Yousseif, A;
(2016)
Insights into obesity from bariatric surgery & genetics.
Doctoral thesis , UCL (University College London).
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Abstract
Bariatric surgery is the most effective treatment for the management of severe obesity. In Chapters 3 & 4 of this thesis, in two prospective parallel-group studies we compared the effects of the ‘gold-standard’ operation Roux-en-Y gastric bypass (RYGBP) vs. the newer, increasingly performed procedure, sleeve gastrectomy (SG). We showed that in adiposity-matched patients RYGB and SG resulted in comparable reductions in circulating leptin levels at 6 and 12 weeks post-surgery. However, RYGB and SG had differential effects on circulating gut hormones levels. Plasma acyl-ghrelin levels declined post-surgery, with superior decreases observed post-SG vs. post-RYGBP. Markedly increased meal-stimulated circulating levels of peptide YY3-36 (PYY3-36), active glucagon-like peptitde-1 (GLP-1) and glucagon were observed following RYGB and SG. However, these changes were significantly greater after RYGB compared to after SG. Both operations comparably enhanced circulating glucose-dependent insulinotropic peptide (GIP) early post-meal. Whereas late postmeal, GIP levels declined post-RYGBP, but were unchanged post-SG. Glucose, insulin and homeostasis model assessment for insulin resistance (HOMA-IR) changes were comparable following RYGBP and SG. Polymorphisms within the fat mass and obesity-associated gene (FTO) associate with adiposity. We have recently shown that normal-weight subjects homozygous for the rs9939609 FTO obesity-risk variant (A) display increased post-prandial appetite and attenuated reduction in plasma acyl-ghrelin levels. In Chapter 5 we extended this work to humans with severe obesity. We found no differences in acyl-ghrelin between obese AA and TT subjects (T being the protective allele of FTO rs9939609). Furthermore, in Chapter 6 we report that AA, AT and TT subjects exhibited comparable weight-loss post-RYGBP, with comparable weight-loss outcomes across the three genotypes seen post-SG. However, comparison of RYGBP vs. SG revealed superior weight-loss outcomes post-RYGBP in TT and AT subjects vs. SG, but comparable weight-loss post-RYGBP and post-SG in AA subjects. In Chapter 6 we report that overall RYGBP resulted in superior weight-loss vs. SG. Patients with type 2 diabetes (T2DM) exhibited comparable weight-loss vs. adipositymatched normoglycaemic patients following RYGBP. However, following SG weight-loss was greater in normoglycaemic patients compared to adiposity-matched T2DM patients. In addition, we report the prevalence of 32 common obesityassociated SNPs (single nucleotide polymorphisms) in our patient cohort, and show that FTO rs9939609 had the strongest effect on BMI. Collectively, this work further adds to the rapidly expanding field of bariatric research. Future research endeavors will bring us closer to developing less invasive surgical procedures and novel pharmacotherapies for the medical management of diabetes and obesity.
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