Leptin Receptor Action in Hepatic Cells

Abstract

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-R S ), considered to lack signaling capability, is detected in many organs. In contrast, OB-R long form (OB-R L ) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfection experiments have demonstrated that OB-R L 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-R L . Hepatoma cell lines selected for appreciable levels of OB-R L 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-␣. 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-R L 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.Leptin, a 16-kDa non-glycosylated secretory protein, is produced by adipose cells, released into the circulation, transported across the blood-brain barrier, and acts in a central manner on the hypothalamus to regulate mammalian energy homeostasis (1-5). Leptin signaling is mediated by the leptin receptor (OB-R), 1 a member of the hematopoietin receptor family that appears most closely related to the signal-transducing subunits of the IL-6 type cytokine receptors (6 -8). In humans and rodents, two predominant forms of OB-R are detected. Both isoforms have identical extracellular domains and ligandbinding affinity, but differ in the intracellular domains which represent alternative splice products. The major OB-R short form (OB-R S ) has a 34-amino acid cytoplasmic domain and is found in many organs. However, despite normal ligand binding activity, OB-R S has been described as being incapable of signaling (9, 10). In contrast, the long form (OB-R L ) containing a 302-amino acid cytoplasmic domain, is primarily expressed in specific nuclei of the hypothalamus (11) and is considered to be the signaling-competent receptor isoform (9, 10, 12).Reverse transcriptase-polymerase chain reaction and RNA protection analyses have revealed that various peripheral organs, including liver, have detectable levels of mRNA encoding the OB-R L . The relative amount ranges from 2 to 11% (liver 5%) of the total OB-R mRNA signal (9). Recent...

Selective interaction between leptin and insulin signaling pathways in a hepatic cell line

“…There are conflicting data concerning the signaling capability of the different OB-R isoforms, but in general, stimulation of c-fos expression has been attributed to the signaling capacity of the long form of the receptor and can be demonstrated in PC-12 cells transfected with OB-R L as well as in the hypothalamus and the jejunum in vivo (6,17,18). As shown on (9,14,15,19). Leptin has no effect on glucose metabolism in primary rat adipocytes (20) but stimulates glucose uptake in C 2 C 12 cells (15).…”

“…In HepG2 human hepatoma cells, leptin antagonizes insulin-induced downregulation of PEPCK expression and decreases insulinstimulated tyrosine phosphorylation of IRS-1 but enhances IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity (14); in C 2 C 12 cells, leptin stimulates a non-IRS-1-associated PI 3-kinase and mimics insulin action on glucose transport and glycogen synthesis (15). In OB-R L -transfected HepG2 cells, leptin treatment resulted in the recruitment of p85 to IRS-2 but did not modulate the response to insulin (9). Together, these data point toward cell-and tissue-specific interactions between leptin and insulin signaling that are quite diverse.…”

“…The long form of the OB-R belongs to the gp130 family of cytokine receptors that also includes the receptor for IL-6, leukocyte inhibitory factor, and granulocyte colony stimulating factor. These receptors act by activating cytoplasmic tyrosine kinases of the Janus kinase (JAK) family that in return phosphorylate specific transcription factors of the Stat (signal transducer and activator of transcription) family (7)(8)(9)(10). On phosphorylation, the Stat proteins dimerize and translocate to the nucleus where they bind to specific nucleotide sequences and induce gene expression.…”

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

“…The role of STAT5 in leptin signaling is not known, but it was found to be activated together with STAT3 in COS and hepatoma cell lines cotransfected with OB-R L and STAT cDNAs (6,9,10), and in porcine medullary cells after leptin treatment (35). Functionally, STAT5 regulates expression of milk proteins in the response of mammary tissue to prolactin (63).…”

Double-copy bicistronic retroviral vector platform for gene therapy and tissue engineering: application to melanoma vaccine development

“…tumors. 31,32 In the present study, we compared expression from a MENVnlslacZ is similar in configuration to the MoMLVbased SAMENnlslacZ vector (see Materials and conventional MSCV vector with that from several MSCVbased derivatives in four human melanoma cell lines. A methods), which was evaluated in parallel.…”