Assignment 2 - Leptin Structure

Figure 1: Crystal Structure of Leptin. (Taken from NCBI website).

The human leptin gene is just over 16,000 base pairs in length, and is located on chromosome 7, at 7q31.3 (NCBI). It encodes a 16 kDa, 167 amino acid protein with four antiparallel alpha helices, similar to the long-chain helical cytokine family of proteins (Zhang et al., 2007). The tertiary structure of the protein includes a "hydrophobic core" of amino acids facing inward on each helix, and a disulphide bond between cysteine residues 96 and 146. This disulphide bond is particularly important to folding of the protein and for binding the leptin receptor (Fruhbeck, 2006). As seen in the protein alignment below, Cys96 and Cys146 are conserved between species as varied as human, chicken and sturgeon. Sections of the four alpha helices are also well conserved between species (Zhang et al., 2007).

Figure 1: Alignment of protein sequences for Mus musculus leptin

 (Accession number NM_008493), Gallus gallus leptin (AF012727), Acipenser

 schrenckii leptin (DQ784816) and Homo sapiens leptin (U43653). Prepared using

 ClustalW software.

 

The scores associated with this alignment indicate that the most similar sequences are those from the mouse and sturgeon, while the human sequence is least similar to any of the others.

Table 1: Alignment Scores for Mouse, Human, Chicken and Sturgeon

Leptin Protein Sequences

SeqA Name       Len(aa)  SeqB Name       Len(aa)  Score

=======================================================

1    mouse      167      2    human      167      83   

1    mouse      167      3    chicken    163      96   

1    mouse      167      4    sturgeon   146      99   

2    human      167      3    chicken    163      80   

2    human      167      4    sturgeon   146      84   

3    chicken    163      4    sturgeon   146      95   

=======================================================

Assignment 1 - Leptin (My Favourite Hormone)

Leptin is a 167 amino acid, 16kb protein hormone which is synthesized and secreted by adipose tissue.  It is also produced in lesser amounts in tissues such as the placenta, ovaries, mammary epithelium, and bone marrow (Dardeno et al., 2010). Its levels within the body follow a circadian rhythm, peaking late at night and decreasing during the day. Leptin secretion has been shown to be affected by sex hormone levels, with women generally having more of the hormone than men (reviewed in Dardeno et al., 2010).

Figure 1: Normal mouse (left) and ob/ob mouse. Taken from "Genome News Network"

Leptin is the product of the obese (ob) gene, originally studied in mice, where a homozygous mutation (ob/ob) was known to cause obesity (Dardeno et al., 2010). It was unknown how this mutation caused obesity; however, until 1994 when Zhang et al. cloned both the mouse and human ob genes (Zhang et al., 1994; reviewed in Dardeno et al., 2010). They discovered that the gene product was a secreted adipose tissue protein, highly conserved between mice and humans, and important in regulating energy balance (Zhang et al., 1994). This protein was later determined to be a hormone, and named leptin, from the Greek root leptόs, meaning “thin,” as it had been shown to reduce the weight of obese mice (Halaas et al., 1995). 

Leptin is an important regulator of the amount of fat stored within the body. It can cross the blood-brain barrier, and acts on different areas of the hypothalamus to stimulate energy expenditure and suppress appetite (Kiess et al., 2008). It has also been shown that leptin acts on areas of the brain that control arousal, mood, and reward, decreasing an animal’s desire for food, while roles in brain development, immune function, and bone metabolism have also been demonstrated (reviewed in Dardeno et al., 2010).

             The leptin receptor (Ob-R) has several isoforms, which are classified as long, short and soluble. These receptors are found throughout the central nervous system, but also in various tissues such as the kidney, liver, intestine, stomach and heart (Kiess et al., 2008). When leptin binds its receptor, several signaling pathways are activated, including the Jak2/Stat3, PI3K, and MAPK pathways, leading to the observed effects on appetite and body weight (Dardeno et al., 2010).

Although it has been shown that leptin cannot simply cure obesity (obese humans are generally resistant to the hormone), ongoing research with leptin and leptin sensitizers may lead to therapies for weight loss and weight loss maintenance in the future.

References:
Dardeno, T.A., Chou, S.H., Moon, H.S., Chamberland, J.P., Fiorenza, C.G., and Mantzoros, C.S. (2010). Leptin in human physiology and therapeutics. Frontiers in Neuroendocrinology 31 377-93.
Halaas, J.L., Gajiwala K.S., Maffei M., Cohen S.L., Chait B.T., Rabinowitz D., Lallone R.L., Burley S.K., Friedman J.M. (1995). Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269(5223) 543-6.
Kiess, W., Petzold, S., Töpfer, M., Garten, A., Blüher, S., Kapellen, T., Körner, A., Kratzsch, J. (2008). Adipocytes and adipose tissue. Best Practice and Research Clinical Endocrinology and Metabolism 22 135-53.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., and Friedman, J.M. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505) 425-32.