leptin is the product of the obese gene , located on chromosome 7 in humans . when exogenous leptin is injected into leptin - deficient obese mice ( ob / ob mice ) , the protein promotes satiety and weight loss [ 25 ] . the effects of leptin on these obese mice sparked a leptin intense focus in obesity research over the past 15 years . obese humans have high circulating leptin levels which are directly correlated to the total amount of adipose tissue . leptin helps regulate bodyweight in humans by negative feedback promoting satiety when energy stores are elevated . the current model suggests that obesity in humans is due to a desensitization to leptin . obese subjects have a diminished response to leptin , and in some subjects the diminished response is due to a mutation in the leptin receptor gene . the high prevalence of obesity in the usa is strongly correlated with the risk of multiple diseases , including cancer . the association between cancer and obesity may , in part , be explained by elevated circulating leptin . leptin has been classified as a growth factor because it stimulates three key pathways well known for their roles in cell growth : proliferation , survival , and motility and migration ( figure 1 ) . it is well documented that the binding of leptin to the leptin receptor ( obr ) activates the janus kinase - signal transducer and activator of transcription ( jak - stat ) , the mitogen - activated protein kinase ( mapk ) , and the phosphatidylinositol 3-kinase ( pi3k ) pathways in both normal [ 1022 ] and malignant cells [ 20 , 2341 ] . supporting a role of leptin in cancer pathogenesis are reports that dna polymorphisms in the leptin and obr genes are associated with increased risk and progression of breast , prostate , and oral cancer . evidence generally supports leptin as a growth factor , promoting cell division and evasion of cell death . numerous reports indicate that leptin has both antiapoptotic [ 28 , 33 , 34 , 36 , 4654 ] and proliferative effects [ 24 , 25 , 27 , 2931 , 33 , 34 , 36 , 41 , 47 , 49 , 50 , 52 , 53 , 5559 ] ( table 1 ) . it appears that leptin - mediated proliferation of these cancers occurs through the activation of the jak - stat [ 25 , 27 , 2931 , 34 , 41 ] , pi3k [ 24 , 31 , 33 , 36 ] , and mapk [ 24 , 31 ] pathways , whereas apoptosis avoidance is promoted by leptin via the jak - stat [ 28 , 34 ] and pi3k [ 33 , 36 ] pathways ( figure 1 ) . migration is enhanced by leptin in several normal [ 10 , 2022 , 60 , 61 ] and cancerous tissues [ 20 , 23 , 26 , 32 , 35 , 37 , 39 , 40 , 6264 ] ( table 1 ) . leptin treatment increases the growth and migration of cholangiocarcinoma cells in vitro and cholangiocarcinoma is inducible in obese fa / fa zucker ( faulty obr ) rats . in metastatic colon cancer cells , leptin provokes the formation of lamellipodia and augments invasion through the mapk and pi3k pathways . it has since been confirmed that leptin increases migration through the mapk and pi3k pathways in prostate [ 37 , 39 , 40 ] , liver , cartilage , and breast [ 23 , 40 , 64 ] cancers , as well as the jak - stat pathway in colon , prostate , liver , and breast   cancers . compounding the complexity of leptin 's role in carcinogenesis is that leptin may have differential responses in closely related cells ; leptin induces migration in papillary thyroid cancer cells but not in anaplastic and follicular thyroid cancer cells . in addition to its role in cellular proliferation , apoptosis avoidance , and migration , leptin is a potent angiogenic factor . using an in vitro angiogenesis assay , leptin enhances the formation of capillary - like tubes by human umbilical venous endothelial cells . in 5- to 6-week - old c57bl/6j mice this response is synergistic with vascular endothelial growth factor ( vegf ) and fibroblast growth factor-2 . myometrial cells and the blood - vessel walls of uterine myomas contain leptin , though the surrounding normal tissue does not . this suggests that leptin may be involved in angiogenesis and the development of uterine cancer . vegf levels are augmented by leptin in various cancers [ 37 , 38 , 58 , 68 ] . it has been reported that the leptin - induced upregulation of vegf may be due to activation of the il-1 system . this leptin - mediated il-1 up - regulation appears to be accomplished by activation of the mapk and pi3k pathways , among others [ 37 , 38 ] . leptin and obr expression are correlated with the grade of the tumor , differentiation , and microvessel density [ 58 , 69 ] . it is noteworthy to mention that per ole iverson and coworkers blocked the obr which suppressed rat leukemia cell growth by inhibiting angiogenesis . interestingly , hypoxia can induce vegf production in cells , and it has been demonstrated that leptin expression is also augmented under similar conditions . however , leptin expression and secretion has since been demonstrated in several tissues of the body ( cancerous and noncancerous ) including the pituitary gland and hypothalamus . barbara morash and colleagues provided the first report of leptin expression in glioma following detection of leptin expression in the rat c6 glioma cell line . it was later shown that c6 cells express more leptin and obr than normal glial tissue . leptin and obr expression subsequently has been confirmed in human primary gbm tissue as well as established human gbm cells lines . leptin and obr are overexpressed in human primary brain tumors when compared to normal glial tissue . furthermore , the expression of the leptin - obr system correlates with histological grade : gbm has the greatest levels of leptin and obr while low - grade gliomas have the least . this suggests that leptin / obr autocrine / paracrine signaling increases the malignant characteristics of gliomas . leptin / obr overexpression in glioma , coupled with recent evidence that the release of leptin from adipose tissue promotes melanoma and colon cancer , provides strong evidence that leptin plays a role in cancer pathogenesis . in the rat c6 cell line , leptin knockdown using rna interference produced a reduction of both leptin mrna and leptin protein . this knockdown caused a twofold increase in cell death suggesting that endogenous leptin promotes cell survival . furthermore , exogenous leptin enhances migration and invasion of the rat c6 cells through increased levels of matrix metalloproteinase-13 ( mmp-13 ) . the leptin - mediated up - regulation of mmp-13 occurs through the mapk pathway . while there is increasing evidence of leptin 's role in angiogenesis [ 37 , 38 , 58 , 68 ] , no studies ( to our knowledge ) however , hypoxia , which is a characteristic of solid tumors , is more pronounced with higher grades of glioma   and may explain the increased expression of leptin and obr in gbm compared to lower - grade glioma . it is increasingly evident that the enhanced mental stimulation from environmental enrichment ( ee ) delays the advancement of neurodegenerative disorders such as huntington 's , parkinson 's , and alzheimer 's , slows the progression of cancer [ 75 , 7981 ] , and increases the activity of natural killer cells . environmental enrichment refers to the living conditions of the subject . in the context of the rodent , ee is achieved through conditions that allow the rodent to roam more freely , engage with the surroundings , be housed with other rodents , and have better access to exercise equipment . for humans , increased social and physical activity leads to ee . the response to ee is related to the type of stress the subject experiences : ee increases eustress and decreases distress . eustress is the result of positive stressors like exercise and social interaction whereas distress is the result of negative stressors like mental stress and social isolation . the augmentation of eustress and the reduction of distress are associated with longer survival and slower tumor growth [ 75 , 79 , 81 ] . probably the most significant human data to date are those reported by barbara andersen and her colleagues who showed that distress reduction through psychological intervention resulted in a 45% decrease in the risk of breast cancer recurrence   and a 59% reduction in the risk of dying following breast cancer recurrence . the physiological basis for this finding is an active area of investigation . using mouse models for melanoma and colon cancer , cao et al a study has yet to be designed that blocks obr or alters leptin levels in gbm subjects or animal models . recall that ee - induced activation of the brain - adipocyte bdnf / leptin axis causes cancer remission and inhibition in mice , and distress reduction lowers the rate of recurrence in breast cancer patients . environmental enrichment and psychological treatment increase bdnf and thereby reduce systemic leptin via sympathetic activation of beta - adrenergic receptors in adipose tissue . this hypothalamic - sympathoneuronal - adipocyte axis does not address the potential leptin - obr autocrine signaling loop of gbm . factors that influence the transcriptional regulation of the leptin gene in the rat c6 cells are different than those in adipose tissue [ 83 , 84 ] , and therefore successful treatments may need to be more specific to gbm . therapies that are successful at crossing the blood - brain barrier and reducing the leptin - obr signaling loop in gbm are needed and should be a focus of future research . leptin , which may be controlled by specific stimulation of the brain via ee or psychological intervention , has significant influence on tumor growth . in gbm and other cancer cells , leptin promotes cancer by stimulating cellular pathways that are advantageous for proliferation , angiogenesis , and evasion of death . unfortunately , most of what is known about leptin and glioma stems from the rat c6 cell line . future studies should focus on established human gbm cell lines and primary gbm neurosphere cultures both in vitro and in vivo .
the hormone leptin has a variety of functions . 
 originally known for its role in satiety and weight loss , leptin more recently has been shown to augment tumor growth in a variety of cancers . within gliomas , there is a correlation between tumor grade and tumor expression of leptin and its receptor . 
 this suggests that autocrine signaling within the tumor microenvironment may promote the growth of high - grade gliomas . 
 leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence : antiapoptosis , proliferation , angiogenesis , and migration . 
 conversely , a loss of leptin expression attenuates tumor growth . in animal models of 
 colon cancer and melanoma , a decline in the expression and secretion of leptin resulted in a reduction of tumor growth . in these models , positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome . 
 this review explores the link between leptin and glioblastoma .