Metabolic diseases are caused by a complex interaction between genetics and environment (GxE). We utilised genetically diverse outbred mice fed two different diets to study GxE in precise detail. Mice displayed profound variation in metabolic risk factors spanning hyperinsulinemia, obesity, fasting glycemia, glucose intolerance and hepatic steatosis with ~40% of mice developing hyperinsulinemia on chow diet and ~30% remaining metabolically healthy on Western diet. By classifying mice based on metabolic health, we identified a genome wide significant quantitative trail locus associated with metabolic health, confirming that ‘health’ is genetically programmed and not simply the absence of disease. Using systems genetics largely involving genetic analysis of tissue specific proteomes, we pinpointed a causal metabolic health gene at the locus. This gene is intimately involved in metabolic homeostasis and fuel switching in a range of tissues. This study paves the way for the discovery of further metabolic health genes, an attractive approach for identifying novel therapeutic targets.