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Leptin and the immune system: how nutritional status influences the immune response

European Cytokine Network. Volume 11, Number 1, 7-14, March 2000, Revue


Author(s) : G. Matarese, Laboratorio di Immunologia, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli “Federico II”, via S. Pansini, 5 - 80131 - Napoli, Italy. gmatarese@napoli.com.

Summary : Several observations suggest the presence of an interaction between immune and the endocrine systems. Leptin is an adipocyte-derived hormone, that belongs structurally to the long-chain helical cytokine family such as interleukin-2 (IL-2), interleukin-12 (IL-12), growth hormone (GH), and signals by a class I cytokine receptor (Ob-R). This cytokine represents an important link between fat mass on the one side and the regulation of energy balance and reproductive function on the other. Indeed, obese leptin-deficient ob/ob mice display low body temperature, hyperphagia, infertility and evidence of immune defects with lymphoid organ atrophy, mainly affecting thymic size and cellularity. Acute starvation, associated with decreased leptin levels, causes thymic atrophy and reduces the delayed type hypersensitivity (DTH) reaction to antigens in normal mice, resembling that observed in ob/ob mice. Leptin replacement reverses the immunosuppressive effects of acute starvation in mice. Leptin differentially affects the in vitro proliferation and cytokine production by naive and memory T cells, increasing IL-2 secretion and proliferation of naive T cells, while inducing IFN-g production in memory T cells with little effect on their proliferation. Presence of leptin seems to be necessary for the induction and mainteinance of the pro-inflammatory Th1 immune response. These findings support the hypothesis that leptin plays a key role in linking nutritional state to the T cell function. According to this view, leptin might represent an important target for immune intervention in a variety of pathophysiological conditions.

Keywords : leptin, immune response, T-lymphocytes, nutritional status, inflammation.




Undernutrition has been associated with impairment of cell-mediated immunity. Indeed, it predisposes to death in infectious diseases in man and laboratory animals [1, 2]. The recent cloning of the obese gene product, leptin, has determined fundamental insight into the understanding of the regulation of food intake, basal metabolism and energy expenditure [3]. Initially, leptin was considered an anti-obesity hormone. According to this view, rising levels of leptin signal to the brain that excess of energy is being stored as fat. This determines decrease in food intake, increase in energy expenditure and stabilization of body weight [4-7]. Experimental evidence has shown a number of other effects of leptin on peripheral tissues such as ovary, blood vessels, bone marrow, and more recently T-lymphocytes [5, 8-11]. Specifically, leptin has been suggested to function as a prominent regulator of immune system activity, linking the function of T-lymphocytes to nutritional status. This review describes several of the key aspects of leptin in the regulation of food intake and T-lymphocyte functions, and summarizes the current state of knoweldge about how these signals interact to form the complex circuit controlling body weight and immune response.


In 1994 Friedman and colleagues reported the cloning of the obese gene and named the encoded protein leptin [3]. Leptin is a 167 amino acid protein, synthesized and secreted primarely by adipose tissue. Structurally, it is a long-chain helical cytokine similar to IL-6, IL-11, IL-12, LIF, G-CSF, CNTF, and oncostatin-M [12]. Leptin has a 67% sequence homology in species as diverse as human, gorilla, chimpanzee, orangutan, rhesus monkey, dog, cow, pig, rat and mouse [13]. This protein is produced by adipose tissue in proportion to fat mass and at low levels by other tissues such as skeletal muscles, placenta and stomach [5, 14, 15]. Once released into circulation, it subsequently acts on the brain to inhibit food intake, stimulates thermogenesis and modulates other physiological actions [16], including lipid metabolism [17], hematopoiesis [10], pancreatic beta cell and ovarian function [5]. Furthermore, leptin shows a marked gender dimorphism in serum concentrations, being higher in females than in males with the same body fat mass [18].

A variety of stimuli can rapidly induce leptin expression and secretion in mice and humans, for example the inflammatory mediators TNF-alpha and IL-1 [19-21]. Indeed, leptin is produced during acute phase response and represents an early reactant together with C-reactive protein [22, 23] and IL-1 during systemic inflammation and fever [24-26]. Despite its heterogeneous biological effects in extraneural tissues, the leptin receptor (Ob-R) is expressed predominantly in the hypothalamus. It was first cloned from mouse choroid plexus [27] and its primary structure shows homologies to the class I cytokine receptors family, such as IL-6R, LIFR, gp130, and G-CSFR [27, 28]. The Ob-R gene encodes for five alternatively spliced forms: Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd and Ob-Re. Only Ob-Rb, known as the long-form, contains several motifs required for signal trasduction,whereas the other forms lack some or all of these motifs. The short-splice forms of Ob-R are expressed in several tissues and seem unable to signal into the cell. Their role is still unclear: they may function in the transport of leptin across the blood-brain barrier and for leptin degradation [5]. Ob-Rb is usually expressed at high levels in hypothalamic neurons and in other cell types, including T cells [11], vascular endothelial cells [8, 9], and the CD34+ hematopoietic bone marrow precursor [10]. The binding of leptin to its receptor increases the activity of the receptor-associated kinases of the Janus kinase family (JAK), that contributes to the phosphorylation of the DNA-binding activity of signal trasducer and activator of transcription such as STAT1, STAT3, and STAT5 [29, 30]. Leptin also appears to reduce the intracellular levels of cAMP by the activation of cAMP-phosphodiesterases [31]. STAT proteins and cAMP are very important regulators of cell cycle, proliferation and lymphocyte functions.

Leptin's structural similarities with the helical cytokines, the great homology of its receptor with the class I cytokine receptor family, and the expression of the Ob-Rb on CD4+ T cells are factors currently promoting extensive studies about the possible role of leptin in the regulation of the T cell-mediated immune response.


The mutation of the leptin gene or of the leptin receptor gene causes obesity in mice weighing three times more than normal mice, even when pair fed with the same diet, and showing a five-fold increase in body fat content [5]. Both leptin deficient (ob/ob) and leptin receptor deficient (db/db) mice display many abnormalities seen in starved animals, including decreased body temperature, hyperphagia, decreased energy expenditure, decreased immune function, and infertility [5]. Ob/ob mice are unable to produce functional leptin because of a non-sense mutation of the obese gene resulting in the synthesis of a truncated protein, that is apparently degraded in the adipocyte [32]. In db/db mice the mutation of the Ob-Rb gene creates a new splice donor that inserts a premature stop codon into the Ob-Rb 3'-end, resulting in the replacement of the Ob-Rb long isoform by the short Ob-Ra isoform [33]. The study of this mutation has already established the Ob-Rb long isoform as being critical for leptin function [28].

From an immunological point of view, leptin deficient mice have been described to display reduced cellularity in spleen and thymus, in the cell-mediated pro-inflammatory immune response, and in antibody production [34]. Similar evidence has been found also in db/db mice [35, 36]. In these mice increased infection susceptibility and reduced ability to reject primary allogeneic skin grafts have been described. These immune defects could partially be considered as consequence of immunosuppressive effects of diabetic hyperglycemia and high cortisol levels present in these animals. Food restriction experiments that reduce plasma cortisol and hyperglicemia, are not able to reverse these immune defects. Leptin replacement completely restores a normal immune response in these mice, suggesting that leptin defect is directly involved in these immune system abnormalities [11].

Studies on ICAM-1/Mac-1 knockout mice reveal other important aspects [37]. These mice show many immunological defects and altered migration of lymphocytes and monocytes from the blood stream into peri-pheral tissues. Furthermore, they present increased infection susceptibility and reduced T cell activation under antigen specific stimulation. Interestingly, late in their life they develop obesity with increased body weight and body fat percentage, even when they are fed with the same diet as the normal littermate controls. This obesity seems to be due to the role of leucocytes in the regulation of fat deposition in the periphery and of their defected migration. These results can be considered as a "reverse image" of what we have observed about the influence of the adipose tissue, producing leptin, on the lymphoid tissue. In other words, lymphocytes can be affected in their functions by adipocytes and in turn lymphocytes and monocytes can influence fat deposition in the peri-phery with their presence in the tissues. Consequently, the immuno-endocrine cross-talk can be very important for the adipocyte-lymphocyte homeostasis.


Initially the obese gene product, leptin, was considered an anti-obesity hormone. According to this view, increasing leptin serum concentrations signal to the brain and other sites that excess energy is being stored as fat, and this means that there is enough food availability. This signal determines increased energy expenditure, decreased food intake, and stabilization of body weight. This mechanism may contribute to the long-term stabilization of body weight over time in many animals. Over the last few years increasing evidence supports the alternative view that leptin signals to the brain that energy stores are sufficient [16]. Starvation is well known to threaten survival of individuals, and numerous systems have been developed to defend against it. Starvation induces reduction of fertility, of basal metabolism, decrease in thyroid and sex hormones, and finally activation of the stress response trough the hypothalamic-pituitary-adrenal axis (HPA) [38]. All these systems are engaged to save energy for vital functions such as central nervous system and heart metabolism. In this context plasma leptin levels are dynamic, rise and fall according to the body fat, and the energy state changes. Acute fasting leads to a rapid reduction in plasma concentrations in both humans and mice, that is disproportionate to the reduction in body fat that results from the starvation [39]. Food consumption has the opposite effect on plasma leptin levels [40]. In response to feeding or administration of gastrin, leptin is rapidly secreted by stomach where it is produced and stored [14]. This results in acute elevation of leptin levels, that seem to be necessary for the correct reproductive and immune function, together with the basal adipocytes-derived leptin. Reproductive and immune systems can be rapidly tuned, and modulated by the presence of leptin mainly because they are less immediately essential systems compared to vital functions such as brain and heart.

Finely tuned cognate immune response requires large-scale clonal expansion of cells and antibody-synthesis. The inhibition of this system can be important in saving energy stores during starvation. Rapid fall in leptin levels seems to block the optimal function of CD4+ T cells. Leptin replacement during starvation is able to blunt the immunosuppression associated to food deprivation; indeed DTH inflammatory response reduced during fasting can be restored with leptin replacement during starvation (Table 1) [41].

In humans, obesity is rarely associated with genetic deficiency in the leptin system [42]. Indeed, the vast majority of obese humans do not have mutations in the leptin or leptin-receptor genes, but have high levels of circulating leptin because of their increased body fat mass [43]. By analogy with type II diabetes mellitus, these individuals may have functional leptin resistance, an impaired central and peripheral responsiveness to circulating leptin [5]. More recently, a few obese gene mutations in members of a Turkish family [44] and mutations in the leptin receptor in a French family with massive obesity and reproductive abnormalities have also been described [45]. The classical hypercortisolaemia, cold intolerance and severe diabetes of ob/ob mice are not observed in leptin deficient humans. Interestingly, these patients show alterations in immunity, probably related to low total T cell counts and functionally impaired cell-mediated immune response, resembling that observed in ob/ob mice. Furthermore, the dramatic reduction in leptin levels significantly predisposes these people to death the infectious diseases in early childhood. Indeed, the idea that the reduced survival is due to leptin deficiency is supported by observing very high frequency of death of the leptin-deficient children compared to normal weight children in the youngest generation of the same Turkish family, all raised in the same enviroment and with the same access to nutrients [44].

Low body weight in humans and rodents has been associated with increased frequency of infectious diseases and they are the most common cause of secondary immunodeficiency worldwide [2, 46]. In humans, low body weight and consequent low leptin levels are typically present in two conditions: anorexia nervosa and malnutrition, both associated with immune deficits [46, 47]. It is problematic to completely dissect all the potential factors involved in these conditions. In fact they range from the broad consequences of protein caloric malnutrition [48] to deficiency of single micronutrients, such as zinc [49], selenium [50], vitamins A [51], C, and E, all necessary for immune fuction. To these elements must now be added the potential effects of leptin deficiency. Leptin seems to be a key mediator of the immune suppression induced by starvation, directly acting on CD4+ T cell functions and indirectly affecting the presence of other hormones. Indeed, it prevents the raising of glucocorticoids produced during starvation and the falling of growth hormone and thyroid hormones [38], each of which may mediate immune suppression indirectly [41]. Both leptin and micronutrients deficits have been associated with delayed development of the immune system during fetal growth [52] and this also causes extreme increase in frequency of death for infections early in life [1]. Since 1810 Menkell linked malnutrition to lymphoid tissue atrophy, mainly affecting the thymus, and nutritional thymectomy became a common medical term [53-55]. Leptin also prevents thymic atrophy if administred during starvation [56].

Linked to a functional but not real leptin deficiency is the most common form of human obesity, associated to central/peripheral leptin resistance [5]. Epidemiological studies show increase in infection frequency in these patients mainly affecting the respiratory and urinary tracts [57, 58]. Many factors contribute to this, such as the alteration in the normal dynamics in lungs ventilation and in urinary flow from kidneys due to the excess in body fat. Another of these factors can also be the leptin-receptor desensitization expressed on CD4+ T-lymphocytes due to the very high leptin levels, finally perceived from T cells as a condition of leptin deficiency. This as well as the real leptin deficiency observed in malnutrition or genetic leptin deficiency, can cause many of the immune deficits observed in each of these pathologic conditions.


The first evidence of a possible involvement of leptin in the modulation of the immune system derives from the study of its structure and of its receptor. As previously shown, leptin belongs to the vast class of long helical cytokines and its receptor is homologous to the class I cytokine receptors [5]. These similarities suggest the possible role of leptin in immune system homeostasis. Furthermore, the analysis of the immune functions of both ob/ob and db/db mice shows impaired in vitro T cell-mediated immunity with low IL-2 and IFN-gamma production and decreased DTH responses in vivo, as compared to normal, age matched littermate controls. Chronic leptin replacement in ob/ob mice restores the T cell function, increasing the secretion of the pro-inflammatory cytokines IL-2 and IFN-gamma as well as the DTH response in vivo. These effects are not seen when leptin is injected into db/db animals that lack the leptin receptor, suggesting that leptin may have a direct and specific effect on T cells [11, 34-36].

Leptin's effects on human CD4+ T-lymphocytes have been extensively investigated in vitro. Addition of physiological concentrations of leptin to mixed-lymphocyte reactions (MLRs) induces a marked dose-dependent increase in the proliferative responses of highly purified CD4+ T-lymphocytes. Both human naive (CD45RA+) and memory (CD45RO+) CD4+ T cells express Ob-Rb mRNA. Differential effects of leptin have been shown on proliferative responses and cytokine profiles of these two T-lymphocyte subsets. In the presence of leptin naive cells increase their proliferative responses and IL-2 secretion, while memory cells show substantial increase in IFN-gamma together with suppression of IL-4 secretion despite little effect on the proliferative responses. These results indicate that leptin may bias T cell responses towards a Th1 pro-inflammatory phenotype. None of the in vitro actions of leptin is seen when T-lymphocytes from db/db mice are used, confirming the specificity of these effects on T cell responses (Table 1) [11].

Pro-inflammatory cytokines such as IFN-gamma can upregulate adhesion molecules and certain accessory molecules can bias T cell response towards the production of specific cytokines. Human PBMCs and murine splenocytes when incubated with leptin alone for 36-48 hours show marked cellular clumping but not when performed with db/db mice cells. These effects were mainly due to increased expression of the adhesion molecules ICAM-1 (CD54) and VLA-2 (CD49b) on CD4+ T cells (Table 1) [11].

In normal individuals, nutritional deprivation affects immune function and also rapidly reduces the amount of circulating leptin in mice and humans [38, 39]. DTH-response in normal mice results markedly reduced when 48 hours starvation is imposed at priming with the antigen. Exogenous leptin replacement during the 48 hours starvation is able to completely reverse this inhibition. These findings demonstrate that the presence of leptin in the microenvironment where immune responses take place is necessary for priming of T cells (Table 1) [11]. Clinical trials involving starvation to modulate the pro-inflammatory immune response in human autoimmune diseases have been recently reported [59, 60]. Rheumatoid arthritis (RA) patients after 7 days starvation and then refeeding, showed a significant decrease in erythrocyte sedimentation rate, C-reactive protein level, joint count, CD4+ and CD8+ counts and expression on T cells of activation markers (CD69) together with increase in IL-4 secretion. Starvation in RA patients determined a marked reduction of leptin levels with concomitant decrease in activation of CD4+ T cells and an increase in the number and/or the function of IL-4 producing Th2 cells. This confirms that factors such as leptin associated with loss of body weight during acute starvation, appear to have an inhibitory effect on CD4+ T-lymphocyte activation when they are dramatically reduced.

Lymphoid atrophy is a well recognized consequence of nutritional deprivation. The thymus is particularly sensitive to food deprivation and has been designated the "barometer of malnutrition" [53-55]. Leptin seems to play a pivotal role in the pathogenesis of starvation-induced thymic atrophy. Indeed, 48 hours acute starvation in normal mice, causes a dramatic fall in the total thymocyte count particularly affecting the CD4+ CD8+ double positive and the CD4+ CD8­ single positive compartments when compared to ad-libitum fed mice [56]. Leptin replacement during starvation completely protected against these starvation induced changes in thymocyte numbers and subpopulation proportions (Table 2) [56]. The reduction in thymic size and cellularity is related structurally to a loss in the cortical thymocytes with an increase in the number of apoptotic cells. These effects were completely blunted by leptin injection. Also splenic CD4+ lymphocytes seem to be sensitive to starvation; leptin treatment also restored T cell counts in this organ [56].

Ob/ob mice present marked reduction in thymic cellularity particularly affecting CD4+ CD8+ double positive cells. Leptin treatment of ob/ob mice has a significant impact on the thymus. Specifically, it increases the total thymocyte counts and the single subpopulations of thymic cells. Furthermore, leptin treatment in vivo reduced the level of apoptosis in thymocytes from ob/ob mice to that observed in normal wild-type control mice [56]. These results are also confirmed in vitro by dexamethasone-induced apoptosis assays of normal mice thymocytes. Addition of exogenous leptin to the cultures during the assay completely prevented thymocyte apoptosis. The ability of leptin to protect against thymic athrophy also seems to involve a direct anti-apoptotic mechanism. Whether these protective effects are mediated directly by leptin action on the thymus or by reduction of glucocorticoids both in starved animals or ob/ob mice, needs further investigations and cannot be excluded [61]. However, reduced leptin concentrations are pivotal also in explaining starvation-induced lymphoid atrophy.


The increasing evidence regarding the role of leptin in bone marrow precursor development [10] and T cell function [11, 56], can support a novel view about the role of adipose tissue in the final balance of the T cell-mediated immune response. Adipocytes so far have been mainly considered as long term energy storage sites and as producers of cholesterol for steroid hormones synthesis. Adipose tissue is also present anatomically to protect many organs surrounding different districts of the body. Its presence has been mainly associated with its metabolic function and not with the important role of contributor for the T cell function and homeostasis. With the discovery of the novel effects of leptin on T-lymphocyte functions, it is possible to consider the adipose tissue, that surrounds lymph nodes, thymus and bone marrow, no longer just as a protective and energetic tissue but as a dynamic structure necessary for T cell activities. Its proteic product, leptin, creates a permissive microenvironment, that enables the immune system to function and to sustain an optimal pro-inflammatory immune response [11]. Heavy reduction in the adipocyte mass and consequently in leptin levels, determines the release of a negative signal, that impairs T cell priming and the production of pro-inflammatory mediators, such as IFN-gamma, necessary for the induction of a Th1 response. These findings give to adipose tissue a very important role not only in metabolism and steroidogenesis but also in the immune response. Conversely, leucocytes are belived to contribute to the adipose tissue metabolism, for their ability to influence fat deposition and the developement of obesity [37]. Better understanding of the cross talk between adipocytes and lymphocytes and the increasing mass of information on novel activities of these two cellular compartments will shed more light in the future on the complex immuno-endocrine network of the body.



The large number of studies performed to analyze the interactions among nutritional state, cytokines, and immunity indicate the extreme complexity of this cytokine network. Clinical trials are testing the efficacy of administration in humans of leptin as anti-obesity hormone [62]. Recent evidence from the literature shows that recombinant leptin in obese subjects, in which leptin resistance reigns, does not determine great weight reducing effects [63]. As expected, its efficacy seems to be higher in obese subjects with genetic leptin deficiency, representing a minority of the obese population [64]. With the increasing evidence of leptin effect on T cell, only clinical research will decide whether administration of leptin to malnourished or immunosuppressed individuals will be of therapeutic benefit. Beyond these cases, it remains uncertain whether leptin will find greater use in the treatment of obesity or in immunosuppressed individuals. Given leptin's multiplicity of activities [65-68] we belive that in the future, additional and unexpected consequences of leptin influences on immune function will emerge.

Acknoledgements. We would like to thank Dr. Antonio Di Giacomo, Dr. Veronica Sanna for critical reading of the manuscript. We are also particularly indebted to Prof. Serafino Zappacosta and Dr. Silvia Fontana for their constant enthusiastic support. The work is supported by the AISM (Associazione Italiana Sclerosi Multipla).


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