The incidence of obesity and type 2 diabetes mellitus (T2DM) is increasing, and new experimental models are required to investigate the diverse aspects of these polygenic diseases, which are intimately linked in terms of aetiology. Feline T2DM has been shown to closely resemble human T2DM in terms of its clinical, pathological and physiological features. Our aim was to develop a feline model of diet-induced weight gain, adiposity and metabolic deregulation, and to examine correlates of weight and body fat change, insulin homeostasis, lipid profile, adipokines and clinical chemistry, in order to study associations which may shed light on the mechanism of diet-induced metabolic dysregulation. We used a combination of partially hydrogenated vegetable shortening and high-fructose corn syrup to generate a high-fat–high-fructose diet. The effects of this diet were compared with an isoenergetic standard chow, either in the presence or absence of 1·125 % dietary monosodium glutamate (MSG). Dual-energy X-ray absorptiometry body imaging and a glucose tolerance test were performed. The present results indicate that dietary MSG increased weight gain and adiposity, and reduced insulin sensitivity (P < 0·05), whereas high-fat–high-fructose feeding resulted in elevated cortisol and markers of liver dysfunction (P < 0·01). The combination of all three dietary constituents resulted in lower insulin levels and elevated serum β-hydroxybutyrate and cortisol (P < 0·05). This combination also resulted in a lower first-phase insulin release during glucose tolerance testing (P < 0·001). In conclusion, markers of insulin deregulation and metabolic dysfunction associated with adiposity and T2DM can be induced by dietary factors in a feline model.