Function/Pathology
The main function of Leptin in the body is to maintain energy balance and thus body weight by controlling the appetite (amount of food intake) and stimulating the break down of energy. Leptin does so by interaction with receptors (LR) in the hypothalamus. There are two specific groups of neurons in the hypothalamus that have receptors for the leptin hormone. These include the agouti-related peptide (AgRP), neuropeptide Y(NPY) producing neurons and a group of neurons that produce pro-opiomelanocortin (POMC). AgRP and NPY stimulate the appetite as they are orexigenic, while POMC acts to decrease appetite (anorexigenic)[2].
Appetite
Leptin hormone in circulation easily crosses the blood-brain barrier and binds to its receptors on the two groups of neurons described. This results in activation (depolarization) of POMC producing neurons which increase the synthesis of POMC and melanocortins[2]. In contrast, leptin binding to receptors on AgRp and NPY neurons has an inhibitory effect and decreases the production of AgRp and NPY[2]. The overall effect is decreased appetite and an increase in energy metabolism. In the case of decreased leptin levels, the appetite is stimulated because of less inhibition of the appetite stimulators (AgRp and NPY) and decreased stimulation of POMC synthesis. In addition to the two main groups of neurons mentioned, leptin receptors have also been found on other neurons that produce neuropeptides which have an effect on food intake[4]. These other neuropeptides are all anorexigenic and are listed in the table below(effect of leptin on neuropeptide expression) along with NPY and POMC/melanocortins.
Energy Metabolism
Along with suppressing the appetite, leptin can alter energy metabolism in order to maintain an energy balance. Like some of the cytokines, leptin can act to stimulate the sympathetic nervous system (SNS). The stimulation of SNS causes release of epinephrine which increases the breakdown of fat into free fatty acids(lipolysis) and inhibits division of preadipocytes[3]. Insulin levels are also reduced by epinephrine, an effect also seen in response to increased leptin. This indicates an indirect mechanism of energy balance by leptin through the SNS. The regulation of energy metabolism is also attributed to leptin's effect on the thyrotropin-releasing hormone (TRH) levels. High leptin levels increase TRH levels and thus the level of thyroid stimulating hormone (TSH)[2]. This triggers production of thyroxine and thus increased metabolic rate (energy metabolism).
Reproduction
Leptin is found to be an important hormone in regulation of the reproductive system. This is because leptin can signal to the brain whether or not fat (energy) stores are high enough for reproduction. Leptin does this through the gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus which signals releas of FSH and LH from the pituitary[2]. Leptin's role in regulation of reproductive hormones has been shown in mice with two mutant alleles for the leptin(ob) gene. These mutant mice had very low fertility, but injecting recombinant leptin hormone increased the ability of these mice to reproduce[4].
Immune system
The molecular properties of leptin are very similar to the cytokines which are messenger proteins used by the immune system. Leptin has a direct effect on the immune system by increasing production of monocytes (develop into macrophages) and the release of cytokines that induce the inflammatory immune response (IL-6 and TNFalpha)[3]. As well, most stem cells that give rise to blood cells (hematopoietic cells) have the leptin receptor. Leptin-receptor binding on these cells stimulates production of blood cells and thus cells of the immune system (white blood cells)[3].Pathology
Obesity
Abnormal levels of leptin hormone or its receptor (LR) can result in high energy intake and low energy metabolism which can equate to loss of the energy (body fat) balance mechanism. High amounts of body fat leading to obesity can be caused by mutaion in the leptin gene (ob)
or the leptin receptor gene(db). In addition to excess body fat, supression of the immune response, reduced sexual maturity, insulin resistance and reduced thermoregulation are also observed in animals with a mutation in the leptin or leptin receptor gene[1]. Obesity due to mutations in the leptin or leptin receptor gene can be detected by measuring the levels of leptin in the blood. If the result is abnormally high/increased leptin levels the obese state is likely caused by mutations in the leptin receptor which causes a resistance to leptin. Very low leptin levels in comparison to normal levels for the weight of the individual indicates that are mutations in the leptin (ob) gene which leads to low levels of circulating leptin[3].The obese state caused by defects in the leptin hormone or leptin receptor, can manifest other conditions such as diabetes, cardiovascular disease or reduced sexual maturation[1]. Given this, measurement of blood leptin may be ueseful for diagnosing reproductive disorders or assesing the risk level for certain cardiovascular diseases.
References
1. Ahima, R.,S. (2002). Obesity gene therapy: slimming immature rats. Gene Therapy. 10:196-197. Retrieved Nov. 3, 2008 from http://www.nature.com/gt/journal/v10/n3/full/3301920a.html
2. Robertson, D., Leinninger, G., Myers, M.(2008). Molecular and neural mediators of leptin action. Physiology & Behavior. 94: 637-642
3. Robinson, C., Kordon, D., & Hanoune, J. (2002). Brain Somatic Cross-Talk and the Central Control of Metabolism. Germany. Springer-Verlag, Berlin, Heidelberg.
4. Trayhurn, P., Mercer, J., & Rayner, D. (1999, February). Leptin: Fundamental aspects. International Journal of Obesity & Related Metabolic disorders, 23, s22.
