Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis.
The growing worldwide obesity epidemic is frequently linked to an increased risk of developing diseases such as diabetes, cardiovascular disease, and cancer. These diseases are associated with the infiltration of macrophages in white adipose tissue (WAT), the artery wall, and tumors, respectively; and these macrophages likely contribute to disease progression and pathogenesis. Abdominal WAT, adipose tissue surrounding the heart and artery wall, as well as carcinoma cells, secrete many factors that could induce macrophage infiltration. Leptin is an adipocyte-secreted hormone, and deficiency of either leptin or its receptor has been shown to cause morbid obesity in animals and in humans. However, what is more commonly noted in human obesity is the presence of central leptin resistance leading to hyperleptinemia. As leptin receptors are present on macrophages, we hypothesized that leptin could act as a monocyte/macrophage chemoattractant. Our current study demonstrates: 1) leptin is a potent chemoattractant for monocytes and macrophages, inducing maximal chemotactic responses at 1 ng/ml; 2) leptin-mediated chemotaxis requires the presence of full-length leptin receptors on migrating cells; 3) leptin causes increased influx of intracellular calcium in macrophages; and 4) activation of janus kinase/signal transducers and activators of transduction (JAK/STAT), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) pathways are all necessary for leptin-induced macrophage migration. Taken together, these data demonstrate that leptin is a potent monocyte/macrophage chemoattractant in vitro and that canonical cell motility machinery is activated upon macrophage exposure to leptin. These data have implications for the impact of hyperleptinemia on obesity-related pathophysiological conditions such as diabetes, cardiovascular disease, and cancer.
Gruen
Marnie L
ML
Vanderbilt University Medical Center, Department of Molecular Physiology and Biophysics, Nashville, Tennessee, USA.
Hao
Mingming
M
Piston
David W
DW
Hasty
Alyssa H
AH
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002633:Chemotaxis; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction
D002118:Calcium; D018932:Chemokine CCL2; D053612:Janus Kinases; D020738:Leptin; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050791:STAT Transcription Factors; C515448:LEPR protein, human; C515447:leptin receptor, mouse