Understanding mechanisms responsible for the development of glucose intolerance is of fundamental importance. Often, complex problems can be most easily solved when working backwards. In this regard, it is clear that glycaemic defects and associated metabolic abnormalities can be rapidly reversed by either bariatric surgery or very-low energy diets, with much of this improvement attributed to improved metabolic function in the liver. Thus, using a combination of stable isotope and GC-MS approaches, we investigated the reversal of high-fat diet (HFD) induced metabolic impairments by switching chronically (8wk) HFD fed mice back to a regular chow diet for 7 days. The reversal group showed a voluntary reduction in energy intake compared to both the chow and HFD groups, resulting in a reduction of body mass, fat mass, plasma leptin, and liver triglyceride (TAG) compared to the HFD group. However these parameters were still elevated compared to the chow controls, thus representing an intermediate phenotype. Nonetheless, the reversal mice exhibited a normalization of fasting blood glucose and glucose tolerance. Insulin levels under fasting and OGTT conditions were also normalized. However, there were minimal effects of HFD or diet-reversal on total, PEP and glycerol gluconeogenesis. Remarkably, reversal mice still maintained the reduction in plasma FFA concentration that is characteristic of HFD mice. This was explained by the liver of reversal mice having a dramatic reduction in de novo lipogenesis that was counteracted by elevated hepatic TAG synthesis rate, thus acting to ‘soak’ up circulating adipose tissue derived FFA. This is likely to constitute a futile cycle of hepatic FFA esterification followed by lipolysis and oxidation, as there was still a net loss in hepatic TAG concentrations in reversal mice. Muscle TAG content in reversal mice remained elevated and was similar to the HFD group, yet lipid synthesis was normalised to chow-fed levels. Interestingly, liver lipid synthesis was ~10 and ~20-fold higher than that in muscle under chow and HFD conditions, respectively. These findings suggest that elevated rates of hepatic lipid synthesis and content are not necessarily involved in maintaining the insulin resistant and glucose intolerant state.