Cognitive Impairment and Metabolite Profile Alterations in the Hippocampus and Cortex of Male and Female Mice Exposed to a Fat and Sugar-Rich Diet are Normalized by Diet Reversal

Abstract

Diabetes impacts on brain metabolism, structure, and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. Mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed the HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex but were more distinct in the hippocampus. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine, N -acetylaspartate, total creatine and total choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. In conclusion, cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.

Taurine Supplementation as a Neuroprotective Strategy upon Brain Dysfunction in Metabolic Syndrome and Diabetes

“…Namely, mice fed a lard-based 60%-fat-rich diet for 6 months showed increased taurine in the cortex (+7%), hypothalamus (+9%), and, most prominently, hippocampus (+12%), when compared to low-fat-fed mice [ 159 ]. Recently, we further demonstrated that a high-fat and high-sugar diet led to increased hippocampal levels of taurine after 4 weeks, which persisted for several months (ranging from +8% to +14% relative to low-fat-diet-fed controls), which were reversed by diet normalization [ 38 ]. Such increase in brain taurine levels in mice with diabetes might have resulted from a compensatory mechanism for cellular protection against metabolic syndrome.…”

“… Concentrations of taurine in the plasma ( A ) and cerebral cortex of various species ( B ), in different areas of the mouse brain ( C ), and in the mouse cortex during development ( D ). Plasma taurine levels are indicated as mean and range for humans [ 2 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], guinea pigs [ 28 , 29 ], rat [ 30 , 31 , 32 , 33 , 34 , 35 , 36 ], and mice [ 37 , 38 , 39 , 40 , 41 ]. The plotted brain taurine concentration ranges are based on the concentrations reported in 1 H MRS studies for humans [ 42 , 43 , 44 , 45 , 46 , 47 ], tree shrews [ 48 ], guinea pigs [ 49 ], Sprague–Dawley rats [ 50 , 51 , 52 , 53 , 54 , 55 ], and C57BL/6J mice [ 38 , 56 , 57 , 58 , 59 , 60 ].…”

Taurine or N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice

“…Food and water were provided ad libitum . Diets were acquired from Research Diets (New Brunswick, NJ-USA): a lard-based diet with 60% kcal of fat (D12492) and a control diet containing 10% kcal of fat (D12450J), with total energy of 5.21 and 3.82 kcal/g, respectively, and caloric intake was monitored as previously (García-Serrano et al , 2022).…”

“…RNA was isolated from the hippocampus with Trizol (#15596026, Invitrogen), and then 1 μg of total RNA was reverse transcribed with random hexamer primers using the qScript cDNA SuperMix (#95048, Quantabio, England), according to the manufacturers’ instructions. The resulting cDNA was used for quantitative RT-PCR as detailed previously (Garcia-Serrano et al ., 2022) using PerfeCTa SYBRgreen SuperMix (#95054, Quantabio, England) and the primers listed in table 1 . Gene expression was determined using the comparative cycle threshold (CT) method (ΔΔCT) with normalization to the average expression of L14 and GAPDH.…”

“…MRS was performed at 8 weeks under isoflurane anaesthesia as detailed in Garcia-Serrano et al (2022). In brief, isoflurane (Vetflurane, Virbac, Carros, France) anaesthesia was delivered using 1:1 (v/v) O2:air as carrier gas at variable rate of 1-2% for maintaining stable respiration between 60 and 100 breaths per minute.…”