The rs12970134 variant near the melanocortin receptor 4 (MC4-R) has gained relevance suggesting an age dependent phenotypic effect in the induction of obesity in young age. A previous study evaluating Show more
The rs12970134 variant near the melanocortin receptor 4 (MC4-R) has gained relevance suggesting an age dependent phenotypic effect in the induction of obesity in young age. A previous study evaluating 740 Caucasian children has shown this association in prepubertal children older than 8 years. The aim of this study was to assess whether the obesogenic effect of M4CR gene contributed to obesity also in adolescence. After 8 years participants of the original study were contacted and invited to perform an anthropometric evaluation. Out of 35 carriers of the AA risk allele of MC4-R, 12 subjects accepted to participate. Adolescent subjects with the AA risk allele of MC4-R were matched with 24 and 48 subjects, respectively for AG and GG variants. Differences between the three MC4-R genotypes for anthropometric data, for percentage of overweight and obesity and for changes in BMI-SDS over visit have been assessed. At Visit 1 (baseline examination study), the AA risk genotype was confirmed to be associated with higher BMI-SDS (1.3 ± 0.4 vs 0.4 ± 0.1) and waist circumference (66.5 ± 5.8 vs 60.9 ± 7.1) when compared to the GG genotype (p < 0.016 both). At Visit 2 the AA genotype not only was associated with a higher BMI-SDS (1.07 ± 0.5 vs 0.02 ± 0.8) and WC (95.6 ± 13.3 vs 64.9 ± 13.5) when compared to GG genotype, but also when compared to AG genotype (vs 0.5 ± 0.1 and 62.9 ± 10.0, p < 0.016). Whereas AA genotype demonstrated no change of BMI-SDS between visit 1 and visit 2 (p00.32), AG and GG genotype showed a significant reduction (p = 0.01 and 0.001 respectively). Furthermore, a higher percentage of patients were affected by overweight/obesity in the AA genotype compared to AG and GG genotypes (50% vs 20.8% vs 16.5% p = 0.03). This study demonstrates that the rs12970134 variant not only exerts an obesogenic influence in the prepubertal age but remains a major risk factor also during adolescence. Show less
Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most ab Show more
Recent findings relate obesity to inflammation in key hypothalamic areas for body weight control. Hypothalamic inflammation has also been related to oxidative stress. Palmitic acid (PA) is the most abundant free fatty acid found in food, and in vitro studies indicate that it triggers a pro-inflammatory response in the brain. Melanocortins are neuropeptides with proven anti-inflammatory and neuroprotective action mediated by melanocortin receptor 4 (MC4R), but little is known about the effect of melanocortins on oxidative stress. The aim of this study was to investigate whether melanocortins could alleviate oxidative stress induced by a high fat diet (HFD) model. We found that NDP-MSH treatment decreased PA-induced reactive oxygen species production in astrocytes, an effect blocked by the MC4R inhibitor JKC363. NDP-MSH abolished nuclear translocation of Nrf2 induced by PA and blocked the inhibitory effect of PA on superoxide dismutase (SOD) activity and glutathione levels while it also per se increased activity of SOD and γ-glutamate cysteine ligase (γ-GCL) antioxidant enzymes. However, HFD reduced hypothalamic MC4R and brain derived neurotrophic factor mRNA levels, thereby preventing the neuroprotective mechanism induced by melanocortins. Show less