Leptin

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Leptin

Structure:

Leptin is a secreted protein that is encoded by the ob gene. Leptin is composed of four alpha-helices (see Figure 1 below). As described by Zheng, et al., the alpha-helices of leptin are very similar. The four helices can be superimposed upon each other with a high degree of sequence and structural similarity. It is also important to note that the sequence of amino acids is highly conserved among species. According to Zheng, et al. there is a "67% sequence identity among such diverse species as human, gorilla, chimpanzee, orangutan, rhesus monkey, dog, cow, pig, rat and mouse" (Zheng, et al., 1997). This sequence similarity suggests that leptin is an important protein required for regulation of fat.

Figure 1. Image of leptin. It can be seen from this figure that leptin is composed of four alpha helices. Image obtained from PDB (PDB ID 1AX8).

As can be seen by the following figure, leptin is composed of two peptides. While only one gene encodes this protein (ob), there are two peptides formed. This is due to posttranslational modification that cleaves the incomplete protein into the functional two peptides. It is this form of the protein that is secreted into the bloodstream.

Figure 2. Image of cleaved alpha helix peptide. Image obtained from PDB.

Further analysis of the crystal structure of leptin by Zheng, et al. suggested that leptin may be structurally similar to proteins of the long-chain helical cytokine family. "The extracellular domain of the OB-R shows strong homology to the glycoprotein gp130 signal-transducing subunits of the interleukin-6 (IL-6) receptor, the G-CSF receptor and the LIF receptor, which couple to the JAK/STAT signal-transduction pathway. The structural similarity of the ligands and the sequence similarity of their receptors suggest a similar ligand-receptor mode of binding" (Zheng, et al., 1997).

Function:

Leptin is secreted into the bloodstream and helps to regulate the amount of fat stored in the body. It acts as a sort of lipostat; more leptin in the bloodstream increases energy expenditure and decreases food intake while less leptin decreases energy expenditure and increases food intake. The following cartoon gives a great overview of how leptin works in the body to regulate fat storage.

Figure 3. Relationship between amount of fat in body to leptin secretion. The yellow circles are adipocytes. Permission granted by R.A. Bowen. http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/bodyweight/leptin.html.

The study of the ob gene has become increasingly popular due to its possible application to treating obese individuals. Studies in mice have shown that the injection of leptin into the bloodstream of genetically obese mice causes a significant reduction in food intake and a large increase in energy expenditure. These mice lose a significant amount of their body weight and are able to maintain this weight with subsequent leptin injections. It is believed that individuals who are obese have become resistant to leptin. These individuals appear to have the ability to make leptin but are unable to properly use the protein to regulate body fat (Leptin, 1997). This suggests that the problem in these individuals may be related to a lack of binding of the leptin protein to its receptor. Being obese seems to throw the leptin lipostat off and while there is an increase in leptin secretion as one gains weight, the body does not seem to sense that the protein is being made. Mutations in either the leptin protein or leptin receptor could be the cause of the body's inability to recognize that leptin is being made. Another possibility is that the leptin being made is not able to be secreted into the bloodstream. This may be due to a structural mutation in the protein that renders it unable to pass through the membrane of the adipocyte where it is created and into the bloodstream where it can bind to its receptor.

The exact binding mechanism that occurs between leptin and its receptor is currently unknown. However, one research group has used a unique method to try and determine the exact binding site on the leptin protein. Peelman, et al. has superimposed the structure of leptin onto the known structures of proteins from the cytokine family described by Zheng, et al. The receptor binding sites of these cytokine proteins were known and sequence similarity was investigated between the cytokines and leptin. Peelman, et al. found three possible binding sites on leptin that show a high sequence similarity to the binding sites found in the cytokines. While the exact location and mechanism of binding is unknown, the work of Peelman, et al. sheds new light on areas that need to be further investigated.

References:

Leptin. 1997. <http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/bodyweight/leptin.html> Accessed 15 February 2005.

*Peelman, et al. Mapping of the leptin binding sites and design of a leptin antagonist. JBC 279 (39), 41038-41046 (2004).

PDB. 2005. <http://www.rcsb.org/pdb/index.html> Accessed 15 February 2005.

Zhang, F., et al. Crystal Structure of the obese protein leptin-E100. Nature 387, 206-209 (1997).

*Free full-text of this paper can be found at <http://www.jbc.org/cgi/content/full/279/39/41038>

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