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The global pandemic of obesity continues to escalate worldwide and results in severe multisystem metabolic dysfunction in the expanding population of its sufferers. It is associated with the concurrent pathologies of type 2 diabetes, cardiovascular disease, cancer and sleep apnea, which have also increased in prevalence over the past decade. Obesity can be mapped in social networks and is recognised as a fundamental element of the metabolic syndrome contributing to the global burden of diabesity and oncobesity. Its impact on global health has resulted in a massive burden on healthcare services and is among the most prominent contributors to mounting healthcare costs. Despite its pathological impact, the non-surgical management of obesity through behavioural, lifestyle and pharmacotherapies has not offered dependable benefits in severely obese patients. Bariatric surgery has demonstrated consistent weight loss in morbidly obese subjects and is increasingly performed worldwide to treat morbid obesity. Furthermore, these operations may produce beneficial metabolic effects especially with respect to improvement in type 2 diabetes and the metabolic syndrome. Understanding surgical weight loss mechanisms and metabolic modulation is required to enhance patient benefits and operative outcomes. A surgical model of Roux-en-Y gastric bypass (RYGB) was developed as an experimental platform to investigate the metabolic effects of bariatric surgery. The model was studied through a systems biology approach to characterize systemic and gastro-intestinal surgical metabolic modulation. Analysis of postoperative faecal samples from this rodent model revealed a powerful shift in gut microbial ecology and also highlighted the role of RYGB surgery in regulating the cross-talk between the gut microbiome and its mammalian host. Similar metabolic changes were also identified in human subjects undergoing bariatric surgery. Analysis of plasma and cardiac tissue revealed shifts in metabolic activity, reflected by enhanced cardiac energy metabolism. Overall, the results of this work identify some of the potential mechanisms behind bariatric surgical weight loss and systemic metabolic enhancement. This study not only supports the term metabolic surgery but also identifies the global multi-systemic benefits of bariatric surgical procedures. As such, the findings presented in this thesis may in future contribute to the enhancement of current bariatric procedures and the development of the next-generation of innovative metabolic therapies.