Leptin

Leptin, a word that has gained popularity over the last 2 decades when it was discovered in 1994 [1]. When it was first discovered, it was thought to be the promising conclusion to the obesity issue we deal with today. In this article, we will discover what leptin is, where it is synthesized, what it does, and its general function in the body – let’s smoke this one!
 

What is Leptin?

Leptin is a hormone found in the body that is made up of 146 amino acids, making it a peptide [2]
 

Types of Leptin

Leptin is a hormone that, a bit like testosterone, has two states in which it is found [6][7][11]. These two states, again like testosterone, are bound and free leptin making up total leptin. Bound leptin is leptin that is bound to a particular protein/leptin receptors across the body to enact signaling and change on the body (what change is discussed later)[6][11]. Meanwhile, free leptin is leptin in the blood stream. These two variations of leptin are, in a way, independent and dependent to one another as they both make up total leptin and change based on physiological state. However, bound leptin is thought to have a strong relationship with energy expenditure of the body while free leptin is considered a marker of total fat mass of the body – so, both are closely related, yet serve slightly different markers [11].

In terms of amount, the amount of bound leptin and free leptin proportions differ from person to person with as low as 20% bound leptin found in more obese people to 45% in leaner (sub 20%, male) individuals, all the way up to 80% bound in certain genetic disorders [6][12]. The amounts of bound and free leptin change based on a variety of factors (energy state, fatty acid levels, pregnancy, obesity, etc.) [11][12].

 

Where does it come from?

Leptin is primarily found in adipocytes (fat cells) and then released into the blood stream to act on other parts of the body [3][8]. Other areas of leptin synthesis are the placenta of women, the mucosal lining of the stomach, muscle, and mammary lining (female breast lining); however, the majority of synthesis still predominates in adipose tissue (fat tissue)[3][6][8]. Within cells, leptin is most highly found along the rough endoplasmic reticulum [3].

 

Why so many synthesis sites?

It is thought that there are various sites of leptin synthesis and release, because the body uses leptin to a variety of reasons that are evidenced by the location of synthesis and the speed of release. Certain sites, like gastric (stomach) sites are fast release sites of leptin, because they communicate to the acute feedback mechanism to the neural system to indicate gastric emptying (stomach emptying into intestines)[9]. Other leptin sites, like mammary and placental synthesis sites are thought to provide leptin during pregnancy and infancy as leptin levels are typically higher around pregnancy; this is also one of several reasons (along with higher essential fat levels) why women have double the amount of leptin that men do when body fat is adjusted [5][9][10]. Then, sites in the muscle are thought to produce some leptin, because they have a connection in regulating fatty acid metabolism in the same cell or muscle tissue [9]. Finally, the most common production site in adipocytes (fat cells) have a more long term, chronic, day to day impact on the bodily system [8].
 

What does it do?

Leptin still needs significant research to fully understand its function, but among the many ways it impacts the body, there are a few that are clear. Leptin is a large driving force in satiety and hunger cues in the short term via its, presumably, gastric synthesis sites [9]. Leptin also has an impact on fetal development, especially concerned with brain development, but also in other areas, although not everything is yet understood about leptin’s impact around pregnancy [13][14]. Leptin may also have some impact on metabolism, but again, this is not well researched and requires more to be fully elucidated [9]. Leptin seems to also have an effect when looking into immune function with a reduction in leptin leading to decreased synthesis of immune cells [6]. However, its most powerful and well understood role is its impact on energy homeostasis. Leptin seems to be, in general (there are exceptions), a good indicator of energy state within the body – if the body is in a hypo caloric (lacking calories) or hyper caloric (surplus of calories) [6][8].
 

How does it function?

Leptin is synthesized within certain cells, we know this by now, but the act of synthesis and release from the cell is a modulated one – just like everything in the body. If the body is in a caloric deficit, leptin synthesis decreases from the cells, and less is released into the blood stream [6]. As leptin acts on activation sites in the hypothalamus of the brain, leptin has an impact on the perception of satiety and the energy state of the body as the hypothalamus is responsible for that regulation [6][15][16][17]. On the flip side, if the body is in a caloric surplus, leptin levels climb, and satiety signals are increased by the added act of leptin on the brain.

Synthesis of leptin is affected by the fatty acid stores within the cell; as fatty acid levels drop, the cell shrinks, and this reduces the release of leptin into the blood stream [6]. This is the reason why free leptin is correlated closely to total body fat mass as the lower free leptin, the lower total fat mass (general exceptions apply) [6]. However, there are many factors that impact leptin synthesis and release from feeding patterns, corticoids, infection, obesity, etc, [6].

How to change leptin levels?

There are various established ways to manipulate, or change leptin levels in the body, here are a few of those methods:

Calories

As we have established, the amount of energy in the system has an impact on leptin levels as leptin levels are one of the feedback mechanisms for the brain to know when it is in an energy deficient state [6][15][16][17]. So, simply consuming more calories will have a profound impact on leptin synthesis and release as fat cells will plump up with fatty acids. Or, if we, for some reason, wanted to decrease leptin amount, we could cut back our calories and see a decrease in leptin; this decrease in leptin is sensitive within a few days – even before any noticeable weight loss occurs [6].
 

Nutrient Consumption

The type of nutrient consumed also has an impact on leptin, even if talking about a caloric deficit. Consuming higher fats, even in a caloric deficit, seems to improve leptin amounts [2]. There is some debate if the type of fat also has a significant impact on leptin levels with unsaturated fats decreasing leptin levels and saturated fats increasing leptin levels [2]. Also, on a meal to meal basis, carbohydrates, specifically higher glycemic foods, seem to increase leptin higher than fat; however, if this matters in the overall makeup of the nutrition protocol is unlikely considering leptin is generally not a good feedback mechanism meal by meal, but rather, day by day or week by week [2][6]. Conversely, lower glycemic foods and fiber tend to lower leptin levels, but may increase leptin sensitivity (better recognition and regulation) [2].

Physical Activity

Physical activity is a controversial subject in relation to leptin manipulation. Some studies indicate that leptin shows no significant change with increased physical activity and exercise [8]. However, there may some reduction of leptin in extreme cases (marathons, triathlons) [8]. So, moderate exercise seems to show no real impact, and what impact there may be might be able to be explained by the increased metabolic demand of exercise from the thermic effect of physical activity, if not the increase in musculature on basal metabolic rate [8].

How is it cleared from the system?

Leptin is not a molecule that is completely broken down to a point where the body can use its constituent parts entirely. Once leptin has run its course it is cleared by the kidneys [18]. The exact amount of clearance by the kidneys is still rather up in the air with numbers running between 50 – 80% clearance of total body leptin, and other organs (that remain unidentified) likely offer the remainder of leptin clearance [18][19]. Either way, the renal system (kidneys) is likely the biggest contributors to leptin clearance from the body.

Summary

Now that we have a good basis of information on the nature of leptin, we can see that it has a profound impact on satiety signaling, hunger cues, and is a marker for the current energy levels of the body. Not only that, it can be used as a marker for overall body fatness. It has other functions, some undiscovered, but its main role is to help regulate the energetic level of the body by acting on the brain. The more leptin, in general, the more satiated a person will feel, and the opposite being true with less leptin. Leptin is primarily released by fat cells, but does get synthesized in other areas, especially in women where leptin is in much higher proportional levels than in men. Factors that impact leptin regulation are hormonal state, fat cell size, and fatty acid content within cells, so the amount of calories, the types of nutrients, and possible exercise have an impact on leptin synthesis and release from the cells.

Writer: Nicolas Verhoeven

                                                                                                        Citations

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[7] Proto, C., Romualdi, D., Cento, R. M., Romano, C., Campagna, G., & Lanzone, A. (2007). Free and total leptin serum levels and soluble leptin receptors levels in two models of genetic obesity: the Prader-Willi and the Down syndromes. Metabolism, 56(8), 1076-1080. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17618952

[8] Margetic, S., Gazzola, C., Pegg, G. G., & Hill, R. A. (2002). Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord, 26(11), 1407-1433. Retrieved from http://www.nature.com/ijo/journal/v26/n11/full/0802142a.html

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[10] Pérez-Pérez, A., Sánchez-Jiménez, F., Maymó, J., Dueñas, J. L., Varone, C., & Sánchez-Margalet, V. (2015). Role of leptin in female reproduction. Clinical Chemistry and Laboratory Medicine (CCLM), 53(1). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/25014521

[11] Brabant, G., Horn, R., Von zur Mühlen, A., Mayr, B., Wurster, U., Heidenreich, F., … Feldt-Rasmussen, U. (2000). Free and protein bound leptin are distinct and independently controlled factors in energy regulation. Diabetologia, 43(4), 438-442. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10819236

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[13] Udagawa, J., Hatta, T., Hashimoto, R., & Otani, H. (2007). Roles of leptin in prenatal and perinatal brain development. Congenital Anomalies, 47(3), 77-83. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17688465

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