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Details for receptor: leptin receptor

EndoNet ID: ENR00979

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Synonyms

  • LEP-R
  • Ob-R
  • leptin receptor
  • OB receptor
  • OB-R

General information

  • The expression of the Ob-R in human white adipose tissue is not restricted to adipocytes but is present in resident endothelial and immune cells. [1]
  • Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells and thecal cells. [2]
  • The LRb is not only expressed in hypothalamic cells, but also in tissues including skeletal muscle, liver, adipose tissue, and pancreatic ß cells. [3]
  • Ob-Rb, which contains a long intracellular domain, is the only isoform with both of the protein motifs necessary for activation of the Janus kinase 2 and signal transducers and activators of transcription (JAK-STAT). [4]
  • The leptin receptor is expressed in most tissues but that the long form is prevalent in the hypothalamus. [5]
  • The long form of LEP-R (Ob-Rb) mediates the Jak-STAT intracellular signaling pathway. [6]
  • Among the proteins induced by leptin-mediated STAT signaling is suppressor of cytokine signaling-3 (SOCS3), which inhibits leptin activation of the Jak-STAT pathway. [6]
  • All isoforms have similar ligand-binding domains but differ at the C-terminus, intracellular domain. [4]
  • The long form of LEP-R (Ob-Rb) does not contain intrinsic enzymatic avtivity but instead signals via a noncovalent associated tyrosine kinase of the Jak kinase family (Jak2 in the case of LEP-R). [7]
  • The presence of functional leptin receptors in brains regions and peripheral organs that are important in cardiovascular control such as heart, kidneys and adrenals led to suspect that leptin played a key role in blood pressure control. [8]
  • Exists in different isoforms (Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re and Ob-Rf) that derive from alternative splicing of mRNA. [4]
  • TIMP-1 production in LX-2 human hepatic stellate cells by leptin stimulation is associated with increased expression of OB-R. [9]
  • The Ob-Rb receptor, which is widely expressed in human placenta and adipose tissue, mediates leptin action by signaling via the Janus kinase/STAT pathway including the downstream suppressor of cytokine signaling-3 feedback inhibitor and/or other common pathways such as the p38 MAPK, p42/p44 MAPK, and NF-κB pathway. [10]

Links to other resources

UniProt P48357
Ensembl ENST00000431694

Binding hormones

  • leptin
    (trough: blood
    )
    • Leptin circulates bound to leptin-binding proteins in plasma and others proteins, including a soluble form of its receptor, and in a "free" form. [11]
    • After its transport through the blood-brain barrier mediated by the LRa, leptin binds and activates the long form of the leptin receptor (LRb) in the hypothalamus. [3]
    • Has been identified within the hypothalamus in brain regions rich in GnRH neurons such as the arcuate nucleus. [12]

Anatomical structures with this receptor

  • cell_of_endometrium_of_uterus

    Influences

    • positive IL-1 beta
      • Leptin stimulated IL-1 antagonist (IL-1Ra), IL-1beta secretion and expression of IL-1 receptor type I (IL-1R tI) in endometrial epithelial cells and endometrial stromal cells. [13]
  • arcuate_nucleus_of_hypothalamus

    Influences

    • positive alpha-MSH
    • negative AGRP
    • negative NPY
      • Decrease in Leptin causes increase in NPY secretion in rats during lactation [14]
    • positive POMC
    • negative GnRH-I
      • Decrease in Leptin causes inhibition of GnRH/LH secretion in rats during lactation [14]

    Induced phenotypes

    • regulation of synapse organization
      • Leptin induces a fast rewiring of POMC and Npy/Agrp cells in the ARC - peripheral leptin treatment rapidly restored the synaptic inputs in these groups of cells. [15]
  • acidophil_somatotroph_cell_of_anterior_pituitary

    Influences

    • positive GH
      • Leptin-deficient patients although exhibited normal height, presented decreased GH response to ITT and physical exercise, whereas leptin-resitant patients subjects have significant growth delay during early childhood and decreased GH secretion. [16]
  • adipose_tissue

    Influences

    • negative leptin
      • Leptin receptor is involved in regualting the circulating leptin concentration. [17]
      • Tonic suppression of leptin synthesis could be mediated by effects of leptin on the adipocyte leptin receptor acting in an autocrine fashion. [17]
    • negative insulin
      • Leptin has an important physiological role an inhibitor of insulin secretion and the failure of leptin to inhibit insulin secretion from the beta-cells may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to non-insulin-dependent diabetes mellitus. [18]

    Induced phenotypes

    • negative regulation of insulin receptor signaling pathway
      • Leptin inhibits insulin receptor signaling in cultured cells. [19]
    • regulation of glucose homeostasis
      • The ability of leptin to regulate insulin secretion from the pancreatic beta cells might contribute to the abnormalities in glucose homeostasis in obesity . [19]
    • negative regulation of gene expression
      • Leptin inhibits the expression of the reate-limiting enzyme for long chain fatty acid synthesis, acetyl CoA carboxylase, in cultured adipocytes. [20]
    • insulin resistance
      • The obesity-related increase of Leptin production positively correlated with increased insulin resistance. [21]
      • More direct measures of insulin sensitivity have indicated leptin as potential mediator of insulin resistance in obesity. [22]
    • hyperinsulinemia
      • The obesity-related increase of Leptin production is positively correlated with hyperinsulinemia. [21]
    • obesity
      • Elevated Leptin expression and increased pasma leptin levels are associated with obesity and are presumably part of an adipostat mechanism [19]
    • Both, the long and the short isoforms of the leptin receptor, are present in adipose tissue. [10]
  • paraventricular_nucleus_of_hypothalamus

    Influences

    • positive TRH
      • Leptin stimulates TRH mRNA production and releases TRH but only from hypothalamic neurons of the PVN. S.138 [23]
    • positive CRH
      • after leptin administration CRH genexpression have been noted after 6h and 5d [24]
    • negative norepinephrine
      • Leptin lowers noradrenalin concentration in PNV [25]
  • granulosa_cell

    Induced phenotypes

    • negative regulation of steroid hormone biosynthetic
      • Leptin inhibited insulin-induced steroidogenesis by bovine granulosa cells. [26]
      • Leptin, at physiologic concentrations, directly affects insulin-induced steroidogenesis of granulosa cells. Normally fluctuating concentrations of leptin in blood may play an important role in communicating the metabolic status of the animal to the reproductive system. [26]
      • Leptin significantly suppresses LH-induced estradiol production. This is consistent with an endocrine action of leptin on the human ovary, with possible implications for female reproduction in health and disease. [2]
      • High dose of leptin suppressed LH-stimulated estradiol production in human granulosa cells. [2]
    • Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells; however, the short isoforms were expressed at much higher levels. [2]
  • theca_cell

    Induced phenotypes

    • negative regulation of steroid hormone biosynthetic
      • Leptin inhibited steroidogenesis by bovine theca cells. [27]
      • Leptin, at physiologic concentrations, directly affects steroidogenesis of thecal cells. Normally fluctuating concentrations of leptin in blood may play an important role in communicating the metabolic status of the animal to the reproductive system. [27]
      • In cultured theca cells, leptin did not alter androstenedione production, alone or in the presence of LH. Leptin caused a concentration-related inhibition of the IGF-I augmentation of LH-stimulated androstenedione production. Leptin can directly inhibit IGF-I action in ovarian theca at concentrations commonly present in obese women. [28]
    • Transcripts encoding both the long and short isoforms of the leptin receptor were present in human thecal cells; however, the short isoforms were expressed at much higher levels. [2]
  • preadipocyte

    Influences

    • positive VEGF-165
      • Leptin induced VEGF mRNA expression in cultured pre-adipocytes but not in adipocytes. [29]
  • skeleton_muscle

    Induced phenotypes

    • positive regulation of fatty acid oxidation
      • Leptin promotes fatty acid (FA) oxidation in skeletal muscle through activation of AMP-activated protein kinase which, in turn, phosphorylates and inhibits acetyl-coenzyme A carboxylase, leading to reduced malonyl-coenzyme A and increased FA flux into the mitochondria via carnitine palmitoyl transferase-1. [30]
  • pancreas

    Influences

    • negative insulin
      • Functional leptin receptor is present in pancreatic islets and suggest that leptin overproduction, particularly from abdominal adipose tissue, may modify directly both basal and glucose-stimulated insulin secretion. [31]

    Induced phenotypes

    • non-insulin-dependent diabetes mellitus (NIDDM)
      • In mutant mouse models, leptin deficiency or resistance, respectively, results in severe obesity and the development of a syndrome resembling NIDDM. One of the earliest manifestations in these mutant mice is hyperinsulinemia. [18]
  • heart

    Induced phenotypes

    • regulation of cardiac myocyte metabolism
      • Leptin can regulate the baseline physiology of the heart, including myocyte contractility, hypertrophy, apoptosis and metabolism. [32]
      • Db/db mouse has abnormal left ventricular function in vivo, with impaired glucose uptake during ischemia, leading to increased myocardial damage. [33]
      • Although the hearts of glucose-intolerant ob/ob mice are capable of maintaining their function under conditions of increased fatty acid supply and hyperinsulinemia, they are insulin-resistant, metabolically inefficient, and unable to modulate substrate utilization in response to changes in insulin and fatty acid supply. [34]
  • kidney

    Induced phenotypes

    • positive regulation of diuresis by pressure natriuresis
      • Intravenous administration of leptin for five days to normal rats stimulated a diuresis with urine volumes being twice normal. [35]
      • Administration of leptin directly into the renal artery stimulated a natriuresis but not a kaliuresis suggesting an effect of leptin at the level of the collecting tubule. [36]
  • peritoneal_mesothelial_cell

    Influences

    • positive TGF-beta 1
      • The TGF-beta synthesis induced by leptin was amplified by glucose through increased leptin receptor expression. [37]
  • placenta

    Induced phenotypes

    • trophoblast cell proliferation
      • The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblast cells [38]
    • In humans, the leptin receptor is co-localized with leptin to the syncytiotrophoblast at the maternal interface. [39]
    • Placenta has both the long and the short isoforms of the leptin receptor. [10]
  • T-lymphocyte

    Induced phenotypes

    • positive regulation of T cell activation
      • Leptin promotes lymphocyte survival in vitro by suppressing Fas-mediated apoptosis. [40]
      • Leptin binding to ObR results in increased STAT-3 activation in T cells [40]
  • fat_cell

    Induced phenotypes

    • regulation of lipid metabolic process
      • Leptin receptor is the receptor for obesity factor leptin and is involved in the regulation of fat metabolism. [41]
  • hepatocyte

    Induced phenotypes

    • negative regulation of insulin receptor signaling pathway
      • Exposure of hepatic cells to leptin, at concentrations comparable with those present in obese individuals, caused attenuation of several insulin-induced activities, including tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1), association of the adapter molecule growth factor receptor-bound protein 2 with IRS-1, and down-regulation of gluconeogenesis. In contrast, leptin increased the activity of IRS-1-associated phosphatidylinositol 3-kinase. These in vitro studies raise the possibility that leptin modulates insulin activities in obese individuals. [42]
Reference