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Published in final edited form as: Brain Behav Immun. 2008 Oct 25;23(4):405–410. doi: 10.1016/j.bbi.2008.10.007

Three questions about leptin and immunity

Giamila Fantuzzi 1
PMCID: PMC2699448  NIHMSID: NIHMS110964  PMID: 18996468

Abstract

Leptin is a protein produced by adipocytes (and other cell types) that acts in the brain to regulate appetite and energy expenditure accordingly to the amount of energy stored in adipose tissue. Leptin also exerts a variety of other functions, including important roles as a regulator of immune and inflammatory reactions. The present article is not meant to be a comprehensive review on leptin and immunity, but rather highlights a few controversial issues about leptin's place in the complex network of mediators regulating immune and inflammatory responses. Three issues are discussed: 1) Where am I going, or What is the cellular target of leptin for modulation of immune responses?; 2) Where am I coming from, or Is the cellular source important in determining leptin's effects on immune responses?; and 3) What am I doing, or What are leptin's effects on immune and inflammatory responses?

Introduction

Leptin, a protein mainly secreted by adipocytes and therefore classified as an adipokine, was discovered in 1994 as the long sought-after satiety factor missing in obese ob/ob mice (Friedman, 2002), a strain arising from a spontaneous mutation and identified in 1950 in the Jackson Laboratories (Ingalls et al., 1950). The leptin receptor (OBR) was identified shortly thereafter and confirmed to be the gene mutated in obese diabetic db/db mice, a strain also arising from a spontaneous mutation at the Jackson Laboratories (Hummel et al., 1966). Obese Zucker fa/fa rats also have a missense mutation in OBR (Phillips et al., 1996). Further analysis revealed the existence of several isoforms of OBR (Tartaglia, 1997), which likely exert disparate physiological functions. The long form of OBR (OBRb), the only one capable of signaling through the Signal Transducer and Activator of Transcription (STAT)-3 pathway and the only isoform missing in db/db mice, is required for leptin's regulation of appetite, while the function of the short OBR isoforms is still under debate (Myers et al., 2008).

Leptin released from adipocytes enters the circulation and reaches appetite-regulating centers in the Central Nervous System (CNS), where it acts as a satiety factor by binding to and activating OBRb expressed on neurons. Thus, leptin relays to the brain information about the size of adipose stores, allowing for appropriate regulation of food intake and energy expenditure in concert with a series of other hormones and neurotransmitters. For a detailed review of the leptin system in the regulation of appetite see (Myers et al., 2008).

In addition to regulation of food intake, leptin also affects a variety of other physiological functions, including fertility, bone metabolism, immune responses and others. There appears to be a threshold effect for leptin, which broadly reflects the amount of energy stored in adipose tissue: below this critical threshold – which is likely different for the various systems regulated by leptin – the body perceives a state of starvation and reduces non-essential, energy-consuming functions (Grunfeld, 2002).

The interaction between leptin and the immune system is the focus of the present article. Excellent reviews have recently discussed various aspects of leptin's effects on immune and inflammatory responses and the reader is referred to these articles for a comprehensive coverage of this topic (Lam and Lu, 2007; Matarese et al., 2007). The present review will discuss three controversial issues in the interaction between leptin and immunity, specifically: 1) the cellular target(s) of leptin in modulating immune and inflammatory responses, 2) the cellular source(s) of leptin essential for immune responses, and 3) the overall effects of leptin on immunity and inflammation.

The three questions

Where am I going, or What is the cellular target of leptin for modulation of immune responses?

Leptin exerts its appetite-regulating activities by binding to and activating OBRb expressed in various areas of the brain, including the hypothalamus - where leptin is a critical factor in the homeostatic control of food intake and energy expenditure - as well as the cortex and limbic areas - where leptin regulates cognitive and reward responses to feeding (Ahima, 2008). However, OBRb are ubiquitously expressed in the periphery; most cell types, including each type of immune cell tested to date, are able to directly respond to stimulation with exogenous leptin in vitro (Lam and Lu, 2007). Although evidence for a direct effect of leptin on immune cells in vitro is extensive and uniformly convincing, the relative role played by different tissues and cells expressing OBR in vivo in modulating immune and inflammatory responses has only partly been investigated.

The CNS and PNS as potential targets for leptin's modulation of immunity and inflammation

Leptin exerts control of food intake by crossing the blood brain barrier and acting in the CNS, with major effects on homeostatic control of feeding mediated by modulation of POMC and NPY/AgRP neurons (Myers et al., 2008). Neuronal expression of OBRb and activation of STAT-3 through phosphorylation of Tyr1138 in the intracellular portion of OBRb are critical in determining leptin's inhibition of appetite (Myers et al., 2008). This same central pathway also regulates some of leptin-induced peripheral effects, such as hepatic insulin resistance (Buettner et al., 2006). However, the role of these and other centrally-mediated mechanisms in leptin's modulation of immune and inflammatory responses has not been formally investigated to date using available tools such as neuron-specific OBR-deficient mice. The important role of leptin in regulating CNS inflammation in multiple sclerosis is the topic of an excellent review (Matarese et al., 2008). However, it is likely that direct stimulation of immune cells, rather than neurons, by leptin is responsible for these effects (see below).

Activation of the vagus mediates important anti-inflammatory activities, which could potentially be modulated by leptin through its effects on vagal afferents (Wang et al., 1997). Nevertheless, the role of the vagus in mediating leptin's effects on inflammatory responses remains controversial. In fact, whereas induction of IL-1β expression in the hypothalamus by leptin is not affected by subdiaphragmatic vagotomy (Hosoi et al., 2002), the anti-inflammatory effects of leptin on acetic acid-induced colitis are abrogated by perivagal administration of capsaicin (Bozkurt et al., 2003). Furthermore, the anti-inflammatory activities of vanadyl sulfate, which are partly mediated by blocking communication of between the periphery and the CNS via the vagus, are still observed in db/db mice, indicating that the presence of OBR is not necessary for this response (Johnson et al., 2005). Therefore, whether direct effects of leptin on the CNS and PNS are important for modulation of immunity and inflammation remains to be determined.

Immune cells as a target of leptin

In vitro, leptin exerts direct modulating effects on activation, proliferation, maturation and production of inflammatory mediators in a variety of immune cells, including lymphocytes, NK cells, monocytes/macrophages, dendritic cells, neutrophils and eosinophils (Lam and Lu, 2007). These effects are mediated by activation of a variety of signal transduction pathways, including STAT-3, PI3K, P38 MAPK and others, by binding of leptin to OBR expressed by immune cells (Lam and Lu, 2007). Despite clear and consistent in vitro data, whether direct binding of leptin is essential for regulation of immunity and inflammation in vivo remains to be conclusively determined, as discussed below.

Both ob/ob and db/db mice, as well as malnourished mice which have very low leptin levels, are characterized by profound thymic atrophy, which mostly affects double positive (CD4+ CD8+) immature thymocytes, a type of cell that requires leptin as a survival, anti-apoptotic factor (Howard et al., 1999). However, it remains unclear whether lack of leptin or its receptor specifically affects subpopulations of T lymphocytes in the periphery. In fact, leptin has differential effects in vitro on proliferation of naive versus memory T cells (Lord et al., 2002) and on Tregulatory (Treg) versus T effector (Teff) cells (see below for details) (De Rosa et al., 2007). It is thus possible that leptin or OBR deficiency is associated with specific changes in peripheral T cell subpopulations. The observation that administration of leptin to aged mice improves peripheral T cell receptor diversity indicates that leptin can significantly affect the peripheral T lymphocyte compartment (Dixit et al., 2007).

Short-term administration of leptin restores thymic cellularity in ob/ob mice and reverses LPS-induced thymic atrophy in lean mice (Gruver and Sempowski, 2008; Hick et al., 2006). Leptin administration is also effective at enhancing thymopoiesis and increasing the number of recent thymic emigrants in aged mice (Dixit et al., 2007). However, the cellular target of leptin in restoring thymic cellularity is still unclear. Bone marrow chimera experiments have generated conflicting results. In fact, whereas one group indicated that reconstitution of db/db mice with WT bone marrow did not restore thymic cellularity, the opposite results were reported by different investigators (Palmer et al., 2006; Trotter-Mayo and Roberts, 2008), leaving this issue open to further analysis. Our recent unpublished bone marrow transplant data support a direct, though not complete, effect of leptin on thymocytes.

Transfer of CD4+CD45RBhigh effector cells into immunodeficient SCID or RAG-1 KO hosts is a widely used experimental model of inflammatory bowel disease, in which recipient mice develop chronic T cell-mediated colonic inflammation (Izcue et al., 2006). The principle of this model is based on depletion of immune-suppressive Treg cells from the transferred lymphocyte population. Since recipient mice are lymphocyte-deficient, the only source of T lymphocytes in these mice are the aggressive Teff transferred cells, whose activity cannot be counteracted by the suppressive activity of Treg lymphocytes (Izcue et al., 2006). Using this model, a direct effect of leptin on Teff cells can be demonstrated. In fact, mice receiving OBRb-deficient CD4+CD45RBhigh cells have delayed-onset colitis compared to mice receiving OBRb-competent cells (Siegmund et al., 2004a). Since in this setting leptin is able to act on each cell type except for the transferred lymphocytes, these data indicate that immune cells can be a direct target of leptin's action in vivo. However, the effect of leptin on epithelial, endothelial and other non-bone marrow-derived cells also likely contributes to the overall in vivo activity of leptin on immunity and inflammation.

Where am I coming from, or Is the cellular source important in determining leptin's effects on immune responses?

White adipocytes are quantitatively the most important source of circulating leptin in the body (Friedman, 2002). However, other tissues, including the mammary, gastric and colonic epithelia, skeletal muscle, the placenta and lymphocytes can produce leptin, which may act in an autocrine/paracrine way in the microenvironment to modulate cellular responses (Lam and Lu, 2007). For example, leptin secreted by gastric mucosa may be involved in protection against peptic ulcers, while leptin produced by colonic epithelial cells could potentially contribute to cell proliferation and activation of goblet cells (Adeyemi et al., 2005; Hardwick et al., 2001). Evidence about the role of lymphocyte-derived leptin in regulation of immunity and inflammation is discussed below.

Effect of leptin on T regulatory cells: is lymphocyte-derived leptin necessary?

That both murine and human activated T lymphocytes express leptin mRNA and have the ability to synthesize and secrete bioactive leptin has been demonstrated in several settings (De Rosa et al., 2007; Sanna et al., 2003; Siegmund et al., 2004a). Data indicate that human CD4+CD25+ Treg cells produce higher levels of leptin compared with CD4+CD25- Teff cells (De Rosa et al., 2007). Ample evidence discussed above demonstrates that T lymphocytes express functional OBR and there is indication that Treg cells have higher OBR expression compared to Teff cells (De Rosa et al., 2007; Lam and Lu, 2007). Thus Treg cells may be more sensitive than Teff cells to the modulating effects of leptin, possibly through an autocrine role.

The relative role of adipocyte- versus lymphocyte-derived leptin in regulating immunity and inflammation has been studied both in vitro and in vivo. Neutralization of T cell-derived leptin in cultures of human lymphocytes reversed the hyporesponsiveness of Treg cells to proliferative stimuli, a typical characteristic of this population, while suppressing proliferation of Teff cells (De Rosa et al., 2007). Importantly, leptin-neutralized proliferating Treg cells maintained their suppressive capacity towards Teff cells (De Rosa et al., 2007). Thus, in vitro experiments point to an important autocrine/paracrine role for T lymphocyte-derived leptin in regulating proliferation of T lymphocytes and modulating the balance between Treg and Teff cells. However, in vivo data obtained using murine models seem to contradict the importance of the autocrine leptin pathway for regulation of Treg function. Although increased numbers of CD4+CD25+ FoxP3+ Treg lymphocytes have been described in both ob/ob and db/db mice (De Rosa et al., 2007; Matarese et al., 2005; Taleb et al., 2007), cell transfer experiments questioned the necessity for lymphocyte-derived leptin in regulation of Treg expansion. In fact, transfer of WT Treg cells - which are able to secrete and respond to leptin in an autocrine fashion - into the leptin-deficient environment of an ob/ob mouse led to a dramatic expansion of the transferred WT Treg population compared with a parallel transfer into a leptin-competent host (De Rosa et al., 2007). Furthermore, administration of exogenous leptin to ob/ob mice that had received WT Treg cells inhibited proliferation of the transferred population (De Rosa et al., 2007). These data indicate that lymphocyte-derived leptin is not sufficient to fully modulate Treg cell proliferation in vivo in mice, suggesting that adipocyte-derived leptin might play an important role in this setting. Finally, the role of leptin (regardless of its cellular source) in regulating proliferation versus suppressive activity of Treg cells in vivo remains contradictory, with one report indicating a selective role of leptin in modulating Treg proliferative capacity (De Rosa et al., 2007), while others demonstrate no effect on proliferation (Matarese et al., 2005; Taleb et al., 2007), with instead a major outcome in terms of suppressive ability towards Teff cells (Taleb et al., 2007).

Effect of leptin on T effector cells: is adipocyte-derived leptin sufficient?

Outside the realm of Treg function, comparison of the ability of transferred WT versus leptin-deficient CD4+CD45RBhigh effector cells in inducing colitis in SCID mice indicated no significant role for T lymphocyte-derived leptin in regulating inflammatory responses (Fantuzzi et al., 2005). Comparable results were obtained using the model of ConA-induced fulminant autoimmune hepatitis (Fantuzzi et al., 2005). Complementing these data, transplantation of WT white adipose tissue into ob/ob mice effectively restored their ability to mount an inflammatory response in the model of dextran sulfate sodium-induced colitis (Sennello et al., 2006). These data indicate that adipocyte-derived leptin, which is the only source of leptin in ob/ob mice transplanted with WT adipose tissue, is sufficient to completely restore inflammatory responses as well as to reverse thymic atrophy in these mice (Sennello et al., 2006). In conclusion, although lymphocyte-derived leptin may contribute to modulation of the lymphoid microenvironment, adipocyte-derived leptin is likely sufficient to modulate immune and inflammatory responses.

What am I doing, or What are leptin's effects on immune and inflammatory responses?

The role of leptin as a modulator of immune and inflammatory responses has been investigated in several experimental models of autoimmunity and inflammation, with results that sometimes appear contradictory. Although in vitro data on the effect of leptin in modulating activation and function of rodent and human immune cells are consistent (Lam and Lu, 2007), in vivo data are less clear-cut, in part as a result of the experimental models used. In fact, most of the investigations have been performed using ob/ob and db/db mice or fa/fa rats, which have profound metabolic abnormalities associated with congenital deficiency of leptin or its receptor. Interpretation of these results presents several challenges, since it is almost impossible to dissociate the direct effects of leptin or OBR deficiency from those of obesity, diabetes, hepatic steatosis and the other alterations present in these animals. Administration of leptin to ob/ob mice using schedules aimed at minimizing its weight-reducing effects has been a commonly used strategy to try to circumvent these issues. However, even short-term administration of leptin profoundly alters the metabolism of ob/ob mice and therefore does not represent an optimal solution. The use of tissue-specific or inducible leptin or OBR deficient models, which has already been applied to the study of leptin's effects on metabolic responses (Cohen et al., 2001; Guo et al., 2007), will likely help overcome the above-mentioned problems.

In humans, the role of leptin in modulating the immune system in vivo mostly derives from evidence gathered from the extremely rare conditions of massive obesity associated with leptin or OBR deficiency, in which reduced lymphocyte proliferation and cytokine production has been observed (Farooqi et al., 2002; Farooqi et al., 2007). Studies aimed at evaluating the effect of leptin on immunity through modulation of leptin levels by short-term fasting and administration of exogenous leptin have generated less conclusive results, possibly due to the difficulty in reducing leptin below a critical threshold level (Chan et al., 2006). Although not discussed in this review, leptin's effects in regulation of immune responses likely have consequences on susceptibility to infections, both in experimental animals and humans (Lam and Lu, 2007). Children with leptin or OBR mutations appear to be more sensitive to infections, although the extreme rarity of these mutations only allows for circumstantial evidence (Farooqi et al., 2002; Farooqi et al., 2007). Low leptin is also likely involved in the immunosuppression of malnutrition and starvation (Schaible and Kaufmann, 2007).

This section will discuss two open issues on the role of leptin as a modulator of immunity, inflammation and sickness behavior.

Does leptin mediate the anorexia of inflammation?

Anorexia is one of the components of sickness behavior that accompanies inflammatory responses (Konsman et al., 2002). One of the questions investigated shortly after the discovery of leptin and its effect on appetite was the potential involvement of this adipokine in mediating the anorexia of infection and inflammation. In fact, early reports indicated that administration of inflammatory stimuli to rodents or humans acutely increased leptin gene expression in adipose tissue, resulting in elevated circulating leptin levels (Anderson et al., 2007; Grunfeld et al., 1996). It was thus tempting to speculate that increased leptin levels would act in the hypothalamus to induce the typical anorectic responses of inflammatory diseases. However, different experimental models generated conflicting results. Thus, experiments in which LPS was administered to ob/ob mice demonstrated a profound susceptibility of these animals to the anorectic effects of inflammation, even more pronounced than what observed in their lean littermates (Faggioni et al., 1997). In contrast, db/db mice developed less severe anorexia compared to their lean controls (Faggioni et al., 1997), while LPS-induced anorexia in fa/fa rats was not dramatically different compared to lean rats (Lugarini et al., 2005). Interestingly, aspects of sickness behavior other than anorexia, such as reduced social exploration after administration of LPS, IL-1β or exposure to hypoxic conditions, were exacerbated in db/db mice, suggesting a differential involvemt of leptin in regulation of various aspects of the sickness response (Johnson et al., 2007; O'Connor et al., 2005). In lean mice and rats, neutralization of leptin's bioactivity reversed LPS-induced anorexia (Harden et al., 2006; Sachot et al., 2004). In humans, leptin may be involved in mediating anorexia and cachexia in chronic kidney disease, in which elevated circulating leptin levels have been reported (Mak and Cheung, 2007). More controversial remains the link between leptin and the anorexia of cancer, since cancer patients do not consistently show elevated leptin levels, and actually often have low serum leptin (Sato et al., 2002). In conclusion, leptin may participate in the network of mediators involved in the anorectic response to inflammation, but it most likely acts in concert with various cytokines and other factors.

What is the effect of leptin on inflammation?

The role of leptin in mediating inflammation and tissue damage has been investigated in a variety of experimental models of acute and chronic inflammation as well as autoimmunity. The results indicate a complex role for this molecule and an even more complex interrelation between the direct effects of leptin and those associated with its deficiency, such as obesity and diabetes.

Initial observations that leptin favors a Th1 pattern of cytokine responses (Lord et al., 1998) lead to the hypothesis that leptin deficiency or reduced leptin levels would be protective in models of autoimmune diseases in which Th1 responses play a major role, such as experimental allergic encephalomyelitis (EAE) – a model for multiple sclerosis – and collagen-induced arthritis (CIA) – a model for rheumatoid arthritis. This indeed turned out to be the case, with ob/ob and db/db mice showing protection from inflammation and tissue damage in both models (Lam and Lu, 2007; Matarese et al., 2008). Calorie restriction, with associated reduction in serum leptin levels, was also associated with reduced severity in the EAE model, thus confirming the results obtained using leptin- or OBR-deficient mice (Piccio et al., 2008). The important and complex role of leptin in modulating inflammation in patients with multiple sclerosis is discussed in (Matarese et al., 2008). The selective effect of leptin on Th1-mediated conditions was later challenged by the observation that supplementation of lean mice with leptin increased responses to an ovalbumin challenge, a prototypical Th2-mediated model (Shore et al., 2005). Each of the three models mentioned above is mediated by T lymphocytes and requires separate sensitization and challenge steps for disease to develop. Leptin, with its ability to influence both dendritic cell and lymphocyte function (Lam and Lu, 2007) can potentially modulate disease severity at both levels. Leptin- and OBR-deficient mice were also protected from fulminant hepatitis induced by administration of Concanavalin A, a T lymphocyte-mediated model in which pre-sensitization is not necessary (Siegmund et al., 2002a). Thus, leptin appears to favor inflammation in models in which pathology is mediated by T lymphocytes. Interestingly, non-genetically-induced obesity, which is associated with increased leptin levels, does not appear to increase severity in these models (Piccio et al., 2008; Siegmund et al., 2002a), possibly due to development of leptin resistance in obese mice (Myers et al., 2008). Leptin resistance is a condition in which high levels of leptin secondary to obesity are associated with alterations in leptin signaling, likely due to increased expression of suppressor of cytokine synthesis (SOCS)-3, an inhibitor of STAT-3 signaling (Myers et al., 2008). Recent evidence indicates that chronic activation of the pro-inflammatory transcription factor NFκB leads to overexpression of SOCS-3 and, consequently, to development of leptin resistance in states of overnutrition (Zhang et al., 2008).

In contrast with the above-mentioned lymphocyte-mediated models, leptin deficiency is generally associated with a more severe outcome in pathologies induced by activation of the innate immune system. These models include, among others, administration of LPS, zymosan, IL-1β or TNFα, exposure to ozone to induce airway inflammation as well as induction of acute pancreatitis (Faggioni et al., 1999; Pini et al., 2008; Rivera-Sanchez et al., 2004; Sennello et al., 2008; Zyromski et al., 2008). Furthermore, in contrast with lymphocyte-mediated conditions, diet-induced obesity increases disease severity in this second group of models, at least where this has been tested. Therefore, whereas leptin appears to be play a direct role in promoting inflammation in experimental models mediated by T lymphocytes, leptin deficiency increases disease severity in innate immunity-mediated models, possibly secondary to obesity. However, exceptions to this apparent lymphocyte versus innate immunity dichotomy have been reported: for example, ob/ob mice are protected from colitis induced by administration of dextran sulfate sodium - a model mediated by activation of innate immunity (Siegmund et al., 2002b) -, but they are susceptible to colitis induced by IL-10 deficiency, a condition dependent on CD4+ T lymphocytes (Siegmund et al., 2004b). Therefore, the role of leptin in modulating inflammation and autoimmunity appears to be highly context-dependent and may be influenced by the network of cells and mediators involved in the specific pathological response.

Conclusions

The evidence presented in this article indicates that leptin is an important factor in modulating immune and inflammatory reactions, both in humans and experimental animals. However, several issues, including those discussed above, need to be clarified in order to obtain a better understanding of the mechanisms through which leptin participates in the complex network of immune and inflammatory mediators.

Figure.

Figure

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Leptin, produced by adipocytes but also by other cell types, exerts a variety of complex modulating effects on the immune system. Immune cells, neurons and other cell types express functional leptin receptors and are therefore potential targets of leptin's effects. Despite clear in vitro evidence of direct activities of leptin of immune cells, in vivo data are more controversial. In this article, leptin asks three fundamental questions about its own origin, destination and function.

Footnotes

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