inflammatory response. Adipocytes
are the most important producers of leptin. Different types of cells
involved in the immune and inflammatory response express the long form
of OB-R, which allows leptin to modify their response to various
stimuli. Leptin alters the balance of T cell-derived cytokines in favor
of a Th1 response. In vivo, leptin regulates inflammation,
playing an inhibitory role on monocyte/macrophage-mediated responses
while exerting a permissive role on lymphocyte-mediated inflammation.
Leptin either induces or increases cell proliferation of different cell
types, including T lymphocytes, CD34+ cells, leukemia
cells, and endothelial cells. Leptin also acts as an inhibitor of
glucocorticoid-induced apoptosis in T lymphocytes and of apoptosis
induced by cytokine withdrawal in leukemia cells. The anti-apoptotic
role of leptin combined with its permissive effect on the proliferation
of T lymphocytes is likely responsible for the lymphoid atrophy
observed in leptin-deficient animals and during starvation or chronic
malnutrition.
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ACKNOWLEDGEMENTS
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We wish to thank Drs. Charles A. Dinarello, Kenneth R. Feingold,
Carl Grunfeld, and Leland Shapiro for their support and for critically
reviewing the manuscript.
Received June 2, 2000;
accepted June 2, 2000.
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ABSTRACT
THE DISCOVERY OF LEPTIN...
