title: Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation.
abstract: Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Division of Breast Surgery, KKR Sapporo Medical Center Tonan Hospital, Sapporo, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Kamekura
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kawata
authors.affiliation: Division of Breast Surgery, KKR Sapporo Medical Center Tonan Hospital, Sapporo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Kawada
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Jitsukawa
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.|Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Himi
authors.affiliation: Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ichimiya
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D020738:Leptin; D000071223:Suppressor of Cytokine Signaling 3 Protein