Study of obesity : metabolite profiling, gene expression and genotyping

Chong, Eric Tzyy Jiann (2018) Study of obesity : metabolite profiling, gene expression and genotyping. Doctoral thesis, Universiti Malaysia Sabah.

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Abstract

Globally, there are 1.9 billion overweight (OW) adults and more than 650 million of them are obese (OB). In Malaysia, about 17.7% of the population are OB and more than 0.6 million OB adults are reported in East Malaysia. Worryingly, obesity is associated with several severe health disorders such as cardiovascular diseases, type 2 diabetes and cancers. Even though the aetiology of obesity is still not fully understood, an effective treatment to combat and reduce the seriousness of the obesity endemic is critically needed. Therefore, this study aims to utilize metabolite profiling, gene expression and genotyping approaches to further understand this particular perspective. Blood samples from 30 OB and 30 normal (NR) subjects were collected for blood biochemistry tests. Non-polar metabolites were extracted from 40 OB and 40 NR subjects, and profiled using a liquid chromatography-Orbitrap mass spectrometry for metabolite and pathway analyses. Total RNA was isolated from the peripheral blood of 30 OB and 30 NR subjects to investigate the expression of the genes in the involving pathway. Besides that, a total of 1030 blood samples were collected from age-matched subjects in the East Malaysian population for genotyping analysis. In this study, a higher mean of weight, body mass index, systolic blood pressure, haemoglobin concentration, red and white blood cell counts and triglyceride (TG) concentration was observed in the OB subjects. In metabolite profiling, most of the metabolites that were significantly up-regulated in the OB subjects were lipid species including ceramide, ceramide phosphoethanolamine, phosphatidylcholine (PC), TG, phosphatidylserine, and phosphoethanolamine. Pathway analysis was performed using the identified metabolites and this showed that the sphingomyelin-ceramide metabolic pathway in sphingolipid metabolism was highly impacted in the OB subjects. The two main genes that regulate this pathway are the sphingomyelin phosphodiesterase 1 (SMPD1) and the sphingomyelin synthase 2 (SGMS2) genes. Gene expression studies targeting the SMPD1 and SGMS2 genes revealed that the expression of the SGMS2 was significantly down-regulated by 0.825-fold in the OB group. Among the 1030 subjects recruited for genotyping analysis, 21.6% were OW and 11.0% were OB. Genotyping of the rs4246445, rs2229425, rs2228305 and rs2229422 single nucleotide polymorphisms (SNPs) in the fatty acid synthase gene showed no significant evidence to associate these SNPs with the risk of being OW and obesity in the East Malaysian population, including in the haplotype analysis. In addition, these SNPs were demonstrated to be independent of each other in the linkage disequilibrium analysis. Interestingly, genotyping of the rs3751723 SNP in the iroquois homeobox 3 gene revealed that the variant G/G genotype was associated with the risk of obesity in the East Malaysian population, especially in subjects who did not consume fast food. Moreover, East Malaysian females who carried the variant G allele of this SNP also showed a higher risk of being OW but this allele had protective effects against being OW and OB among smokers in the population. A further assessment of this SNP using a meta-analysis revealed no significant links with the risk of obesity in all comparison models including the allelic, homozygous, heterozygous, dominant and recessive, but the meta-analysis concisely suggested that the variant G allele as a reduce risk factor for obesity overall. In conclusion, this is the first study to report that the expression of the SGMS2 gene is inhibited in the OB subjects and consequently promoted the accumulation of the ceramide and PC metabolites, which was further validated in the metabolite profiling. Interestingly, both blood biochemistry and metabolite profiling analyses also constantly observed an increased concentration of TG in the OB subjects. These findings provide an insight into obesity treatment. The genotyping data of this study can be beneficial in future personal- or population-based study designs in obesity management and prevention.

Item Type:	Thesis (Doctoral)
Keyword:	Obesity, Overweight, Metabolite profiling, Gene expression, Genotyping
Subjects:	R Medicine > RC Internal medicine > RC31-1245 Internal medicine > RC581-951 Specialties of internal medicine > RC627.5-632 Metabolic diseases
Department:	FACULTY > Faculty of Science and Natural Resources
Depositing User:	DG MASNIAH AHMAD -
Date Deposited:	12 Mar 2025 14:39
Last Modified:	12 Mar 2025 14:39
URI:	https://eprints.ums.edu.my/id/eprint/43123

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