Leptin is a 16kDa cytokine like adipokine encoded by the obese (ob) gene, which mainly acts through the central nervous system (CNS) [1]. Leptin initiates inhibition of food intake and stimulates energy expenditure by activating receptors on neurons in the hypothalamus. While the circulating leptin level is proportional to the mass of WAT in order to control the energy metabolism, elevated leptin levels observed in obesity fail to promote this effect, a phenomenon also known as leptin resistance. However, the central action of leptin is not limited to food intake and energy expenditure. Leptins pleiotropic effects also infl uence immunity, reproduction, glucose metabolism, hematopoiesis and bone development. Leptin is thought to act also on peripheral tissues such as skeletal muscle or pancreas.
Leptin binds to the leptin receptor (OB-R; CD295) encoded by the diabetes (db) gene. Among six different splice forms (Ob-Ra through Ob-Rf),the long isoform Ob-Rb is required for the physiologic actions of leptin. The receptor is expressed at high levels at different sites of the hypothalamus. It has been shown, that leptin receptor activation at these sites inhibits the synthesis of appetite-promoting peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) [2]. In addition, leptin binding activates the synthesis of satiety peptides such as products of pro-opiomelanocortin (POMC) [2].
Leptin signaling (see Figure 1) involves Janus kinase 2 (Jak2)-mediated phosphorylation of two tyrosine residues within the cytoplasmic tail of the receptor [3]. Phosphorylation of Tyr985 activates the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway [4, 5], while phosphorylation of Tyr1138 activates signal transducer and activator of transcription 3 (STAT3) [3]. Jak2 also phosphorylates insulin receptor substrate-1 and -2, resulting in activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway [6, 7]. Intrinsic activation of the receptor is controlled by a signaling inhibitor, suppressor of cytokine signaling 3 (SOCS3) [3, 8]. A recent study indicates that central leptin controls lipogenesis by engaging the PI3K pathway as well as the endocannabinoid system of adipocytes [9].