Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, [5] a protein that in humans is encoded by the LEPR gene. [6] [7] LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 (cluster of differentiation 295). Its location is the cell membrane, and it has extracellular, trans-membrane and intracellular sections (protein regions).
The Leptin Receptor was discovered in 1995 by Louis Tartaglia and his colleagues at Millennium Pharmaceuticals. [8] This same team demonstrated the leptin receptor was expressed by the mouse db gene. [9] Furthermore, in 1996, after co-discovering the Leptin gene with Jeffrey Friedman et al. in 1994, (which involved a reverse genetic/positional cloning strategy to clone ob and db), Rudolph Leibel, working with collaborators also at Millennium Pharmaceuticals and colleague Streamson Chua, confirmed cloning of the leptin receptor by demonstrating that an apparent leptin receptor cloned from a choroid plexus library using leptin as ligand, mapped to a physical map that included db and fa. [10] [11]
Like other cytokine receptors, Leptin receptor protein has three different regions: i) extracellular, ii) trans-membrane, and iii) intracellular. The extracellular part has 5 functional domains: [12] i) membrane distal 1st cytokine receptor homology (CRH1), ii) Immunoglobulin like (Ig), iii) 2nd cytokine receptor homology (CRH2) and iv) two membrane proximal fibronectine type-III (FNIII) domains. CRH1 domains is not essential for Leptin binding, but may have regulatory roles. [12] Ig domain interacts with Leptin and is essential for conformational change in the receptor upon ligand binding. [12] CRH2 is essential for leptin binding, deletion of this domain abolishes the leptin binding. [12] FNIII domains are essential for receptor activation upon leptin binding. [12] The structure of the quaternary complex of the complete extracellular part in complex with the cognate ligand Leptin (i.e. 2 receptor and 2 ligand) has been solved by both electron microscopy [13] and SAXS. [14]
The leptin hormone regulates adipose-tissue mass through hypothalamus effects on hunger and energy use. It acts through the leptin receptor (LEP-R), a single-transmembrane-domain receptor of the cytokine receptor family. [15] In hypothalamic neurons, adequate leptin receptor function and subsequent regulation of energy metabolism and body weight depends on interactions of the receptor with gangliosides in the cell membrane. [16]
Variations in the leptin receptor have been associated with obesity [17] [18] and with increased susceptibility to Entamoeba histolytica infections. [19]
The db/db mouse is a model of obesity, diabetes, and dyslipidemia wherein leptin receptor activity is deficient because the mice are homozygous for a point mutation in the gene for the leptin receptor. [20] In db/db mice, induced swimming helped to overcome obesity by upregulating uncoupling proteins. [21]
The leptin hormone and its receptor, also known as maternal plasma leptin, play developmental roles during pregnancy. [22] Leptin receptors have been identified in the placenta of pregnant women and also in fetal tissues. [23] Those leptin receptors are secreted by the placenta; they increase leptin levels during pregnancy thereby aiding the fetal development. [23]
Leptin is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.
Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.
Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme that, in humans, is encoded by the PTPRC gene. PTPRC is also known as CD45 antigen, which was originally called leukocyte common antigen (LCA).
The prolactin-releasing peptide receptor (PrRPR) also known as G-protein coupled receptor 10 (GPR10) is a protein that in humans is encoded by the PRLHR gene.
Melanocortin 4 receptor (MC4R) is a melanocortin receptor that in humans is encoded by the MC4R gene. It encodes the MC4R protein, a G protein-coupled receptor (GPCR) that binds α-melanocyte stimulating hormone (α-MSH). In mouse models, MC4 receptors have been found to be involved in feeding behaviour, the regulation of metabolism, sexual behaviour, and male erectile function.
ADGRV1, also known as G protein-coupled receptor 98 (GPR98) or Very Large G-protein coupled receptor 1 (VLGR1), is a protein that in humans is encoded by the GPR98 gene. Several alternatively spliced transcripts have been described.
Melanocortin 3 receptor (MC3R) is a protein that in humans is encoded by the MC3R gene.
Interleukin 10 receptor, beta subunit is a subunit for the interleukin-10 receptor. IL10RB is its human gene.
Interleukin 11 receptor, alpha subunit is a subunit of the interleukin 11 receptor. IL11RA is its human gene.
Receptor-type tyrosine-protein phosphatase N2 (R-PTP-N2) also known as islet cell autoantigen-related protein (ICAAR) and phogrin is an enzyme that in humans is encoded by the PTPRN2 gene. PTPRN and PTPRN2 are both found to be major autoantigens associated with insulin-dependent diabetes mellitus.
The ob/ob or obese mouse is a mutant mouse that eats excessively due to mutations in the gene responsible for the production of leptin and becomes profoundly obese. It is an animal model of type II diabetes. Identification of the gene mutated in ob led to the discovery of the hormone leptin, which is important in the control of appetite.
The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.
Adipose tissue is an endocrine organ that secretes numerous protein hormones, including leptin, adiponectin, and resistin. These hormones generally influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes and obesity.
RPGRIP1L is a human gene.
Douglas L. Coleman was a scientist and professor emeritus at the Jackson Laboratory, in Bar Harbor, Maine. His work predicted that there exists a hormone that can cause mice to feel full, and that a mutation in the gene encoding this hormone can lead to obesity. The gene and corresponding hormone were discovered about 20 years later by Jeffrey M. Friedman, Rudolph Leibel, and their research teams at Rockefeller University, which Friedman named leptin.
Teleost leptins are a family of peptide hormones found in fish (teleostei) that are orthologs of the mammalian hormone leptin. The teleost and mammalian leptins appear to have similar functions, namely, regulation of energy intake and expenditure.
Rudolph Leibel is the Christopher J. Murphy Professor of Diabetes Research, Professor of Pediatrics and Medicine at Columbia University Medical Center, and Director of the Division of Molecular Genetics in the Department of Pediatrics. He is also co-director of the Naomi Berrie Diabetes Center and executive director of the Russell and Angelica Berrie Program in Cellular Therapy, Co-director of the New York Obesity Research Center and the Columbia University Diabetes and Endocrinology Research Center.
Louis Anthony Tartaglia is an American biochemist, pharmaceutical scientist, and entrepreneur. As a scientist, he is known for first identifying and cloning the leptin receptor in 1995, a discovery that prompted immediate coverage in US national media given its expected clinical significance. He is also known for studying signaling mechanisms from the tumor necrosis factor (TNF) receptors, and for publishing studies in the fields of obesity and diabetes which are often discussed in subject reviews. After moving from academia to industry in 1990, for over a decade he accompanied the growth of Millennium Pharmaceuticals, reaching top positions within the company. From executive roles he has occupied in venture capital firms, and as a member of several advisory boards, Tartaglia has helped start a number of therapeutics oriented companies that have found their way into the market, among them Agios, Editas, Rhythm, and Zafgen.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
