Enzyme-resistant glucose-dependent insulinotropic polypeptide (GIP) agonists offer therapeutic potential for type 2 diabetes treatment. In addition, there is emerging evidence suggesting that GIP plays a direct role in modulating aspects of brain function. This study compared effects of dietary modification and/or twice-daily injection of the stable GIP agonist, (d-Ala(2))GIP, on metabolic control, cognitive function and hippocampal synaptic plasticity in high-fat fed mice. Young Swiss mice were maintained on high-fat diet for 155 days, at which point half of the animals were switched to standard maintenance diet. Mice were subsequently injected with (d-Ala(2))GIP (25 nmol/kg bodyweight; b.i.d.) or saline vehicle for 28 days. Both dietary intervention and (d-Ala(2))GIP treatment were equally effective in restoring non-fasting glycaemic control (P