Circulating Oxytocin Is Genetically Determined and Associated With Obesity and Impaired Glucose Tolerance.

CONTEXT: Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well-powered studies addressing the relationship of circulating OXT with obesity and diabetes. OBJECTIVES AND DESIGN: Here, we measured OXT in a study cohort (n = 721; 396 women, 325 men; mean age ± SD, 47.7 ± 15.2 years) with subphenotypes related to obesity, including anthropometric traits such as body mass index [BMI (mean ± SD), 26.8 ± 4.6 kg/m2], waist-to-hip ratio (WHR; 0.88 ± 0.09), blood parameters (glucose, 5.32 ± 0.50 mmol/L; insulin, 5.3 ± 3.3 µU/mL), and oral glucose tolerance test to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the interindividual variation in OXT serum levels might be explained by genetic variation. RESULTS: The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference, and triglyceride levels. The OXT concentration in subjects with BMI <25 kg/m2 was significantly lower (n = 256; 78.6 pg/mL) than in subjects with a BMI between 25 and 30 kg/m2 (n = 314; 98.5 pg/mL, P = 6 × 10-6) and with BMI >30 kg/m2 (n = 137; 106.4 pg/mL, P = 8 × 10-6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (P = 4.6 × 10-3). Heritability of OXT was estimated at 12.8%. In a GWAS, two hits in linkage disequilibrium close (19 kb) to the OXT reached genome-wide significant association (top-hit rs12625893, P = 3.1 × 10-8, explained variance 3%). CONCLUSIONS: Our data show that OXT is genetically affected by a variant near OXT and is associated with obesity and impaired glucose tolerance.

The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone.

The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E-mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF-receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma.