br Leptin Adiponectin a permissive imbalance Leptin a satiet

Leptin/Adiponectin: a permissive imbalance Leptin, a satiety hormone, is encoded by the obesity (ob) gene. It essentially functions as an energy sensor which is involved in the regulation of body weight by sending signals to the XL413 hydrochloride to reduce appetite (Woods and D'Alessio, 2008). Obesity results in increased leptin levels with a strong positive correlation between serum leptin concentrations and the percentage of body fat (Considine et al., 1996). Liuzzi et al. have reported serum leptin concentrations ranging from 15 to 170 ng/ml in 284 obese women, compared to a physiological serum concentration of 10 ng/ml (Liuzzi et al., 1999). While leptin is required in the breast for normal mammary gland development and lactation (Hu et al., 2002), it has also been shown to influence breast carcinogenesis. Leptin and its receptor obR have been found to be significantly overexpressed in breast cancer tumors compared to healthy mammary glands (Garofalo et al., 2006). The involvement of leptin in breast carcinogenesis has been investigated by inhibiting the expression of leptin using a knockdown strategy in vitro and in vivo. Leptin-deficient breast cancer cells in mice show mammary tumor growth inhibition and fewer metastatic lesions in distant organs compared to control cells; whereas excessive leptin expression promotes cancer progression and changes to the biology of breast cancer cells into a more aggressive phenotype (Strong et al, 2013, Strong et al, 2015, Cleary et al, 2003). Interestingly, leptin has been found to induce a proliferative response in breast cancer cells but not in normal breast cells (Dubois et al., 2014). In agreement with these preclinical data, a positive correlation was observed between leptin and tumor size and stage of disease and high levels of leptin appeared to be associated with the presence of metastases and a low rate of survival in breast cancer patients (Chen et al, 2006, Maccio et al, 2010). Binding of leptin to its receptor, six isoforms having been identified so far (obRa-obRf), induces activation of different signaling pathways, including the Janus-family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT), MAPK or PI3K pathways which in turn mediate its effects on breast cancer cell proliferation, survival and invasion (Cirillo et al, 2008, Yin et al, 2004). Of relevance, the JAK/STAT signaling pathway appears to be particularly important in mediating direct proliferative effects of leptin in breast cancer cells. Leptin binding leads to the formation of a tetrameric receptor/ligand complex and induces the phosphorylation and activation of JAKs. In turn, activated JAKs phosphorylate cytoplasmic domain of obR, which lack any intrinsic kinase activity, leading to the recruitment of signaling molecules including members of the STAT family. After phosphorylation and dimerization, STATs are released form the receptor complex and migrate into the nucleus where they can modulate transcription of target genes (White et al., 1997). STAT3 protein has been found to be particularly important in leptin-induced cell growth since it modulates transcription of critical genes such as c-myc or cyclin D1 (Yin et al., 2004). Specific inhibition of STAT3 phosphorylation has been shown to abolish leptin-induced proliferation of MCF-7 cells (Yin et al., 2004). Leptin exerts its effects not only through the leptin receptor, but also trough interconnection with other signaling systems. The functional molecular crosstalk between leptin and estrogen signaling further contributes to breast carcinogenesis. Firstly, studies have showed that leptin was able to stimulate aromatase activity in adipose stromal cells at high concentrations, contributing to locally elevated estrogen concentrations in the breast and thereby promoting tumor formation (Magoffin et al., 1999). Subsequent studies demonstrated that leptin stimulates promoter PII-dependent transcript expression by suppressing AMPK activity and increasing nuclear localization of CRTC2 (Brown et al., 2009).