**3. Leptin signaling pathways**

Leptin mediates its biological effects by binding to its various alternatively spliced isoforms receptor located at the brain and peripheral tissues. The binding of leptin to its long-form of receptor activates various intracellular signaling pathways, including insulin receptor substrate (IRS)/phosphatidylinositol 3 kinase (PI3K), Janus kinase 2 (JAK2)/Signal transducer, and activator of transcription 3 (STAT3), SH2-containing protein tyrosine phosphatase 2 (SHP2)/Mitogen-activated protein kinase (MAPK), and 5′ adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) [8]. The binding of leptin to its receptor activates JAK2, which in turn phosphorylates the Tyrosine amino acid residues in LepRb and is terminated by a suppressor of cytokine signaling 3 (SOC3) [15].

Leptin input a significant role in energy homeostasis and neuroendocrine function through JAK2/STAT3 signaling pathway. A selective deletion in LepRb or STAT3 in LepRb-expressing neurons ends with obesity and hyperphagia, which further supports the dominant role of the JAK2/STAT3 signaling pathway in the leptin-induced body weight regulation [16]. One interesting fact about leptin and insulin is that both have similar intracellular signaling pathways (PI3K/Akt) in neurons [17]. The ERK, a member of the MAPK family, acts downstream of LepRb and is mediated through

### **Figure 2.**

*Leptin regulates many signaling pathways through receptor (Ob-Rb) binding mechanism. It regulates gene expression through JAK/STAT3 pathway, modulates other signals through PI3K/rho family dependent pathway, induces vasodilation through NO-dependent pathway, and accelerates angiogenesis through PI3K/Akt/mTOR/ s6 kinase/VEGF a and PI3/Akt/NO-dependent pathways. Promotes tumor progression through HIF-1 alpha pathway and enhances platelet aggregation through the PLC pathway. The SOS3 molecule function as a regulator of leptin induced signaling activations by negative feedback mechanism.*

SHP2 or by JAK2. Inhibition of ERK prevents leptin-based sympathetic function in brown adipose, which further supports SHP2/MAPK in leptin energy expenditure and food intake [18]. Leptin's suppressive mode of action on food intake initiates by inhibiting the effect of AMPK in the brain. The inhibition of AMPK regulates feeding through the mTOR (mammalian target of rapamycin)/s6Kinase pathway [19]. In skeletal muscle, leptin directly exists its effect through AMPK signaling and stimulates fatty acid oxidation and glucose uptake [20]. Leptin has a prominent role in the modulation of both innate and adaptive immunity. It stimulates neutrophil chemotaxis and promotes phagocytosis of macrophages through the receptor binding mechanism. It is also known to increase the production of IL-6 and TNF-alpha under pathological conditions [21]. Leptin protective action on neutrophils exerts through PI3K and MAPK depending on signaling and prevents apoptosis of neutrophils. Leptin via STAT3 activation promotes natural killer cell activation [22]. In the adaptive immune response, leptin promotes native T cells proliferation by increasing the expression of interferon-gamma and TNF-alpha in T cells [23].

Apart from the mentioned direct signaling pathways, leptin interacts with many signaling functions as a multifunctional cytokine. Leptin shows a potential functional relationship with Nitric Oxide (NO) and favors NO-mediated lipolysis and vascular tone [24]. The significant other functions of leptin are associated with its predominant role in angiogenesis. It is observed that Endothelial cells (ECs) express OB-R leptin receptors and the binding of leptin to OB-R enables the growth of small blood vessels [3]. Recently, it has been identified that leptin could induce PI3K/Akt/mTOR/ s6Kinase signaling pathway and enhance VEGF mRNA's transcription level while inducing angiogenesis [4]. One of the intriguing possibilities of leptin is that it promotes neovascularization through paracrine mode concerning the volume of fat mass [25]. Leptin could promote proliferation in colonic epithelial cells in vitro conditions. Moreover, the presence of OB-R receptor in human colon cancer cell lines and human Colonia tissue thus supports the angiogenic role of leptin under cancer environment through PI3K/AKT, MAPK/ERK, and JAK2/STAT3 pathways [26, 27]. Leptin could induce apoptosis and regulate actin-myosin cytoskeleton associated with Rho family GTPases (**Figure 2**) [28].
