Leptin receptor (OB-R), also named B219, is a type I cytokine receptor family protein with an significant amino acid sequence identity with an gp130, G-CSF receptor, and the LIF receptor. Multiple isoforms of Human and Mouse OB-R, including a long form (OB-RL) with an a large cytoplasmic domain capable of signal-transduction, and several receptor isoforms with an short cytoplasmic domains (OB-Rs) lacking signal-transducing capabilities, have been identified. The extracellular domains of the short and long forms of OB-R are identical. An OB-R transcript lacking a transmembrane domain and potentially encoding a soluble form of the receptor has also been described. Circulating soluble OB-R, complexed to leptin, has been detected in Mouse serum. Serum soluble OB-R levels have been shown to increase during pregnancy. OB-RL transcripts were reported to be expressed predominantly in regions of the hypothalamus previously thought to be important in body weight regulation. Expression of OB-Rs transcripts have been found in multiple tissues, including the choroid plexus, lung, kidney and primitive hematopoietic cell populations. OB-R has recently been shown to be encoded by the Mouse diabetes (db) and rat fatty (fa) genes. Rodents homozygous for the db or fa mutations have been known to exhibit an obesity phenotype. Mouse OB-R long form encodes a 1162 amino acid (aa) residue precursor protein with an a 22 aa residue signal peptide, an 817 aa residue extracellular domain, a 21 aa residue transmembrane domain, and a 302 aa residue cytoplasmic domain. The extracellular domain of OB-R contains two hemopoietin receptor domains, a fibronectin type III domain and the WSXWS domain. Recombinant murine soluble OB-R has been shown to bind leptin with an high affinity and is a potent leptin antagonist.
Leptin is a hormone secreted from white adipocytes and plays important role in the regulation of food intake and energy balance. Leptin functions via signaling pathways involving OB-R in hypothalamus. Animal models have revealed the influence of Leptin in reducing body weight and regulating blood glucose level. When mutations are introduced in obese gene, mice with impaired function of leptin are massively obese and in high risk of diabetes. Leptin deficiency reduces metablic rate. Leptin deficient mice are less active and with lower body temperature than normal animals. Human Leptin shares approximately 84% sequence identity with the mouse protein. Human Leptin consists of 167 amino acid residue including a 21 amino acid residue signal sequence and 146 amino acid residue mature protein sequence.
The Leptin receptor is a member of the Class I cytokine receptor family. It mediates the activities of Leptin, a multi-functional hormone produced primarily by adipose tissues that plays roles in food intake, energy metabolism, angiogenesis, reproduction, hematopoiesis, bone metabolism, and immune function. The human Leptin R gene encodes 1165 amino acids (aa) including a signal peptide, an extracellular region with cytokine receptor homology (CRH), multiple fibronectin type III domains and a WSXWS motif, a transmembrane domain, and a cytoplasmic domain that supports JAK/STAT signaling. Soluble Leptin R is the primary Leptin-binding protein in blood, where it maintains a pool of available bioactive Leptin, delays Leptin clearance from circulation, and down-regulates blood-brain transmission of Leptin. In humans, soluble Leptin R levels are inversely proportional to adiposity and are elevated in females versus males. Soluble Leptin R is also found up-regulated in patients with chronic heart failure, end-stage renal disease, and anorexia.It is expressed by tumor-initiating stem cells, and is proposed as a link between cancer and obesity.
Leptin Receptor or CD295 belongs to the gp130 family of cytokine receptors that are known to stimulate gene transcription via activation of cytosolic STAT proteins. This protein is a receptor for leptin (an adipocyte-specific hormone that regulates body weight) and is involved in the regulation of fat metabolism , as well as in a novel hematopoietic pathway that is required for normal lymphopoiesis. Leptin Receptor/CD295 is transmembrane catalytic receptors found on NPY/AgRP and alpha-MSH/CART neurons in hypothalamic nuclei. Leptin receptors (Ob-Rs) are coded for by one Human gene that produces six different isoforms, Ob-Ra-Ob-Rf. Ob-Rs exist as constitutive dimers at physiological expression levels. Only the Ob-Rb isoform can transduce intracellular signals and does so through activation of the JAK2/STAT3 , PI 3-K , and MAPK signaling cascades. Activation of Ob-Rs mediates transcriptional regulation of the hypothalamic melanocortin pathway and downregulates endocannabinoid expression. Leptin acts via leptin receptors. Leptin resistance has been proposed as a pathophysiological mechanism of obesity. In obese individuals , Ob-Ra (which is involved in the active transport of leptin across the blood-brain barrier) expression is downregulated and the individual may be unresponsive to leptin signals. Ob-R antagonists are of great interest in the development of pharmacological treatments for obesity. Mutations in the Leptin Receptor/CD295 have been associated with obesity and pituitary dysfunction.
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