Leptin, the product of the Ob gene, is a polypeptide hormone that plays an important role in the regulation of body weight by inhibiting food intake and stimulating energy expenditure. Moreover, leptin exhibits a variety of other effects including the regulation of endocrine function, reproduction and hematopoiesis. Consistently, leptin-deficient mice are not only obese, but display major hormonal disturbances, including hypercorticosteronemia, diabetes, and infertility. In addition, it has been known for many years that leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice have an altered immune response. More recent studies have shown that T cells and B cells express the long signaling leptin receptor isoform (ObRb) and that leptin exerts direct effects on T lymphocytes, including the stimulation of cell proliferation, the promotion of Th1 responses, and the protection of thymocytes from corticosteroid-induced apoptosis. Consistently, ob/ob mice are protected from inflammation mediated by T cells and B cells in some models such as experimental colitis, experimental autoimmune encephalomyelitis, and concanavalin A-induced hepatitis. Conversely, the administration of recombinant leptin increased the severity of experimental autoimmune encephalomyelitis. Using a model of antigen-induced arthritis, we demonstrated that ob/ob and db/db mice have a milder form of arthritis and that cellular and humoral immune responses to the injected antigen are decreased as compared with wild-type mice. Furthermore, ex vivo stimulated lymph node cells from ob/ob and db/db mice produced less interferon gamma and more IL-10 than cells obtained from control mice.
Leptin production is regulated by various proinflammatory cytokines during the acute-phase response, and leptin stimulates the production of both proinflammatory and antiinflammatory cytokines in vitro. ob/ob mice exhibit increased susceptibility to lipopolysaccharide-induced and tumor necrosis factor alpha-induced lethality, suggesting that leptin is also involved in regulating the innate immune response. We recently examined the role of leptin in zymosan-induced arthritis (ZIA), where joint inflammation is dependent on innate immunity. Our results demonstrate that, as opposed to antigen-induced arthritis, ZIA is not impaired in ob/ob and db/db mice. On the contrary, these mice exhibit a delayed resolution of the inflammatory process, with increased circulating levels of IL-6 and serum amyloid A, and a tendency to develop more severe joint damage. Leptin deficiency thus appears to interfere with adequate control of the inflammatory response in ZIA.
Although data obtained in different models of inflammatory diseases suggest that leptin plays a role in immune response, the analysis of direct effects of leptin on lymphocytes in vivo is precluded by the important hormonal and metabolic alterations, which are linked to leptin deficiency. To our knowledge, it has never been thoroughly investigated to which extent immune defects in ob/ob or db/db animals are linked to leptin deficiency or, respectively, leptin receptor deficiency per se, as opposed to confounding factors such as hypercorticosteronemia. To examine the importance of direct effects of leptin on lymphopoiesis and immune response, we generated bone marrow chimeras by transplantation of db/db bone marrow cells into lethally irradiated normal recipient mice, which provide a normal environment for the grafted cells. Donor db/db mice display a marked atrophy of the thymus as compared with db/+ controls. In bone marrow chimeras, the size and cellularity of the thymus were not different between mice grafted with db/db or db/+ bone marrow 12 weeks after the graft, suggesting that the thymic atrophy observed in db/db donors is not due to direct effects of leptin on lymphocytes. Moreover, RT-PCR analyses suggest that CD4/CD8 double positive thymocytes do not express ObRb. Further studies are in progress in order to examine which cell types respond to leptin in the thymus and whether impaired leptin signaling in lymphocytes affects immune responses after antigen challenge in db/db bone marrow chimeras.