lem. There are about one billion adults that are overweight with a body mass index (BMI) over 25, and 300 million are obese with a BMI over 30 (http://www.who.int). Today there are more people overweight than underweight. It causes costly health problems, reduces life expectancy, and is associated with stigma and discrimination, which has a major effect on the quality of life. Obesity and overweight substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, and coronary heart disease. Obesity is also important for the development of obstructive sleep apnea and respiratory problems, gallbladder disease, osteoarthritis, and nonalcoholic fatty liver disease as well as endometrial, breast, prostate, and colon cancers.There are several genes associated with obesity on the human obesity map (1) such as the melanocortin 4 receptor (MC4R), leptin and the leptin receptor. However, the contribution of each specific gene to obesity is low, being highest for the MC4R gene ranging from 1-6% (2). The overall inheritability of BMI is estimated to be about 50 -60%. Recently, three reports have shown a strong association of a singlenucleotide polymorphism (SNP) in a gene called FTO with both childhood and adult obesity. Frayling and colleagues (3) performed a genome-wide association study for about 490,000 autosomal SNPs in a type 2 diabetes population in the United Kingdom. They found that SNP rs9939609 in the FTO gene was strongly associated with type 2 diabetes, but this allele was also strongly associated with an increased BMI. The association between this FTO SNP and type 2 diabetes was abolished by adjustment for the BMI, suggesting that it was due to the increased BMI. The association of this variant with the BMI was replicated in 13 cohorts with over 38,000 individuals. Interestingly, 16% of the adults who were homozygous for this SNP weighed about 3 kg more and had 1.67-fold increased odds of obesity. This association was observed from age 7 yr upward, and it reflects a specific increase in fat mass (3). Independently, Dina et al. (4) found another SNP, rs1121980, in the first intron of the FTO gene, that was strongly associated with severe (BMI Ͼ 40) adult obesity with odds ratio of 1.55 in a population of French individuals of European ancestry). Further genotyping showed a similarly strong association of several SNPs in a cohort of about 900 severely obese adults and 2700 nonobese French controls. Three of the four most significantly associated SNPs (rs17817449, rs3751812, and rs1421085) are puta-

No abstract

Variants of the FTO gene show strong association with obesity, but the mechanisms behind this association remain unclear. We determined the genome wide DNA methylation profile in blood from 47 female preadolescents. We identified sites associated with the genes KARS, TERF2IP, DEXI, MSI1, STON1 and BCAS3 that had a significant differential methylation level in the carriers of the FTO risk allele (rs9939609). In addition, we identified 20 differentially methylated sites associated with obesity. Our findings suggest that the effect of the FTO obesity risk allele may be mediated through epigenetic changes. Further, these sites might prove to be valuable biomarkers for the understanding of obesity and its comorbidites.

BackgroundTMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.MethodsThe evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).ResultsTMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).ConclusionWe conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.

Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the beta-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian beta-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the beta-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.

The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

The solute carrier family 22 (SLC22) is a large family of organic cation and anion transporters. These are transmembrane proteins expressed predominantly in kidneys and liver and mediate the uptake and excretion of environmental toxins, endogenous substances, and drugs from the body. Through a comprehensive database search we identified six human proteins not yet cloned or annotated in the reference sequence databases. Five of these belong to the SLC22 family, SLC22A20, SLC22A23, SLC22A24, SLC22A25, and SPNS3, and the sixth gene, SVOPL, is a paralog to the synaptic vesicle protein SVOP. We identified the orthologs for these genes in mouse and rat and additional homologous proteins and performed the first phylogenetic analysis on the entire SLC22 family in human, mouse, and rat. In addition, we performed a phylogenetic analysis which showed that SVOP and SV2A-C are, in a comparison with all vertebrate proteins, most similar to the SLC22 family. Finally, we performed a tissue localization study on 15 genes on a panel of 30 rat tissues using quantitative real-time polymerase chain reaction.

Objective:To explore the relationship between severity of obesity at age 7 and age 15, age at onset of obesity, and parental body mass index (BMI) in obese children and adolescents.Design:Longitudinal cohort study.Subjects:Obese children (n=231) and their parents (n=462) from the Swedish National Childhood Obesity Centre.Methods:Multivariate regression analyses were applied with severity of obesity (BMI standard deviation score (BMI SDS)) and onset of obesity as dependent variables. The effect of parental BMI was evaluated and in the final models adjusted for gender, parental education, age at onset of obesity, severity of obesity at age 7 and obesity treatment.Results:For severity of obesity at age 7, a positive correlation with maternal BMI was indicated (P=0.05). Severity of obesity at this age also showed a strong negative correlation with the age at onset of obesity. Severity of obesity at age 15 was significantly correlated with both maternal and paternal BMI (P<0.01). In addition, BMI SDS at age 15 differed by gender (higher for boys) and was positively correlated with severity of obesity at age 7 and negatively correlated with treatment. Also, a negative correlation was indicated at this age for parental education. No correlation with age at onset was found at age 15. For age at onset of obesity there was no relevant correlation with parental BMI. Children within the highest tertile of the BMI SDS range were more likely to have two obese parents.Conclusion:The impact of parental BMI on the severity of obesity in children is strengthened as the child grows into adolescence, whereas the age at onset is probably of less importance than previously thought. The influence of parental relative weight primarily affects the severity of childhood obesity and not the timing.