Leptin, a protein produced by adipocytes and released into the systemic circulation, acts as a master hormone, controlling most of the body's functions involved in energy acquisition and utilization. Although leptin is best known for its role in regulating food intake, this adipokine controls several other critical systems, including modulation of various endocrine axes, bone metabolism, as well as the immune/inflammatory response 1.
The observation that an absence of leptin or its receptor results in alterations of the cellularity and function of the immune system was made several years before the term leptin had been coined and the genes for leptin and its receptor identified. In fact, the finding of thymic atrophy and reduced lymphocyte function in ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice dates to the late 1970s and early 1980s 2–5. Cloning of leptin in 1994 and the subsequent rapid identification of its receptor lead to a renewed interest and reevaluation of those discoveries of the late 1970s/early 1980s. In agreement with the early observations of lymphocyte abnormalities in ob/ob and db/db mice, most of the studies on the role of leptin in regulating immune responses focused on the effect of this adipokine on the lymphoid compartment, particularly maturation, function and survival of T lymphocytes. A critical finding of the majority of these studies was the demonstration that leptin skews the immune response towards a Th1 phenotype and protects T lymphocytes from apoptosis 6, 7, possibly accounting for the protective effect of leptin- and leptin receptor-deficiency in models of autoimmune/inflammatory conditions 8–10. Studies on the role of leptin in the modulation of monocytes/macrophages, neutrophils, basophils, eosinophils and natural killer cells soon followed (see 11, 12 for reviews).
However, it was not until 2005 that the first report on the effect of leptin on dendritic cells (DC) was published by Mattioli et al.13. This report demonstrated that human DC express functional leptin receptors and that leptin promotes differentiation of peripheral blood-derived DC, protects them from apoptosis, modulates cytokine production, and – quite importantly – licenses them for Th1 priming of CD4+ T cells 13. In this issue of the European Journal of Immunology, Lam et al.14 describe for the first time the effect of leptin receptor deficiency on DC survival, maturation and function in mice. This report by Lam et al.14describes how murine bone marrow-derived DC express functional leptin receptors and respond to leptin stimulation with activation of the JAK2 pathway. When the investigators attempted to generate DC from the bone marrow of db/db leptin receptor-deficient mice, they obtained a significantly lower yield compared with cells derived from their WT counterparts, even after stimulation and induction of maturation with LPS. Dendritic cells obtained from db/db mice also expressed low levels of co-stimulatory molecules, had high rates of apoptosis and produced low levels of the cytokines IL-12 and TNFα, while at the same time generating high levels of the anti-inflammatory cytokine IL-10, again in comparison with WT-derived DC. Importantly, DC obtained from db/db mice had a low stimulatory capacity towards allogeneic CD4+ T cells. On the other hand, the proliferative and phagocytosing ability of db/db-derived DC was not altered compared with that of WT-derived cells, thus demonstrating that leptin receptor-deficiency does not alter the overall function of DC.
Despite the fact that Mattioli et al.13 and Lam et al.14 evaluated the effect of leptin in DC using two different organisms (human and mouse respectively) and from two opposite experimental perspectives (the addition of leptin in the study by Mattioli et al. 13, leptin receptor-deficiency/blockade in Lam et al.14), the pattern of the findings is astoundingly similar: in both systems, leptin protects DC from apoptosis, induces DC maturation, upregulates production of TNF-α and IL-12 while downregulating IL-10 synthesis, and increases the ability of DC to stimulate CD4+ lymphocytes. The only major difference observed between the two reports concerns the effect of leptin on the expression of co-stimulatory molecules by DC, an effect which was present in the report by Lam et al. 14 but absent in that of Mattioli et al. 13. This disparity is likely due to the different source of DC in the two reports (bone marrow 14versus peripheral blood 13) and differences in the conditions for DC selection and culture.
The report by Lam et al. 14, when evaluated together with the data from Mattioli et al. 13, indicates a possible new path through which leptin maintains optimal trophism and functionality of the immune system. Whereas most of the models proposed to date suggest a direct effect of leptin on T lymphocytes, these novel data point to a likely indirect effect through modulation of DC maturation, survival and stimulatory function. However, the two models are not necessarily mutually exclusive and one can easily envision a paradigm in which leptin acts as a trophic factor for both T lymphocytes and DC. Mutual interaction between the two cell types would then lead to the modulation of T cell function. A combination of direct and indirect effects of leptin on T cells is suggested by data demonstrating that leptin receptor-deficient CD4+ lymphocytes are able to home to the colon and induce an inflammatory response when transferred into leptin receptor-competent scid hosts, but do so with delayed kinetics 15.
Although several data, including those reported in this issue of European Journal of Immunology, indicate that leptin regulates immune function by acting directly on bone marrow-derived cells, a recent report by Palmer et al. 16 questions these conclusions based on results obtained from bone marrow chimeras between WT and db/db mice. By performing transplantation of WT bone marrow into db/db mice and the reciprocal transplantation (i.e., db/db bone marrow into a WT host), as well thymus transplantation (db/db into WT), Palmer et al.16 deduce that expression of the leptin receptor on either bone marrow-derived cells or thymic epithelial cells is not necessary for normal thymocyte development. In contrast, they conclude that the marked metabolic abnormalities present in db/db mice – including high corticosterone levels and dysregulated glucose and lipid metabolism – are responsible for the observed outcome. These data appear to be in disagreement with the demonstration that leptin exerts important regulatory effects by acting directly on immune cells and future experiments will be necessary to clarify this issue.
To complicate matters, demonstration of the actual physiological role of leptin in modulating immune function in humans has been difficult to decipher due to three sets of experimental constrains. Firstly, leptin and leptin receptor deficiency are exceedingly rare conditions in humans. Although experimental evidence indicates the presence of alterations in T lymphocyte function in subjects with leptin deficiency and correction by leptin administration 17, the number of subjects available for these studies is extremely low and it is difficult to dissect the direct role of leptin from the secondary effects due to metabolic and hormonal alterations. Secondly, acute or chronic manipulation of leptin levels in humans is difficult. Attempts to use fasting to acutely reduce leptin below a putative "threshold" that would be necessary to maintain trophic effects on immune and endocrine organs, as well as experiments using administration of recombinant leptin, have generated inconsistent results 18, 19. Thirdly, obesity, a state associated with high leptin levels, is characterized by leptin resistance, which appears to involve alterations in leptin receptor signaling abilities and to extend to receptors expressed by lymphocytes 20.
Despite the presence of the above-mentioned problems, the available data support the notion that leptin is an important trophic factor for immune cells. This includes DC, with leptin protecting DC from apoptosis and favoring their optimal development, maturation and function (summarized in Fig. 1). The presence of sharply reduced levels of leptin, a signal that the body has depleted its energy reserves (in the form of adipose tissue), appears to be an indication to shut down all the non-essential body's functions, including those involved with immune and inflammatory responses.