Recent population-based epidemiological studies strongly hint towards a link between obesity and its occurrence as well as progression of several cancers including melanoma. Although effects of obesity on breast, colon and liver cancers have been extensively investigated, the links between obesity and melanoma remain largely unexplored. Present study aimed to understand the effect of high fat diet-induced weight gain on susceptibility of C57BL/6J mice to melanoma. For this, mice routinely were fed on high fat diet for 6 months (HFD mice). Subsequently, mouse melanoma cells were injected subcutaneously in control as well as HFD mice and followed for tumor initiation and progression. We provide strong evidence that diet-induced obesity leads to increased melanoma progression in male C57BL/6J mice. We observed that increased melanoma progression is associated with enhanced Cav-1 and FASN expression in tumors from HFD mice. Cav-1 and FASN are co-ordinately regulated and Cav-1 interacts with FASN in melanoma cells. Enhanced levels of Cav-1, FASN and pAkt control melanoma cell proliferation. Our study establishes a causative relationship between diet-induced obesity and melanoma progression as well as demonstrates that obesity affects important tumorigenic pathways in melanoma.Many studies have lately emerged providing plausible evidence for the role of obesity, an indispensable component of metabolic syndrome and a severe metabolic disorder, in pathogenesis and progression of cancer. Study by American Cancer Society states that 14% of all cancer deaths in men and 20% of all cancer deaths in women from range of cancer types can be ascribed to excess body weight. 1 Data from the National Health and Nutrition Examination Survey (NHANES) shows increased prevalence of overweight and obese adults in US population 2-4 with a similar trend in children. 2,4 Traditionally, cancers that are associated with obesity are breast, colon, pancreas, liver, cervix, stomach and kidney. 2,4 Among postmenopausal women in UK, 5% of all cancers are attributable to being overweight or obese, 5 and obese Swedish men are at significantly increased risk of occurrence of various cancers. 6 In the recent past, several reports have emerged highlighting a possible link between obesity and melanoma cancers. [7][8][9][10][11][12] Solar radiation has been identified as a principal causal factor for melanoma. However, the role of changing lifestyle patterns associated with obesity may also contribute to the development and progression of melanoma. In a study by Dennis et al., occurrence of melanoma had significant association with highest category of body surface area and body mass index [weight (kg)/height (m 2 )]. 7 In another study, it has been clearly demonstrated that obesity increases the risk of melanoma 11 and body mass index also relates with the risk of melanoma occurence. 13 All these studies provide a firm basis for an association between obesity and increased risk of melanoma occurrence thereby suggesting that strategies to control obesity...

1 The in vivo hypoglycaemic activity of a dialysed fenugreek seed extract (FSE) was studied in alloxan (AXN)-induced diabetic mice and found to be comparable to that of insulin (1.5 U kg À1). FSE also improved intraperitoneal glucose tolerance in normal mice. 2 The mechanism by which FSE attenuated hyperglycaemia was investigated in vitro. FSE stimulated glucose uptake in CHO-HIRc-mycGLUT4eGFP cells in a dose-dependent manner. This effect was shown to be mediated by the translocation of glucose transporter 4 (GLUT4) from the intracellular space to the plasma membrane. 3 These effects of FSE on GLUT4 translocation and glucose uptake were inhibited by wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, and bisindolylmaleimide 1, a protein kinase C (PKC)-specific inhibitor. 4 In vitro phosphorylation analysis revealed that, like insulin, FSE also induces tyrosine phosphorylation of a number of proteins including the insulin receptor, insulin receptor substrate 1 and p85 subunit of PI3-K, in both 3T3-L1 adipocytes and human hepatoma cells, HepG2. However, unlike insulin, FSE had no effect on protein kinase B (Akt) activation. 5 These results suggest that in vivo the hypoglycaemic effect of FSE is mediated, at least in part, by the activation of an insulin signalling pathway in adipocytes and liver cells.

Obesity, owing to adiposity, is associated with increased risk and development of various cancers, and linked to their rapid growth as well as progression. Although a few studies have attempted to understand the relationship between obesity and melanoma, the consequences of controlling body weight by reducing adiposity on cancer progression is not well understood. By employing animal models of obesity, we report that controlling obesity either by orlistat treatment or by restricting caloric intake significantly slows down melanoma progression. The diminished tumor progression was correlated with decreased fat mass (adiposity) in obese mice. Obesity associated factors contributing to tumor progression were decreased in the experimental groups compared to respective controls. In tumors, protein levels of fatty acid synthase (FASN), caveolin (Cav)-1 and pAkt, which are tumor promoting molecules implicated in melanoma growth under obese state, were decreased. In addition, increased necrosis and reduction in angiogenesis as well as proliferative markers PCNA and cyclin D1 were observed in tumors of the orlistat treated and/or calorically restricted obese mice. We observed that growth of melanoma cells cultured in conditioned medium (CM) from orlistat-treated adipocytes was reduced. Adipokines (leptin and resistin), via activating Akt and modulation of FASN as well as Cav-1 respectively, enhanced melanoma cell growth and proliferation. Together, we demonstrate that controlling body weight reduces adipose mass thereby diminishing melanoma progression. Therefore, strategic means of controlling obesity by reduced caloric diet or with antiobesity drugs treatment may render obesity-promoted tumor progression in check and prolong survival of patients.

Fenugreek (Trigonella foenum‐graecum) seeds, used as a condiment, are documented for health benefits including amelioration of abnormalities in lipid homeostasis due to its hypolipidemic properties. However, molecular mechanisms underlying the hypolipidemic effect of fenugreek seeds remain obscure. In this study, hypolipidemic effect of a novel thermostable extract of fenugreek seeds (TEFS) was evaluated in vitro by employing differentiating and differentiated 3T3‐L1 cells, and HepG2 cells cultured in normal or sterol‐enriched conditions. Hypolipidemic effect was studied by quantifying decrease in accumulation of fat or by western blot analysis of adipogenic and lipogenic factors. At molecular level, TEFS inhibited accumulation of fat in differentiating and differentiated 3T3‐L1 cells via decreased expression of adipogenic factors such as peroxisome proliferators activated‐receptor‐γ (PPAR‐γ), sterol regulatory element‐binding protein‐1 (SREBP‐1), and CAAT element‐binding proteins‐α (c/EBP‐α). We also show that following TEFS treatment, cellular triglycerides (TGs), and cholesterol concentrations decreased significantly (P < 0.05) in HepG2 cells via reduced expression of SREBP‐1, at mRNA as well as protein level. Under sterol enriched condition, TEFS upregulated low‐density lipoprotein receptor (LDLR) expression resulting in enhanced LDL uptake. Treating fat supplement fed C57BL6/J mice with TEFS for 15 days resulted in decrease of serum TG, LDL‐cholesterol (LDLc), and body weight in a dose‐ and time‐dependent manner (P < 0.05). Results indicate that hypolipidemic effect of TEFS is due to inhibition of fat accumulation and upregulation of LDLR. Taken together, the study suggests that TEFS may have potential application in the management of dyslipidemia and its associated metabolic disorders.