Leptin receptor, also known as LEP-R or OB-R, is a

type I cytokine receptor Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name ''hemopoietin receptors'', and share a c ...

, a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''LEPR''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295 (

cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

295). Its location is the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

, and it has extracellular, trans-membrane and intracellular sections (''protein regions'').

History

The Leptin Receptor was discovered in 1995 by Louis Tartaglia and his colleagues at

Millennium Pharmaceuticals Takeda Oncology (originally Millennium Pharmaceuticals) is a biopharmaceutical company based in Cambridge, Massachusetts. It is a fully owned subsidiary of Takeda Pharmaceutical. Takeda Oncology's research, development and commercialization act ...

. This same team demonstrated the leptin receptor was expressed by the mouse db gene. Furthermore, in 1996, after co-discovering the Leptin gene with Jeffrey Friedman et al. in 1994, (which involved a reverse genetic/

positional cloning A genetic screen or mutagenesis screen is an experimental technique used to identify and select individuals who possess a phenotype of interest in a mutagenized population. Hence a genetic screen is a type of phenotypic screen. Genetic screens c ...

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''.

Structure

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: 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. Ig domain interacts with Leptin and is essential for conformational change in the receptor upon ligand binding. CRH2 is essential for leptin binding, deletion of this domain abolishes the leptin binding. FNIII domains are essential for receptor activation upon leptin binding. 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 and SAXS.

Function

The leptin hormone regulates adipose-tissue mass through

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

effects on hunger and energy use. It acts through the leptin receptor (LEP-R), a single-transmembrane-domain receptor of the cytokine receptor family. 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.

Clinical significance

Variations in the leptin receptor have been associated with

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

and with increased susceptibility to ''

Entamoeba histolytica ''Entamoeba histolytica'' is an anaerobic parasitic amoebozoan, part of the genus ''Entamoeba''. Predominantly infecting humans and other primates causing amoebiasis, ''E. histolytica'' is estimated to infect about 35-50 million people worldwid ...

'' infections.

Animals models

The db/db mouse is a model of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, and

dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

wherein leptin receptor activity is deficient because the mice are

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

for a

point mutation A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...

in the gene for the leptin receptor. In db/db mice, induced

swimming Swimming is the self-propulsion of a person through water, or other liquid, usually for recreation, sport, exercise, or survival. Locomotion is achieved through coordinated movement of the limbs and the body to achieve hydrodynamic thrust that r ...

helped to overcome obesity by upregulating

uncoupling protein An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from th ...

Leptin receptor and pregnancy

The leptin hormone and its receptor, also known as maternal plasma leptin, play developmental roles during pregnancy. Leptin receptors have been identified in the placenta of pregnant women and also in fetal tissues. Those leptin receptors are secreted by the placenta; they increase leptin levels during pregnancy thereby aiding the fetal development.

References

External links

* {{Clusters of differentiation Clusters of differentiation