My favorite hormone: Leptin
Leptin is a 16kDa peptide hormone that is produced mainly by
white adipocytes within adipose tissue (Hill et al., p393). It circulates in
the blood bound to a family of binding proteins and travels to receptors in the
brain (Heptulla et al., 2001). Production has also been discovered within other
tissues such as the stomach, skeletal muscles, liver, placenta, heart, ovaries
and human mammary gland. This hormone is secreted in a diurnal and pulsatile circadian
rhythm, where circulating leptin levels peak at night and are lowest midday.
Leptin was first discovered in 1994 by Jeffery Friedman from
studies on mice. Leptin is encoded by the OB gene, located on chromosome 7 of
humans (Kiess et al., 2008). It was named after the Greek word ‘leptos’ meaning
thin (Zhang et al, 1994). Experiments on mice with mutations to the ob gene
showed that they failed to produce leptin. This resulted in a huge increase in
weight and body fat in comparison to normal mice (Friedman, 2009).
Figure 1. Mouse with ob mutated gene on left, normal on right.
http://t3.gstatic.com/images?q=tbn:ANd9GcTEZPlYT6AohDwJf8EXaiCa3jrGVqTNClMi1N-vvHQ6RgasoM1P
Structure
The obese gene is encoded by a 167 amino acid polypeptide. Leptin is the produce of this gene and when secreted it is a protein 146 residue long with a single disulfide bond (Kline et al., 1997). Leptin is a cytokine four-helix bundle (its secondary structure is composed of four helices and two interconnecting loops).
Figure 2. Crystal structure of the obese protein leptin.
(Taken from NCBI)
Function
Leptin signals neurons in the hypothalamus of the central
nervous system to suppress appetite (decrease food intake) and stimulate energy
expenditure along with modulate glucose and fat metabolism (Friedman and
Halaas, 1998). It influences body weight by regulating energy balance and
metabolism (Bouassida et al., 2005).
Figure 3. Basic function of Leptin
http://www.diabesity.eu/Leptin.htm
Leptin also plays a role in reproduction by helping control
release of luteinizing hormone which triggers gonadotropin release so
reproductive tract develops and puberty is induced (Caro et al., 1996) . It is
thought that it might have an important role during pregnancy and fetal
development. Studies have shown that leptin levels are higher in pregnant women
and their fetus but decrease dramatically following birth (Kiess et al., 2008).
Women have higher serum leptin concentrations then men of the same body weight
(Castracane and Henson, 2002). They think this may be due to women having a
greater amount of body fat than men of the same weight.
Serious conditions such as obesity, diabetes and infertility
in humans can result from a leptin deficiency or resistance. (Zhang et al., 2005). Damage to the hypothalamus can also
cause obesity by destroying neurons that express the leptin receptors
(Friedman, 2009). This would inhibit signal to the body to decrease food intake
and increase energy expenditure.
Figure 4. Alterations to leptin regulation pathway that can lead to obesity
In a.the failure to produce leptin as shown
in the experiment with the mice with mutations to the ob gene results in
obesity. In b there is decreased secretion of leptin so fat cells will be come
much larger before normal levels are reached, thus as well leading to obesity. In
c there will be high levels of leptin but since there is problem with the
receptors in the hypothalamus actions of leptin fail to occur.
Ongoing Research
This recent discovery has stimulated lots of research to
determine whether it is possible be used to treat health conditions such as
diabetes and obesity. Animal models have
shown that leptin therapy was able to treat type 1 diabetes (Cappari and Bjorbaek, 2012). Preclinical trails
have shown increased sensitivity to insulin when also treated with leptin in
some patients. This increase in sensitivity allowed doses of insulin to be
significantly reduced (30-50%). Clinical
trials are currently underway to determine safety in treatment and efficacy in
lessening hyperglycaemia, glycaemic fluctuations and circulating lipid levels
in patients with this condition (Cappari and Bjorbaek, 2012). Studies have
shown leptin therapy to be unsuccessful in improving diabetes and insulin
resistance in obese patients with type 2 diabetes. At the present time leptin
therapy has only been effective for treating obese patients who have congenital
leptin deficiency (Coppari and Bjorbaek, 2012). They have found majority of
obese patients to have high levels of circulating leptin so therefore most
likely leptin resistant making leptin treatment ineffective.
References:
Caro, J.F., Sinha, M.K., Kolaczynski, J.W., Zhang, P.L.,
Considine, R.V. (1996). Leptin:
the tale of an obesity gene. Diabetes 45, 1455–1462.
Castracane,
V.D., and Henson M.C. (2002). Leptin. Springer, United States of
America. 34p.
Coppari, R., and Bjorboek, C. (2012). Lpetin revisited: its
mechanism of action and potential for treating diabetes. Nature Reviews. 11.
692-708.
Friedman, J, and Halaas, J. (1998). Leptin and the
regulation of body weight in mammals. Nature 395. 763-770.
Friedman, J. (2009). Obesity: Causes and control of excess
body fat. Nature. 459. 340-342
Heptulla, R., Smitten, A., Teague, B., Tamborlane, W., Ma,
Y., Caprio, S. (2001). Temporal Patterns of Circulating LEptin Levels in Lean
and Obese Adolescents: Relationships to Insulin, Growth Hormone, and Free Fatty
Acids Rhythmicity. The Journal of Clinical Endorinology & Metabolism.
88(1). 90-96.
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.
Kline, A., Becker, G., Churgay, L., Landen, B., Martin, D.,
Muth, W., Rathnachalam, R., Richardson, J., Schoner, B., Ulmer, M., and Hate,
J. (1997). Leptin is a four helix bundle:secondary structure by NMR. FEBS
Letters. 407. 239-242.
Zhang,
F., Chen, Y., Heiman, M., DiMarchi, R. (2005). Leptin: Structure, Function and
Biology. Vitamins & Hormones. 71. 345-372.
