Recent studies using different strains of mice have highlighted that genetic makeup has a significant impact on how animals respond to dietary interventions important for understanding the development of obesity, insulin resistance and type 2 diabetes in humans. However, variations in environmental conditions (diet, temperature, diurnal rhythm) can also have a major influence on the outcome, and interpretation, of experiments, although not necessarily in the way expected. Our recent investigations in chow and high fat fed mice have determined that housing temperature significantly alters metabolic rate as well as glucose and lipid metabolism in certain tissues, but this appears to have little impact on whole body glucose homeostasis and fat deposition. Obesity in humans is not always associated with reduced insulin action (Diabetologia 2013, 56:875). A similar dissociation between obesity and insulin resistance can also be demonstrated in mice made obese by feeding a high-starch diet compared to mice made obese by feeding a high-fat diet suggesting that insulin resistance is not a simple correlate of excess adipose tissue. Assessing the insulin signalling pathway and glucose uptake in muscle over the diurnal cycle of feeding and fasting revealed that the compensatory hyperinsulinemia seen in insulin resistant fat-fed rats resulted in similar phosphorylation levels of key insulin signalling proteins in muscle as chow-fed insulin sensitive animals. Despite this similar phosphorylation state, glucose uptake remained lower in muscle of fat-fed rats across the feeding period. These observations suggest that obesity-related insulin resistance is more complex than a simple relationship with excess fat deposition or reduced insulin signalling in insulin sensitive tissues. A more holistic rather than candidate approach may be required to fully understand all the mechanisms involved in this importance predictor of metabolic disease.