**5. 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].

#### **6. 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.

#### **6.1 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**).

#### **Figure 2.**

*Leptin signaling pathways. POMC;pro-opiomelanocortin, SOCS3; intracellular suppressor of cytokine signal 3, PTP1B; protein tyrosine phosphatase 1B, SHP2; tyrosine phosphatase 2, IRS; (insulin receptor substrate)/PI3K; (phosphoinositol 3 kinase), FoxO1; (forkhead box O1) and mTOR; (mammalian target of rapamycin), S6K; ribosomal S6 kinase, ERK; extracellular signal-regulated kinase [73].*

#### **6.2 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].

#### **6.3 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].

#### **6.4 IRS/ PI3K Signaling pathway**

Leptin also activates the IRS (insulin receptor substrate)/PI3K (phosphoinositol 3 kinase) pathway [76, 77] (**Figure 2**). The SH2B1 adapter protein mediates activation of the PI3K pathway by linking the JAK2 and IRS protein via the SH2 domain [78]. In addition, the IRS/PI3K pathway proceeds in two substeps, FoxO1 (forkhead box O1) and mTOR (the mammalian target of rapamycin) (**Figure 2**).

### **7. 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 [79–86]. 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.

#### *Leptin and Its Role in Oxidative Stress and Apoptosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.101237*

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 [90–94]. Glutathione (GSH) is an important nonenzymatic component of the cellular antioxidant system and plays an important role in ROS antioxidation [95–97]. 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 (O2 − .), peroxynitrite, MDA, hydroperoxides, protein carbonyl (PC) contents, GSH, and SOD [106–108]. 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 [111–113]. 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].

#### **8. 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 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 metalloproteinase1 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].

#### **Figure 3.**

*Leptin signaling. AKT; protein kinase B, GRB2; growth factor receptor-bound protein 2, JAK; Janus kinase, Ob-R; leptin receptor, MAPK; mitogen-activated protein kinase, FOS, JUN, JUNB; GENES PI3K; phosphatidylinositol 3 kinase, SHP2; Src homology 2-containing tyrosine phosphatase, STAT3; signal transducer and activator of transcription 3 [127].*

*Leptin and Its Role in Oxidative Stress and Apoptosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.101237*

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].

#### **Figure 4.**

*Intracellular signaling pathways of leptin in connection with cellular proliferation. AKT: Protein kinase B/serine–threonine kinase, ERK: Extracellular signal-regulated kinase, JAK: Janus kinases, MAPK: Mitogenactivated protein kinase, MEK: Mitogen-activated protein kinase, mTOR: Mechanistic/mammalian target of rapamycin, Ob-R: Leptin receptor, PI3K: Phosphatidylinositol3-kinase, STAT: Signal transducer and activator of transcription [140].*
