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

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.


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][4][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.

Leptin release factors
The immune system has a role in regulating energy expenditure and AT lipolysis [45]. White adipose tissue (WAT) is the primary energy store; brown adipose tissue (BAT) is associated with heat production. Sympathetic activity in WAT is increased in conditions associated with decreased leptin synthesis/secretion, such as cold exposure and starvation. By the way, catecholamine and β-adrenoceptor agonists inhibit leptin production; this suppressive effect is mediated by β3-adrenoceptor agonists, which actively reduce leptin levels [46]. Leptin also causes sympathetic nervous system activation, resulting in regulatory feedback inhibition [47]. Intracerebroventricular injections of leptin have been noted to increase metabolic rates through increased norepinephrine release from sympathetic nerve terminals innervating BAT [48].
After a meal, plasma insulin and amino acid levels initiate the mammalian target of rapamycin (mTOR) pathway, which stimulates leptin biosynthesis via mechanisms involving the 5′/3′ untranslated region (UTR) [49]. Cyclic AMP activates cyclic AMP-activated exchange proteins (EPACs). Deletion of EPAC1 genes causes an increase in leptin sensitivity in the hypothalamus. EPAC1 is also involved in leptin secretion and expression in WAT [50].
Leptin antagonizes orexigenic pathways and stimulates anorexigenic pathways. Leptin exerts its general effects on the nervous system through these pathways [7]. Orexigenic neuropeptides that are down-regulated by leptin are orexins, agouti-related peptides, neuropeptide Y, and melanin-concentrating hormone. By the way, the anorexigenic neuropeptides upregulated by leptin are alpha-melanocyte-stimulating hormone, which acts on corticotropin-releasing hormone, cocaine and amphetamine-regulated transcript, and melanocortin-4 receptor (Figure 1) [31].
Glucocorticoids are long-term regulators of leptin expression [52,53]. They increase leptin mRNA levels by acting on adipocytes; in vitro incubation of a synthetic glucocorticoid in rats, adipocytes have been found to increase leptin secretion [54]. Oral glucocorticoids doubled serum leptin levels and leptin mRNA 24-48 hours after absorption. Furthermore, cell cultures incubated with a glucocorticoid and insulin combination synergistically increased leptin mRNA levels [55].
Lactates and hexoses also increase leptin secretion [56]. Because leptin secretion requires ATP, suppressing glucose uptake suppresses leptin secretion. When the energy supply is low, food is needed to increase it. Glucose, the cellular sensor of energy stock, stimulates leptin gene expression and secretion in both muscle and AT via hexosamine biosynthetic [57]. Insulin lowers blood sugar when glucose levels rise above normal and also increases leptin promoter activity [58]. No increase in leptin mRNA levels was observed after adipocytes were incubated with insulin for 1-2 hours, but an increase in leptin release was observed [54].
Regulation of tumor necrosis factor-alpha(TNFα) and leptin may be interdependent and similar as they have comparable functions such as suppressing  lipid synthesis, reducing food intake, and stimulating lipolysis [59]. Leptin limits AT mass. TNFα has the role of stimulating leptin secretion from mature human adipocytes. TNFα therapy has been shown to cause increased leptin levels in humans [60].

Leptin receptor and leptin resistance
Leptin receptors are in the family of cytokine receptors. There are six isoforms encoded by the LepR gene. The OB-Rb receptor is the dominant longest form. Its mutations cause obesity because it cannot bind to the receptor [16]. Obese people have high leptin levels. Circulating leptin levels are correlated with body mass index [61]. On the other hand, in diet-related exogenous obesity, studies in fat mice and humans without leptin deficiency, it has been shown that external leptin treatment does not provide a significant reduction in body weight and food intake [62]. In obese people, leptin levels increase, but hyperglycemia-correcting or appetitereducing effects are not observed [63]. Despite the increased leptin levels in obese patients, the absence of the functions of leptin, an appetite-reducing hormone, suggests leptin resistance [64]. It has been suggested that leptin resistance plays a role in the pathogenesis of obesity triggered by overeating [65]. However, the molecular mechanisms underlying leptin resistance have not yet been clearly elucidated. The inability of leptin to cross the blood-brain barrier, inhibition of the intracellular leptin signaling pathway in neurons, and/or downregulation of leptin receptors are thought to be the underlying mechanisms of leptin resistance. It has been reported that a high-fat diet causes an increase in fat mass, leading to hyperleptinemia and triggering leptin resistance [66]. In high-fat rats ( fa/fa), substitutions in OB-Rb result in reduced signaling capacity, leptin binding affinity, and cell surface expression [67]. Obese fa/fa rats have leptin resistance and are not sensitive to the effects of leptin. Although obese people may have high plasma leptin concentrations due to leptin resistance, they do not experience the effects of leptin [19].
In gastric chief cells (also known as zymogenic cell or peptic cell), leptin is released upon sensing gastrin and secretin and it is actively inhibited by cholecystokinin [68]. The binding of leptin to its receptor activates the Janus kinase (JAK) signal transducer and activator of the transcription 3 (STAT3) signal transduction pathway, inducing cellular anti-apoptotic events, angiogenesis, and proliferation [69,70]. The gene product also interacts with IL-1 and Notch cascade, which are involved in promoting tumor growth. Some other pathways activated are mitogenactivated protein kinases/extracellular signal-regulated kinases pathway (MAPK/ ERK), phosphatidylinositol 3 kinase (PI3K), 5′AMP activated protein kinase (AMPK), and mTOR [71].

Leptin-related cellular pathways
After leptin binds to its receptor on the cell membrane, it acts by stimulating the following signaling pathways in the cell.

JAK2/ STAT3 signaling pathway
In the activation of this signaling pathway, leptin is activated by phosphorylation of its receptor, binding of STAT3, and phosphorylated by JAK2 [72]. Activated STAT3 enters the nucleus and binds to target sites on DNA; and so cellular activity takes place (Figure 2).

SHP2/ERK signaling pathway
Stimulation of the leptin receptor activates the protein tyrosine phosphatase 2 (SHP2), contributing to the activation of the ERK signaling pathway, resulting in a cellular response [72,74].

JAK2/STAT5 signaling pathway
As a result of the stimulation of the receptor, it provides activation of STAT5 by JAK2. Activated STAT5 acts by binding to the target region in the nucleus [75].

The relationship between leptin and oxidative stress
Oxidative stress results from an imbalance between reactive oxygen species (ROS) and the organism's antioxidant defense. Due to oxidative stress, peroxidative damage to macromolecules and membranes of cells occurs in organisms. Moreover, their metabolic activities in cell components are impaired. Known to tissue and organ pathologies occur in the presence of oxidative stress in the organism [79][80][81][82][83][84][85][86]. It has been reported that high leptin levels can induce the formation of ROS, mainly due to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation [87,88]. However, leptin replacement therapy has also been shown to significantly downregulate NADPH oxidase expression in AT of leptin-deficient ob/ob mice [89]. This indicates that leptin has a protective role at normal levels. Free radical-mediated peroxidation of membrane lipids loses its integrity, increasing membrane fluidity and permeability. The lipid peroxidation process is one of the oxidative conversions of PUFAs to products known as malondialdehyde (MDA). MDA is a highly toxic molecule and its secondary products such as thiobarbituric acid reactive agent are commonly used to assess lipid peroxidation [90][91][92][93][94]. Glutathione (GSH) is an important nonenzymatic component of the cellular antioxidant system and plays an important role in ROS antioxidation [95][96][97]. It has been suggested that leptin modulates the activity of various antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in patients with leptin gene mutations [98]. Leptin production is increased by overexpression of the endogenous antioxidant enzyme catalase and correlates with markers of oxidative stress and inflammatory in ob/ob mice [99]. In another study, enzymatic antioxidants including catalase and GSH levels were increased by leptin treatment in ob/ob mice, and leptin treatment decreased MDA levels in rats exposed to oxidative stress [100,101]. It is noted that leptin treatment reverses the effect of streptozotocin (STZ)-induced diabetes by lowering glutathione and catalase levels and increasing lipid peroxidation [102,103] It has been reported that defective antioxidant enzyme activity is recovered after leptin treatment in the plasma of humans with leptin gene mutations and ob/ob mice [97,104]. They are most likely the result of the modulatory effect of leptin on metabolic and hormonal disorders. Recombinant leptin treatment leads to weight loss by reducing food intake and has a reducing effect on oxidative stress caused by a high-fat diet [105].
Hyperleptinemia is the most prominent feature of obesity and is likely to be involved in the pathogenesis of obesity-related pathologies [19]. Studies in obese individuals have shown a correlation between leptin levels and oxidative stress parameters such as nitric oxide (NO), superoxide anion (O 2 − .), peroxynitrite, MDA, hydroperoxides, protein carbonyl (PC) contents, GSH, and SOD [106][107][108]. Studies in which hyperleptinemia was induced by the administration of exogenous leptin in nonobese animals suggest that leptin increases the level of systemic oxidative stress [109,110]. In addition, some in vitro studies have shown that in the presence of high leptin concentration, ROS production is stimulated by endothelial cells, inflammatory cells, and other cell types [111][112][113]. In another in vitro study, it was noted that leptin significantly decreased pro-oxidant biomarkers such as MDA and NO and increased antioxidant markers such as total antioxidant capacity (TAC), SOD, and GPx against cryopreservation-induced oxidative stress in rabbit embryos. It has been suggested that leptin can be used as an antiapoptotic and antioxidant promoter to support embryonic development in vitro under oxidative stress induced by cryopreservation [114]. In one study, treatment with high glucose caused an increase in oxidative stress in pheochromocytoma (PC12) cells with excessive ROS and MDA production and depletion of GSH content, however, leptin treatment caused a decrease in MDA and ROS levels and an increase in GSH content, resulting in hyperglycemic PC12 cells. It has been reported to significantly reduce the oxidative damage mediated by reactive oxygen species caused by the condition. Therefore, it was stated that leptin may have a protective effect against oxidative stress and apoptosis mediated by reactive oxygen species caused by the hyperglycemic state [115]. In addition, hypothalamic oxidative stress induces leptin resistance, which leads to the induction of insulin resistance and obesity. Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) suppresses hypothalamic oxidative stress and improves leptin resistance in the hypothalamus [116].

The relationship between leptin and apoptosis
Recently, some studies have shown that there is an important relationship between leptin and apoptosis; such as in a study, it was determined that there is a Role of Obesity in Human Health and Disease 8 leptin receptor (Ob-R) on the surface of breast cancer cells. Leptin is thought to stimulate these cancer cells with various effects, such as migration and spread. It has been determined that the expression of Ob-R increases as the tumor grows [117]. Another study reported that leptin may affect the risk of breast cancer by increasing estrogen synthesis [118,119]. It is believed that leptin, which is associated with breast cancer, exerts this effect by affecting the JAK/STAT and MAPK pathways, as well as increasing the transcriptional expression of vascular endothelial growth factor receptor-2 (VEGFR-2) and VEGF [120]. In another study, it was determined that the ratio between leptin and adiponectin is important in regulating the development of breast cancer [121]. Again, in some studies, it has been determined that leptin triggers cell proliferation by stimulating the MAPK pathway in breast cancer cells [122]. It has been observed that leptin also stimulates estrogen receptors via MAPK in breast cancer cells [123].
It has also been reported that leptin is associated with lung cancer. Ob-Ra and Ob-Rb were expressed on the surface of lung cancer cells. It has been determined that leptin plays a role in the development and progression of lung cancer as well as its migration [124,125]. It has been reported that leptin also increases cytokine production by stimulating JAK/STAT3, PI3K/AKT, and MEK1/2 signaling pathways [126]. In a study, it was determined that the removal of leptin from the medium in non-small cell lung cancer cell lines inactivates the JAK/STAT3 and Notch signaling pathways, thus stopping cell proliferation and stimulating apoptosis (Figure 3) [128].
In some studies, leptin has been shown to stimulate cell proliferation and prevent apoptosis by activation of the PI3K/AKT signaling pathway in thyroid cancer cells [129,130].
Leptin has been reported to be associated with liver cancer [131]. In one study, they reported elevated leptin levels in patients with hepatocellular carcinoma [132]. It has been determined that leptin increases liver fibrosis by stimulating transforming growth factor-β (TGF-β) synthesis and release. It has also been reported that leptin stimulates the production of a tissue inhibitor of metallo-proteinase1 through the JAK/STAT pathway in hepatic stellate cells [133]. Leptin has also been reported to cause the proliferation of hepatocellular cancer cells by altering cyclin D1, Bcl-2 (B-cell lymphoma-2)-related X protein (Bax), and apoptotic gene activity [134]. Another study demonstrated the presence of leptin receptors on the surface of human colon tumor cells [135]. In colorectal cancer, leptin acts as a very potent mitogen and antiapoptotic cytokine. It has been determined that leptin plays a role in many stages of this type of cancer [136,137]. It has been reported that leptin increase is proportional to tumor development and tumor metastasis [138]. It has been determined that leptin exerts this effect via JAK and the extracellular signalregulating kinase (ERK) pathway [139]. In another study, they found that leptin prevented apoptosis and stimulated cell proliferation via PI3K/AKT/mTOR pathways in colon cancer cells (Figure 4) [141].
In a study conducted in ovarian cancer, it was determined that leptin is directly related to PI3K/AKT signaling pathways, antiapoptotic proteins XIAP (X-linked inhibitor of apoptosis), and Bcl-XL. By activating these pathways, leptin has been reported to suppress cell proliferation and apoptosis [142]. In another study, it was determined that leptin administration to epithelial ovarian cancer cells increases cancer cell proliferation in a dose-dependent manner, and this increase is done by suppressing genes that inhibit cell proliferation [143].
An increase in leptin levels has been found to be associated with the development of prostate cancer [144]. It has been determined that leptin suppresses apoptosis in prostate cancer cells. Leptin has been reported to exert this effect via the MAPK and PI3K pathways [145]. It has also been reported that leptin stimulates the increase of (hypoxia-inducible factor 1), which is known to play an important role in carcinogenesis in prostate cancer cell culture and stimulates the spread and adhesion of these cells [146].

Conclusion
In conclusion, leptin is adiponectin released from AT. As a result of studies, it has been reported that leptin is associated with oxidative stress and apoptosis, as well as regulating body energy metabolism and food intake. Knowing the release of leptin, its receptor, cellular effects, and especially the relationship between oxidative stress and apoptosis will guide various studies on this subject.
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