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.

[1]  G. Fantuzzi,et al.  Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[2]  V. Sánchez-Margalet,et al.  Human leptin enhances activation and proliferation of human circulating T lymphocytes. , 2000, Cellular immunology.

[3]  J. Pickup,et al.  The innate immune response and type 2 diabetes: evidence that leptin is associated with a stress‐related (acute‐phase) reaction , 2000, Clinical endocrinology.

[4]  Graham M Lord,et al.  Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice. , 1999, The Journal of clinical investigation.

[5]  J Licinio,et al.  Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defe , 1999, The Journal of clinical endocrinology and metabolism.

[6]  W. Ricart,et al.  Insulin resistance and inflammation in an evolutionary perspective: the contribution of cytokine genotype/phenotype to thriftiness , 1999, Diabetologia.

[7]  V. Sánchez-Margalet,et al.  p68 Sam is a substrate of the insulin receptor and associates with the SH2 domains of p85 PI3K , 1999, FEBS letters.

[8]  V. Sánchez-Margalet,et al.  Human leptin stimulates proliferation and activation of human circulating monocytes. , 1999, Cellular immunology.

[9]  K. Bulmer,et al.  High levels of circulating proinflammatory cytokines and leptin in urban, but not rural, Indians. A potential explanation for increased risk of diabetes and coronary heart disease. , 1999, Diabetes care.

[10]  A. Dannenberg,et al.  Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. , 1999, American journal of physiology. Cell physiology.

[11]  K. McCowen,et al.  Leptin signaling in the hypothalamus of normal rats in vivo. , 1998, Endocrinology.

[12]  A. Fischer,et al.  Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression. , 1998, Journal of immunology.

[13]  Stephen R. Bloom,et al.  Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression , 1998, Nature.

[14]  M. Lane,et al.  Leptin regulates proinflammatory immune responses. , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[16]  Josep M. Guerrero,et al.  Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes. , 1997, Journal of immunology.

[17]  L. Tartaglia,et al.  Leptin Receptor Action in Hepatic Cells* , 1997, The Journal of Biological Chemistry.

[18]  R. Skoda,et al.  The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line. , 1997, Molecular endocrinology.

[19]  L. Tartaglia,et al.  The Leptin Receptor* , 1997, The Journal of Biological Chemistry.

[20]  J. Fujisawa,et al.  Interaction between Sam68 and Src Family Tyrosine Kinases, Fyn and Lck, in T Cell Receptor Signaling* , 1997, The Journal of Biological Chemistry.

[21]  Dennis J. Rivet,et al.  Multiple Cytokines and Acute Inflammation Raise Mouse Leptin Levels: Potential Role in Inflammatory Anorexia , 1997, The Journal of experimental medicine.

[22]  A. Fischer,et al.  CD4 ligands inhibit the formation of multifunctional transduction complexes involved in T cell activation. , 1997, Journal of immunology.

[23]  W. Alexander,et al.  Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R G Smith,et al.  Functional STAT 1 and 3 signaling by the leptin receptor (OB-R); reduced expression of the rat fatty leptin receptor in transfected cells. , 1996, Endocrinology.

[25]  R. Seeley,et al.  Identification of targets of leptin action in rat hypothalamus. , 1996, The Journal of clinical investigation.

[26]  B. Bennett,et al.  A role for leptin and its cognate receptor in hematopoiesis , 1996, Current Biology.

[27]  J. Darnell,et al.  Leptin activation of Stat3 in the hypothalamus of wild–type and ob/ob mice but not db/db mice , 1996, Nature Genetics.

[28]  L. Tartaglia,et al.  The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Skoda,et al.  Defective STAT signaling by the leptin receptor in diabetic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Mikhail,et al.  Novel B219/OB receptor isoforms: Possible role of leptin in hematopoiesis and reproduction , 1996, Nature Medicine.

[31]  J. Friedman,et al.  Abnormal splicing of the leptin receptor in diabetic mice , 1996, Nature.

[32]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[33]  J. Ihle.  Cytokine receptor signalling , 1995, Nature.

[34]  Thomas Madej,et al.  Threading analysis suggests that the obese gene product may be a helical cytokine , 1995, FEBS letters.

[35]  B. Lowell,et al.  Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. , 1995, The Journal of clinical investigation.

[36]  R. Devos,et al.  Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. , 1995, Science.

[37]  M. Pelleymounter,et al.  Effects of the obese gene product on body weight regulation in ob/ob mice. , 1995, Science.

[38]  Steven L. Cohen,et al.  Weight-reducing effects of the plasma protein encoded by the obese gene. , 1995, Science.

[39]  J. Friedman,et al.  Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Flier,et al.  The adipocyte: Storage depot or node on the energy information superhighway? , 1995, Cell.

[41]  K. Blumer,et al.  Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1 , 1995, Molecular and cellular biology.

[42]  M. Maffei,et al.  Positional cloning of the mouse obese gene and its human homologue , 1994, Nature.

[43]  V. Sánchez-Margalet,et al.  Role of p85 subunit of phosphatidylinositol-3-kinase as an adaptor molecule linking the insulin receptor, p62, and GTPase-activating protein. , 1994, The Journal of biological chemistry.

[44]  J. Hsuan,et al.  A target for Src in mitosis , 1994, Nature.

[45]  D. Shalloway,et al.  An RNA-binding protein associated with Src through its SH2 and SH3 domains in mitosis , 1994, Nature.

[46]  V. Sánchez-Margalet,et al.  Protein kinase C activation promotes cell survival in mature lymphocytes prone to apoptosis. , 1994, Biochemical pharmacology.

[47]  S. Akira,et al.  Cytokine signal transduction , 1994, Cell.

[48]  A. Bøyum,et al.  Isolation of mononuclear cells and granulocytes from human blood. , 1968 .