The increasing prevalence of metabolic disorders is associated to the consumption of highly palatable food products rich in calories. Metabolic disorders, particularly insulin-resistant diabetes mellitus, affect brain function and lead to cognitive impairment [1]. Recent work in an animal models of insulin resistance demonstrated its deleterious effect on memory performance, brain morphology and the neurochemical profile of the cortex and hippocampus [2-4]. Furthermore, a direct link between consumption of high-fat and/or high-sucrose containing diets and cognitive dysfunction has been reported [5-7]. We now investigated the neurochemical modifications in the hippocampus, cortex and hypothalamus of mice exposed to long-term hypercaloric high-fat diet (HFD), relative to mice exposed to a regular diet (RD).C57BL/6J mice (males; 3 months old) were fed either a HFD (60% kcal from fat, n=7) or a RD (10% kcal from fat, n=5) for 6 months. Metabolic dysfunction and insulin resistance were inferred from measurements of 6-hour fasting glycemia and insulinemia, and from a glucose tolerance test (1.5 g/kg glucose gavage). Brain function was assessed by measuring hippocampal-dependent spontaneous alternation in a Y-maze and exploratory behaviour in an open field arena [4]. Then, localized 1H MRS was performed on a 14.1 T, 26 cm VNMRS spectrometer using a home-built 8 mm diameter quadrature surface coil (used both for RF excitation and signal reception) as previously described [3]. C57BL/6 mice were anaesthetized under 1-2% isoflurane in 50% O2 in air. Briefly, field homogeneity was adjusted by FASTMAP, and 1H spectra were acquired from VOIs placed in the hippocampus, cortex and hypothalamus, using SPECIAL with TE of 2.8 ms and TR of 4 s [8], and metabolite concentrations were estimated with LCModel [9]. The entire neurochemical profile was analysed with ANOVA, followed by Student t-tests for paired comparisons.Mice exposed to HFD displayed increased weight gain over the period of diet exposure (P<0.01), higher fasting glycemia (P<0.05) and insulinemia (P<0.01), and impaired glucose clearance in the glucose tolerance test (P<0.01), relative to controls. HFD affected mnemonic function, as revealed by a reduction of 10% in the hippocampal-dependent spontaneous alternation in the Y-maze (P<0.05). A neurochemical profile composed of 19 metabolites was determined in vivo in the mouse hippocampus, cortex, and hypothalamus (fig.1). In the hippocampus, HDF induced an increase in the concentrations of creatine (+17%, P<0.05) but not phosphocreatine, of GABA (+15%, P<0.01), of glutamine (+20%, P<0.05), of taurine (+14%, P<0.01), and of glucose (+159%, P<0.001). In the cortex, HDF induced an increase in the concentrations of creatine (+13%, P<0.05) accompanied by a reduction of phosphocreatine levels (-20%, P<0.05), and also a reduction in glycine content (-29%, P<0.01). In the hypothalamus, long-term HFD caused an increase in levels of creatine (+20%, P<0.05) but not phosphocreatine, of GABA (+16%, P<0.05), of myo-inositol (+21%, P<0.01), and of ascorbate (+106%, P<0.01), compared to controls.The present results demonstrate that a mouse model of obesity-induced insulin-resistance that displays brain dysfunction, exhibits region-specific metabolic modifications in the brain. Due to higher glycaemia, compared to controls, glucose tended to be elevated in the brain HFD-exposed mice, as observed in other diabetes models [2,3], with exception of the hypothalamus, probably related to its glucose sensing function. Nevertheless, HFD-exposed mice displayed a global reduction of the ratio of phosphocreatine to creatine, suggesting reduced energy availability, which is in line with impaired mitochondrial function in the diabetic brain [1]. The hippocampus is importantly affected by insulin resistance [1]. In the particular case of this region, there was an elevation of taurine in HFD vs. RD. Diabetes-induced taurine elevations were reported in the hippocampus of other diabetes models [2,3], and could play a role in the osmotic adaptation to sustained high glucose levels upon uncontrolled diabetes. Notably, HFD was associated to high hypothalamic myo-inositol levels, which could be associated to the known inflammatory response of this region to excessive lipid exposure [10].In HFD-exposed mice, obesity-associated insulin resistance affects the neurochemical profiles of the hippocampus, cortex and hypothalamus in a region-specific manner.