UC Davis

Obesity is characterized by a condition of low-grade chronic inflammation and is associated with increased occurrence of cognitive and mood disorders. While consumption of high-fat diets (HFD) and associated obesity could have a detrimental impact on the brain structure and function, consumption of select dietary bioactives may help prevent these harmful effects. The overall aim of this thesis was to investigate the neuroprotective potential of the dietary flavan-3-ol (-)-epicatechin (EC) in the context of HFD and associated obesity. Our first study investigated the capacity of dietary EC to mitigate hippocampal inflammation and impaired cognition in HFD-fed obese mice. Healthy 6 weeks old male C57BL/6J mice were fed for 13 weeks either a control diet (10% total calories from fat), a high fat diet (60% total calories from fat), or the control and high fat diets supplemented with 20 mg EC/kg body weight. Between week 10 and 12 of the dietary intervention, object recognition memory and spatial memory were evaluated. Gene expressions related to inflammation, oxidative stress, and neurotrophic factor were analyzed in the hippocampus. Impaired recognition memory was observed in HFD-fed mice, which was prevented by EC supplementation. Neither HFD consumption nor EC supplementation affected mouse spatial memory. After 13 weeks of the dietary intervention, HFD-fed mice developed obesity, endotoxemia, and showed increased parameters of hippocampal inflammation. While not affecting body weight gain, EC supplementation prevented all the HFD-induced changes. Taken together, EC supplementation prevented short-term recognition memory in HFD-induced obese mice, which could be in part due to the capacity of EC to mitigate HFD-induced metabolic endotoxemia, inflammation and oxidative stress in the hippocampus. To further understand the capacity of EC to mitigate obesity-induced changes in cognition and mood, we conducted a longer dietary intervention study (24 weeks) with a HFD that is more comparable to the amount of fat consumed by humans. Healthy 8-week old male C57BL/6J mice were maintained on either a control diet (10% total calories from fat) or a HFD (45% total calories from fat), and were supplemented with EC at 2 or 20 mg/kg body weight. Between week 20 and 22, anxiety-related behavior, recognition memory, and spatial memory were measured. Underlying mechanisms were assessed by measuring the expression of selected genes in the hippocampus and by 16S rRNA sequencing and metabolomic analysis of the gut microbiota. After 24 weeks of HFD feeding, mice developed obesity, which was not affected by EC supplementation. HFD-associated increase in anxiety-related behavior was mitigated by EC in a dose-response manner and was accompanied by increased hippocampal brain-derived neurotrophic factor (BDNF), as well as partial or full restoration of glucocorticoid receptor, mineralocorticoid receptor and 11β-HSD1 expression. Higher EC supplementation (20 mg/kg body weight) also restored aberrant Lactobacillus and Enterobacter abundance altered by the HFD and/or the associated obesity. Together, EC mitigated HFD-induced anxiety-related behavior partly by modulating BDNF- and glucocorticoids-mediated signaling and mitigating HFD-associated dysbiosis. Next we conducted an untargeted hippocampal transcriptomic analysis that included mRNAs, miRNAs, and long non-coding RNAs to further understand the underlying neuroprotective mechanisms of EC against HFD-induced obesity. EC reversed the gene expression profile induced by the HFD, counteracting the effects of the HFD. Genes involved in neurofunction-related pathways including Alzheimer’s disease and neurodegeneration and cellular pathways such as insulin signaling pathway were dysregulated by the HFD, and EC counteracted the dysregulation. Functionality analysis revealed that the differentially expressed genes upon EC supplementation regulate processes involved in neurofunction, inflammation, endothelial function, and cell-cell adhesion. Taken together, the effect of EC to mitigate anxiety-related behavior in the HFD-induced obese mice can be, in part, explained by its capacity to exert complex genomic modifications in the hippocampus, counteracting changes driven by the consumption of the HFD and subsequent obesity. In summary, this thesis contributes to the explanation of mechanisms related to the neuroprotective potential of EC in context of HFD and associated obesity. Our results suggest that EC could mitigate HFD-induced alterations in memory and anxiety, in part, by ameliorating neuroinflammation, modulating BDNF-and glucocorticoids-regulated signaling, mitigating dysbiosis, and counteracting the effects of HFD on the hippocampus at a multi-genomic level.