👤 Silvia Lorente-Cebrián

In the UK, the number of comorbidities seen in children has increased along with the worsening obesity rate. These comorbidities worsen into adulthood. Genome-wide association studies have highlighted single nucleotide polymorphisms associated with the weight status of adults and offspring individually. To date, in the UK, parental genetic, lifestyle, and social determinants of health have not been investigated alongside one another as influencers of offspring weight status. A comprehensive obesity prevention scheme would commence prior to conception and involve parental intervention including all known risk factors. This current study aims to identify the proportion of overweight that can be explained by known parental risk factors, including genetic, lifestyle, and social determinants of health with offspring weight status in the UK. A cross-sectional study was carried out on 123 parents. Parental and offspring anthropometric data and parental lifestyle and social determinants of health data were self-reported. Parental genetic data were collected by use of GeneFiX saliva collection vials and genotype were assessed for brain-derived neurotrophic factor (BDNF) gene rs6265, melanocortin 4 receptor (MC4R) gene rs17782313, transmembrane protein 18 (TMEM18) gene rs2867125, and serine/threonine-protein kinase (TNN13K) gene rs1514175. Associations were assessed between parental data and the weight status of offspring. Maternal body mass index modestly predicted child weight status (p < 0.015; R2 = 0.15). More mothers of overweight children carried the MC4R rs17782313 risk allele (77.8%; p = 0.007) compared to mothers of normal-weight children. Additionally, fathers who were not Caucasian and parents who slept for <7 h/night had a larger percentage of overweight children when compared to their counterparts (p = 0.039; p = 0.014, respectively). Associations exist between the weight status of offspring based solely on parental genetic, lifestyle, and social determinants of health data. Further research is required to appropriately address future interventions based on genetic and lifestyle risk groups on a pre-parent cohort. Show less

Obesity increases the risk of developing type 2 diabetes mellitus, characterised by impaired insulin-mediated glucose uptake in peripheral tissues. Liver X receptor (LXR) is a positive regulator of adipocyte glucose transport in murine models and a possible target for diabetes treatment. However, the levels of LXRα are increased in obese adipose tissue in humans. We aimed to investigate the transcriptome of LXR and the role of LXR in the regulation of glucose uptake in primary human adipocytes. The insulin responsiveness of human adipocytes differentiated in vitro was characterised, adipocytes were treated with the LXR agonist GW3965 and global transcriptome profiling was determined by microarray, followed by quantitative RT-PCR (qRT-PCR), western blot and ELISA. Basal and insulin-stimulated glucose uptake was measured and the effect on plasma membrane translocation of glucose transporter 4 (GLUT4) was assayed. LXR activation resulted in transcriptional suppression of several insulin signalling genes, such as AKT2, SORBS1 and CAV1, but caused only minor changes (<15%) in microRNA expression. Activation of LXR impaired the plasma membrane translocation of GLUT4, but not the expression of its gene, SLC2A4. LXR activation also diminished insulin-stimulated glucose transport and lipogenesis in adipocytes obtained from overweight individuals. Furthermore, AKT2 expression was reduced in obese adipose tissue, and AKT2 and SORBS1 expression was inversely correlated with BMI and HOMA index. In contrast to murine models, LXR downregulates insulin-stimulated glucose uptake in human adipocytes from overweight individuals. This could be due to suppression of Akt2, c-Cbl-associated protein and caveolin-1. These findings challenge the idea of LXR as a drug target in the treatment of diabetes. Show less