Leptin and Its Role in Oxidative Stress and Apoptosis: An Overview

*Volkan Gelen, Abdulsamed Kükürt, Emin Şengül and Hacı Ahmet Devecı*

#### **Abstract**

Adipose tissue (AT) in the body plays a very important role in the regulation of energy metabolism. AT regulates energy metabolism by secreting adipokines. Some of the adipokines released are vaspin, resistin, adiponectin, visfatin and omentin, and leptin. In addition to regulating energy metabolism, leptin plays a role in the regulation of many physiological functions of the body such as regulation of blood pressure, inflammation, nutrition, appetite, insulin and glucose metabolism, lipid metabolism, coagulation, and apoptosis. Among all these physiological functions, the relationship between leptin, oxidative stress, and apoptosis has gained great importance recently due to its therapeutic effect in various types of cancer. For this reason, in this study, the release of leptin, its cellular effects and its effect on oxidative stress, and apoptosis are discussed in line with current information.

**Keywords:** Apoptosis, leptin, obesity, oxidative stress

#### **1. Introduction**

Obesity is defined as a chronic disease that results in an increase in adipose tissue (AT) in the body as a result of the energy intake being more than the energy spent. Today, it has become a common and important health problem in both developed and developing countries due to various reasons such as changes in eating habits and inactivity [1, 2]. Obesity directly or indirectly affects national economies. Obesity causes an increase in the rates of noncommunicable diseases, damage to various organs, shortens the life span, and negatively affects the quality of life [3–5]. In the case of obesity, which is so important, the level of leptin increases. Leptin is an adipokine secreted in fat cells [6]. After leptin is released from the fat cell, it reaches the central nervous system via the blood, binds to its receptor, and reduces food intake through this receptor [7, 8]. Leptin is produced by the obese *(ob)* gene in adipose cells by encoding it into mRNA [9, 10]. As the number of fat cells in the body increases, the plasma leptin level also increases. While leptin decreases plasma glucose and insulin levels, it increases metabolic rate and physical activity, resulting in a decrease in body fat [11]. It has been determined that leptin, which has such important effects on fat cells and hunger, is effective on cancer cells. In line with this information, this study aimed to explain leptin synthesis, its receptor, factors affecting its release, and the relationship between leptin, oxidative stress, and apoptosis.

### **2. Leptin**

Leptin (a fat tissue hormone), the *ob* gene product, was the first adipokine discovered. Its discovery is based on work done in the 1950s. It begins with the researchers' discovery of two genes, called diabetic *(db/db)* and obese *(ob/ob)*, in two separate strains of mice [12, 13]. In a study conducted in these mice, which have the same phenotypic characteristics (such as insulin resistance, morbid obesity, lethargy, and infertility), blood leptin level was found to be deficient in the *ob/ob*  gene product, while the *db/db* gene product was found to have a deficient leptin receptor. In addition, in the study where *db* and *ob* genes were examined in detail, *db/db* and *ob/ob* mice were both three times heavier than controls, and both groups of animals had five times more fat than the control [14]. About 40 years after the first studies, the *ob* or *Lep* gene encoding leptin was discovered and given this name because of its weak meaning [15]. About a year later, the isolation of the leptin receptor gene was reported [16].

The mouse leptin gene size is 4.5 kilobases long containing 167 amino acids [15]. Regulation of the leptin gene initiator that controls leptin production, is mediated by glucocorticoid response elements, CCAAT/enhancers, cyclic adenosine monophosphate (cAMP), and specificity protein 1 (SP1) binding sites [17]. Studies have shown that human leptin is 84% similar to mouse leptin and 83% to rat leptin [18]. Besides, a positive correlation was found between plasma leptin concentrations and AT leptin mRNA levels. Therefore, as leptin mRNA increases, plasma leptin concentrations also increase [19].

Human leptin is produced from a gene on chromosome 7. The structure of human leptin, a 16 kilodalton protein, is in the form of a 4 α helical bundle coil, like class-I helical cytokines [20]. The most highly conserved amino acid extension is the GLDFIP sequence [21, 22]. Leptin, synthesized by adipocytes, is a hormone that notifies the brain of energy reserves and affects metabolism, reproduction, growth, and development processes [16, 22]. Circulating leptin levels act at the hypothalamic central level to increase energy expenditure and reduce food intake when the body is well nourished [23]. It induces the storage of triglycerides in AT and has an effect on appetite [7]. When plasma leptin levels increase, it sends a signal of satiety to the brain in the short term, while it sends information about the energy status in the long term [24]. It also influences hypothalamic neuropeptide signaling [25]. The main physiological role of leptin during periods of hunger is to regulate the neuroendocrine system. With regard to obesity, leptin levels rise with increasing adiposity [26]. Circulating leptin levels are high in obese, pointing to the importance of leptin resistance in the obese [24]. Leptin-deficient mice have been found to show neuroendocrine abnormalities similar to starving mice. Leptin supplementation causes neuroendocrine normalization and reduced food intake in leptin-deficient obese rodents and humans, thereby reversing obesity [10]. Mutations of the *ob* gene result in leptin resistance and extreme obesity in mice [15]. *Ob/ob* mice have neuroendocrine abnormalities and they are generally classified as hyperphagic, hypothermic, morbidly obese [27].

It has been reported that leptin plays a proinflammatory role by increasing the inflammatory immune response, and this is associated with the pathogenesis of many complications of obesity [28]. It is noted that leptin can affect both adaptive and innate immunity by inducing proinflammatory response and thus playing a key role in regulating the pathogenesis of various autoimmune/inflammatory diseases [29]. It has been shown that as the degree of obesity increases in adults, the levels of plasminogen activator inhibitor-1 (PAI-1) and leptin, which is a proinflammatory marker, increase. It has been reported that it is responsible for the proinflammatory process, which is associated with an increased level of obesity [30]. Leptin regulates the functions of immune cells, such as natural killer cells, dendritic cells, neutrophils, eosinophils, macrophages, and basophils [23].
