The effects of active immunisation with gastric inhibitory polypeptide (GIP) or (proline3)GIP ovalbumin conjugates on insulin resistance, metabolic dysfunction, energy expenditure and cognition were examined in high-fat-fed mice. Normal mice were injected (subcutaneously) once every 14 d for 98 d with GIP-ovalbumin conjugates, with transfer to a high-fat diet on day 21. Active immunisation resulted in GIP antibody generation and significantly (P<0.01 to P<0.001) reduced circulating non-fasting plasma insulin concentrations compared to high-fat control mice from day 70 onwards. The glycaemic responses to intraperitoneal glucose or nutrient ingestion were significantly improved in all treated mice, with corresponding stimulated plasma insulin levels depressed compared to high-fat controls. These changes were associated with substantially (P<0-001) improved glucose-lowering responses to exogenous insulin and decreases of muscle and fat TAG, pancreatic insulin, circulating total and LDL-cholesterol levels (P<001 to P<0001). Treatment with GIP ovalbumin conjugates was not associated with alterations in energy expenditure, indirect calorimetry or aspects of cognitive function. The observed changes were almost identical in GIP and (Pro(3))GIP immunised mice and were independent of any effects on food intake or body weight. Further tests established that coupling of GIP peptides to ovalbumin abolished any intrinsic insulin-releasing or glucose-lowering activity. These results suggest that induction of GIP-neutralising antibodies with GIP ovalbumin conjugates is an effective means of countering the metabolic abnormalities induced by high-fat feeding and does not adversely have an impact on a marker of cognition function or energy expenditure.