Leptin receptor action in hepatic cells.
Leptin, an adipocyte-secreted hormone, is one of the central regulators of body weight homeostasis. In humans and rodents, two major forms of leptin receptors (OB-R) are expressed. The short form (OB-RS), considered to lack signaling capability, is detected in many organs. In contrast, OB-R long form (OB-RL) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfection experiments have demonstrated that OB-RL transduces an intracellular signaling similar to interleukin (IL)-6 type-cytokine receptors. To define the specificity by which OB-R induces genes and cooperates with signal transduction pathways utilized by other hormones and cytokines, rat and human hepatoma cell lines were generated which stably express human OB-RL. Hepatoma cell lines selected for appreciable levels of OB-RL mRNA display enhanced leptin binding and responded to leptin with an IL-6 receptor-like signaling that includes the activation of STAT proteins, induction of acute-phase plasma proteins, and synergism with IL-1 and tumor necrosis factor-alpha. A leptin-mediated recruitment of phosphatidylinositol 3-kinase to insulin receptor substrate-2 was also detected. However, no significant tyrosine phosphorylation of insulin receptor substrate-2 and modulation of the immediate cell response to insulin were observed. The data suggest that OB-RL action in hepatic cells is equivalent to that of IL-6 receptor. However, leptin does not play a specific role in muting insulin action on hepatoma cells and therefore may not contribute to the diabetic symptoms associated with obesity.
Wang
Y
Y
Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Kuropatwinski
K K
KK
White
D W
DW
Hawley
T S
TS
Hawley
R G
RG
Tartaglia
L A
LA
Baumann
H
H
D000209:Acute-Phase Proteins / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D053605:Leukemia Inhibitory Factor; D008099:Liver / Q000378:metabolism*; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin / Q000502:physiology*; D019947:Receptors, Interleukin-6; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D054411:Receptors, Leptin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C515448:LEPR protein, human; C507837:LIF protein, human; C507838:Lif protein, mouse; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; C515447:leptin receptor, mouse