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(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{dagger}

* Department of Medicine, University of Colorado Health Sciences Center, Denver; and
{dagger} 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


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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
 
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 ({lambda}{varepsilon}{pi}{tau}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 ].


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LEPTIN IS A PLEIOTROPIC MOLECULE
 
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.


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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.

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 ].


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  		Table 1. Peripheral Expression of the Long Form of the Leptin Receptor, OB-Rb

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
 
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 {alpha} (TNF-{alpha}) 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-{alpha} 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-{alpha} 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-{alpha}, 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-{alpha}-, 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.


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EFFECTS OF LEPTIN ON IMMUNITY, INFLAMMATION, AND HEMATOPOIESIS
 
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-{gamma} (IFN-{gamma}) 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-{alpha}, 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-{alpha} 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-{gamma}, and the chemokine macrophage inflammatory protein 1{alpha} 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-{gamma} 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-{alpha} and IL-18, but not of IL-12 and IFN-{gamma} [104 ]. This decreased production of TNF-{alpha} 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-{kappa}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 ].


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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-{alpha} 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-{alpha}-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-{alpha}, 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 ].


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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-{alpha} [28 , 108 , 135 ].


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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
 
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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Leptin and the Proinflammatory State Associated with Human Obesity
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Leptin Induces Growth Hormone Secretion from Peripheral Blood Mononuclear Cells via a Protein Kinase C- and Nitric Oxide-Dependent Mechanism
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Leptin and Wound Inflammation in Diabetic ob/ob Mice: Differential Regulation of Neutrophil and Macrophage Influx and a Potential Role for the Scab as a Sink for Inflammatory Cells and Mediators
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E. Xiao, L. Xia-Zhang, N. R. Vulliemoz, M. Ferin, and S. L. Wardlaw
Leptin Modulates Inflammatory Cytokine and Neuroendocrine Responses to Endotoxin in the Primate
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Hyperleptinemia, Visceral Adiposity, and Decreased Glucose Tolerance in Mice with a Targeted Disruption of the Histidine Decarboxylase Gene
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Decreased Plasma Leptin Concentrations in Tuberculosis Patients Are Associated with Wasting and Inflammation
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Age-Associated Loss of Bone Marrow Hematopoietic Cells Is Reversed by GH and Accompanies Thymic Reconstitution
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Leptin Directly Induces the Secretion of Interleukin 1 Receptor Antagonist in Human Monocytes
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Leptin Enhances the Calcification of Vascular Cells : Artery Wall as a Target of Leptin
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