Human leptin signaling in human peripheral blood mononuclear cells: activation of the JAK-STAT pathway.

Leptin is an adipocyte-secreted hormone that centrally regulates weight control. However, the leptin receptor is expressed not only in the central nervous system, but also in other systems, such as reproductive, hematopoietic, and immune tissues, suggesting various roles in addition to the regulation of food intake and energy expenditure. The leptin receptor bears homology to members of the class I cytokine receptor family. Leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages and human circulating monocytes, where human leptin promotes activation and proliferation. We have recently found that the leptin receptor is expressed not only in monocytes but also in both CD4(+) and CD8(+) T lymphocytes. Besides, leptin enhances proliferation and activation of T lymphocytes when they are costimulated by PHA or Con A. In this paper, we have studied the signal transduction of the leptin receptor in peripheral blood mononuclear cells. We found that leptin stimulation activates the JAK-STAT signaling pathway. More specifically, we found that JAK-2/3 and STAT-3 are activated by tyrosine phosphorylation upon leptin stimulation. Moreover, leptin stimulated tyrosine phosphorylation of the RNA binding protein Sam68 and its association with STAT-3. These effects were dose-dependent (0.1-10 nM) and transient (5-30 min). We also observed the leptin stimulated translocation of activated STAT-3 from the cytoplasm to the nucleus. These results indicate that human leptin receptor in circulating mononuclear cells has the signaling capacity to activate JAK-STAT cascade. This pathway may mediate, at least in part, the action of human leptin in human peripheral blood mononuclear cells.

Human leptin enhances activation and proliferation of human circulating T lymphocytes.

Leptin is an adipocyte-secreted hormone that centrally regulates weight control. However, leptin receptor is expressed not only in the central nervous system, but also in other systems such as reproductive and hematopoietic tissues. Human leptin has previously been shown to enhance cytokine production by murine peritoneal macrophages and human circulating monocytes. In this paper we have assessed the presence of leptin receptors in peripheral human T lymphocytes and we have studied their functional role. Both CD4(+) and CD8(+) T lymphocytes express leptin receptors. Moreover, we show that human leptin dose-dependently enhances proliferation and activation of human circulating T lymphocytes when they are costimulated by PHA or Con A. Leptin alone was not able to activate T lymphocytes. To confirm a direct effect of leptin on T lymphocytes, monocytes were extracted by adhesion to culture flasks. The early activation surface marker CD69 was then induced in both CD4(+) and CD8(+) T lymphocytes after 8 h stimulation with PHA or Con A. Leptin dose-dependently enhanced stimulated CD69 expression. Moreover, leptin dose-dependently enhanced the expression of the late activation markers CD25 and CD71 in both CD4(+) and CD8(+) T lymphocytes after 48 h stimulation with PHA or Con A. Finally, we have found that leptin modulates CD4(+) T lymphocyte activation toward Th1 phenotype by stimulating the synthesis of IL-2 and IFN-gamma. These results demonstrate the presence of the leptin receptor in human circulating CD4(+) and CD8(+) T lymphocytes and a functional role of leptin as a modulator (enhancer) of lymphocyte stimulation with a shift toward Th1 cytokine-production profile. This function of leptin may have some relevance in the pathophysiology of immunologic alterations related to obesity.