Leptin receptor


Leptin receptor, also known as LEP-R or OB-R, is a type I cytokine receptor, a protein that in humans is encoded by the LEPR gene. LEP-R functions as a receptor for the fat cell-specific hormone leptin. LEP-R has also been designated as CD295. Its location is the cell membrane, and it has extracellular, trans-membrane and intracellular sections.

History

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 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 Immunoglobulin like 2nd cytokine receptor homology two membrane proximal fibronectine type-III 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 has been solved by both electron microscopy and SAXS.

Function

The leptin hormone regulates adipose-tissue mass through hypothalamus effects on hunger and energy use. It acts through the leptin receptor, 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 and with increased susceptibility to Entamoeba histolytica infections.

Animals models

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. In db/db mice, induced swimming helped to overcome obesity by upregulating uncoupling proteins.