Obesity prevalence continues to increase worldwide; 69% of U.S. adults are overweight or obese. Despite advances in understanding obesity pathophysiology, weight loss with current non-surgical treatments (diet, exercise and medications) is highly variable, and predictors of weight loss with obesity pharmacotherapy are unknown. In two studies of 328 patients funded by DK67071, obesity was associated with greater fasting gastric volume, accelerated gastric emptying of solids, lower postprandial peak plasma PYY, higher postprandial peak plasma GLP-1, greater calories to achieve satiation [volume to fullness] and to evoke satiety with an ad-libitum meal.. Among candidate genes predisposing to obesity, variants in uncoupling protein (UCP)-3 gene (rs1626521, which influences human mitochondrial function) were associated with gastric motor function, satiation and satiety (significant with correction for testing 15 candidate genes). Our preliminary data shows (a) GLP-1 agonist delays gastric emptying, reduces calorie intake at ad-libitum meal, and weight loss is prominent in T allele carriers of TCF7L2 rs7903146; (b) calorie intake at ad-libitum meal predicted weight loss in response to phentermine-topiramate-ER; (c) ileocolonic delivery ursodeoxycholic acid (UDCA) reduced fasting and postprandial blood glucose, and a subgroup of patients had a marked postprandial insulin response consistent with the hypothesis of pharmacogenetic interaction between UDCA and TGR5 gene variation. We propose to test the overall hypothesis that weight loss with pharmacological agents may be individualized, based on specific abnormalities in quantitative traits, and genotype variation; each could be targeted by pharmacological actions of specific obesity medications. We propose specific aims in three different obesity phenotypes, assessing the potential for a quantitative trait and a related candidate gene to impact the response to treatment compared to placebo among overweight or obese patients: (a) the GLP-1 receptor agonist, exenatide, in those with accelerated gastric emptying, particularly in carriers of TCF7L2 rs7903146 (TT genotype); (b) the centrally acting combination noradrenergic sympathomimetic amine, phentermine, and anticonvulsant, topiramate, in those with reduced satiety (increased appetite), particularly in carriers of variant of UCP-3 rs1626521 genotype, which controls mitochondrial function and cellular energetics; (c) the ileo- colonic delivered UDCA, an activator of TGR5 receptors in obese patients with hyperglycemia treated with metformin, particularly in carriers of variants of TGR-5 rs11554825 genotype. Alternative strategies will be explored through measurements of all quantitative traits that differ between obese and normal weight individuals: gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation, satiety, postprandial PYY and GLP-1, and glycemic indices (postprandial glucose, insulin). Significance: Our study addresses the treatment of obesity, introducing an era of individualizing drug therapy for obesity based on quantitative biomarkers and pharmacogenomics. Therefore, it addresses an important public health challenge.