In the modern day lifestyle, two factors have been primarily associated with the rising prevalence of obesity, the increasing consumption of energy dense food and the decline in physical activity (Varo et al. 2003). With an estimated 500 million adults thought to be obese worldwide (WHO 2013), it is clear we need to stem this epidemic. Much emphasis on research has already been placed on developing strategies to manipulate these two factors and reduce the incidence of obesity but at present an effective and sustainable solution seems elusive. One thing that is clear, with the increase in the cases of obesity, there has also been a concomitant rise in our intake of high refined carbohydrates and sugars. Moreover, the consumption of sugar-sweetened beverages (SSB) has increased over the past four decades (ERS 2004) and consequently, their association with obesity has been well documented (Nissinen et al. 2009, Olsen, Heitmann 2009, Hu, Malik 2010). To undo the damage of diets high in refined carbohydrates and sugars, exercise has been thought to be the answer by many but as yet this has not yielded convincing success in promoting weight loss and repairing the alterations to metabolism associated with chronic hyperglycaemia and obesity. In the first experimental chapter, an in vivo and in vitro approach was used to investigate the effects of high glucose availability on skeletal muscle metabolism. In our in vivo study the effects of 4 weeks sugar-sweetened beverage (SSB) supplementation was investigated on lean, healthy, lightly active individuals with very little or no previous consumption of SSB. Muscle biopsies were taken from each participant pre and post 4 week intervention and through western blotting and real time reverse-transcriptase polymerase chain reaction (RT-PCR), protein and gene expression of several metabolic markers and glucose regulating factors was measured. In the in vitro study, primary human muscle cell cultures were exposed to chronic hyperglycaemia and compared to cultures with normal glucose concentrations for 7 days. Analyses revealed both the in vivo and in vitro studies demonstrated a shift towards increased glycolytic activity and reduced oxidative activity, similar to that found in type 2 diabetes mellitus patients. Furthermore, in both studies an increase in MondoA expression was observed and in the in vitro cell cultures TXNIP expression was also increased. The fact that the findings from in vivo study are comparable to those in the in vitro study, demonstrates the potency of high glucose availability on skeletal muscle. The results are even more alarming as the participants were young healthy individuals, not overweight or obese and with very little previous history of SSB consumption, highlighting just how damaging the effects of SSBs can be and the significant role they play in the development of obesity. In chapter 3 and 4, long term exercise interventions were used to investigate the effects of chronic exercise on metabolism, body composition and energy balance of lean and overweight or obese (Ov/Ob) sedentary women. The aim of these studies was to investigate the compensatory mechanisms in Ov/Ob individuals preventing adaptations to exercise. A novel approach to long term exercise with ad libitum energy intake was used in both of these studies, where participants were not recruited with a desire to lose weight and they were also naïve to the true aims of the study. In chapter 3 a 4 week exercise training intervention was used and in chapter 4 an 8 week training intervention was used. Both studies utilized a group based circuit training format 3 days per week, the 4 week intervention was at a moderate intensity and the 8 week intervention had both a high and low intensity exercise group. Dual-energy xray absorptiometry (DXA) and indirect calorimetry, at rest and during exercise, were used to give and overview of participants’ anthropometric and metabolic profiles, before and after inventions. Blood samples were collected for analysis of several key hormones regulating metabolic adaptations and energy homeostasis in response to exercise. Diet records were also collected from participants to measure any alterations in energy and macronutrient intake. Neither the 4 week nor the 8 week exercise intervention demonstrated significant weight loss of either the lean or Ov/Ob individuals. However, in both the interventions lean participants displayed losses in percentage body fat, even though no weight loss was seen overall. These findings reaffirm those reported in previous literature that during an increase in exercise induced energy expenditure, Ov/Ob individuals with respond with a concomitant increase in energy intake, negating any possible weight or fat loss and possibly even promote weight gain. On the contrary lean individuals do not display the same over-compensation to the increased energy expenditure and there energy intake is unchanged. It is hypothesized that the lean participants were able to display a reduction in body fat through the ability to exercise at a higher absolute intensity. Based on analysis of blood samples, it was possible to further investigate possible regulators that may control a homeostatic mechanism, preventing weight/fat loss in obese individuals. In the 8 week study a significant drop in amylin concentrations was observed in the Ov/Ob participants, compared to no change in the lean subjects. It was proposed that Ov/Ob individuals, who also displayed heightened insulin resistance and hyperleptinemia, have developed an overreliance on amylin for satiety signalling. Moreover, in conjunction with the inability to achieve an absolute intensity high enough to induce adaptive responses to exercise, Ov/Ob individuals with reduced amylin secretion, increase energy intake after exercise and prevent any possible weight or fat loss. Additionally, adaptive responses to exercise were seen in both the 4 week and 8 week exercise studies, Ov/Ob participants displayed a positive movement away from a preference to rely on anaerobic metabolism at a low exercise intensity preintervention, towards more anaerobic metabolism post-intervention. In addition, following the 8 week exercise intervention, the inter-individual variability in response to exercise was investigated. Participants were separated based on their heart rate response, into responders and non-responders and it was revealed that those who clearly demonstrated adaptations, also tended to lose more weight, maintain a negative energy balance, and avoid the maladaptive decrease in amylin concentrations. Suggesting these individuals do not develop the hypothesized leptin resistance, and overreliance on amylin signal, meaning they do not overcompensate for increased exercise induced energy expenditure and can lose weight. In conclusion, it is clear that an exercise only or a one size fits all approach is not the answer in the treatment of obesity. A more multi-dimensional approach is necessary and in order to reduce many of the associated lifestyle disease markers, both diet and levels of physical activity must be addressed in the obese. Recommendations for future intervention studies must address this and combine a diet low in refined carbohydrates and sugars, with high intensity interval training and resistance exercise.