Unravelling the pathophysiology of obesity in Malay adult respondents: integration of multiple determinant data using genomics and metabolomics approaches / Siti Nooraishah Hussin

Obesity is one of the most pressing problems in developed and developing countries, including Malaysia. The prevalence is increasing, thus urges the necessity in finding simple resolution to predict obesity, and subsequently prevent the co-morbidities effect such as CVD, T2DM, hypertension and cancers. Obesity is resulting from interaction between modifiable obesogenic factors such as lifestyle, diet, environment and behaviour, and endogenous genetic predisposition. Glucocorticoid receptor (GCR) activity plays a significant role in the aetiology of obesity and is essential for glucose homeostasis, the development of hyperinsulinaemia, and subsequent increase in fat deposition. There is insufficient knowledge of the GCR in metabolic conditions of obesity. Genetic variants present in GCR are believed to be associated with alteration in glucocorticoid sensitivity. In the present study, the specific features of obesity were compared between the obese and normal lean of the Malay adult respondents. A total of 130 obese (mean BMI, M = 32.90, SE = 0.47, 95% CI = 27.84–36.87) and 116 normal lean (BMI, M = 21.29, SE = 0.12, 95% CI = 18.51–22.84) respondents were evaluated for differences in anthropometric and socio-demographic, biochemical and hormonal determinants, genetics and metabolomics profile. Baseline characteristics were summarised for the samples, and appropriate linkages and integration between the multiple determinants data involved were investigated using genomics and metabolomics approaches. There was significant elevation of lipid profile and cortisol levels of the BclI and N363S SNPS of the obese respondents (p<0.05), suggesting the variants role with hypersensitivity of GC and involvement in the pathophysiology of obesity. In contrast, the rs6194 has significantly decreased level of the lipid profile, HsCRP, cortisol, and other determinants, suggesting the protective effect of this variant towards the development of the obese phenotype. Thus, these loci can be potentially suggested as susceptible markers in the Malay Malaysian population. Early screening for these alleles is suggested to have merit in overall evaluation of a person’s risk in developing obesity later in life. The LC/MS Q-TOF platform was used to carry out a global metabolite profiling in the obese and normal lean respondents. A list of differentially expressed metabolites was profiled using MPP software, ROCCET and MetPA analyses in tying up the biochemical process comparatively displaying the NR3C1 gene function. A total of 49 from 225 metabolites were detected to be significant and differentially expressed between the obese and normal lean groups. Metabolites such as 4Z,7Z,10Z,13Z-eicosatetraenoic acid, 7,7-dimethyl-5Z,8Z,11Z-eicosatrienoic acid, 7-palmitoleic acid, phosphorylcholine, 21-deoxycortisol, dihydrocortisol, aldosterone, corticosterone, 25-dihydroxy-19-nor-22-oxavitamin D3, glucose and L-octaoylcarnitine have been highlighted as potential biomarkers for obesity in the present study. The role of these metabolites, mainly from the arachidonic acid metabolism and steroid biosynthesis were linked with the NR3C1 gene, as this gene has also been associated with its overexpression in inflammatory stress and oxidative disorder. In conclusion, metabolomics approach has contributed in bridging the gap between the genotype and phenotype, and identifying novel changes in specific metabolites and pathways related to the pathophysiology of obesity.