Leptin receptor

History

The Leptin Receptor was discovered in 1995 by Louis Tartaglia and his colleagues at Millennium Pharmaceuticals. 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 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 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 and with increased susceptibility to Entamoeba histolytica infections.

Animal 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.

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

References

1. (November 2008). "Leptin signaling in breast cancer: an overview". Journal of Cellular Biochemistry.
2. (December 1995). "Identification and expression cloning of a leptin receptor, OB-R". Cell.
3. (August 1996). "Identification of microsatellite markers linked to the human leptin receptor gene on chromosome 1". Genomics.
4. (December 1995). "Identification and expression cloning of a leptin receptor, OB-R". Cell.
5. (February 1996). "Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice". Cell.
6. (May 1996). "Mapping of the OB receptor to 1p in a region of nonconserved gene order from mouse and rat to human". Genome Research.
7. (December 2008). "Molecular physiology of weight regulation in mice and humans". International Journal of Obesity.
8. (2017). "The Leptin Receptor Complex: Heavier Than Expected?". Frontiers in Endocrinology.
9. (November 2012). "Ligand-induced architecture of the leptin receptor signaling complex". Molecular Cell.
10. (June 2014). "Structural and mechanistic paradigm of leptin receptor activation revealed by complexes with wild-type and antagonist leptins". Structure.
11. "Entrez Gene: LEPR leptin receptor".
12. (March 12, 2013). "Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis". PLOS Biology.
13. (March 1996). "Mutation screening and identification of a sequence variation in the human ob gene coding region". Biochemical and Biophysical Research Communications.
14. (June 2008). "Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population". Hypertension Research.
15. (March 2011). "A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children". The Journal of Clinical Investigation.
16. (June 2003). "Diabetic kidney disease in the db/db mouse". American Journal of Physiology. Renal Physiology.
17. (June 2007). "Swim training improves leptin receptor deficiency-induced obesity and lipid disorder by activating uncoupling proteins". Experimental & Molecular Medicine.
18. (March 2015). "Leptin in pregnancy and development: a contributor to adulthood disease?". American Journal of Physiology. Endocrinology and Metabolism.
19. (October 2002). "Possible role of placental leptin in pregnancy: a review". Endocrine.