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High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.

ABSTRACT: Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high fat lard diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in NF-E2-related factor 2 (Nrf2) levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.

SUBMITTER: Morrison CD

PROVIDER: S-EPMC2945419 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.

Morrison Christopher D CD Pistell Paul J PJ Ingram Donald K DK Johnson William D WD Liu Ying Y Fernandez-Kim Sun Ok SO White Christy L CL Purpera Megan N MN Uranga Romina M RM Bruce-Keller Annadora J AJ Keller Jeffrey N JN

Journal of neurochemistry 20100727 6

Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either 'western diet' (41% fat), very high fat lard diet (60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the high f ...[more]

PMID: 20557430

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Project description:Many theories have been advanced to better understand why β cell function and structure relentlessly deteriorate during the course of type 2 diabetes (T2D). These theories include inflammation, apoptosis, replication, neogenesis, autophagy, differentiation, dedifferentiation, and decreased levels of insulin gene regulatory proteins. However, none of these have considered the possibility that endogenous self-repair of existing β cells may be an important factor. To examine this hypothesis, we conducted studies with female Zucker diabetic fatty rats fed a high-fat diet (HFD) for 1, 2, 4, 7, 9, 18, or 28 days, followed by a return to regular chow for 2-3 weeks. Repair was defined as reversal of elevated blood glucose and of inappropriately low blood insulin levels caused by a HFD, as well as reversal of structural damage visualized by imaging studies. We observed evidence of functional β cell damage after a 9-day exposure to a HFD and then repair after 2-3 weeks of being returned to normal chow (blood glucose [BG] = 348 ± 30 vs. 126 ± 3; mg/dl; days 9 vs. 23 day, P < 0.01). After 18- and 28-day exposure to a HFD, damage was more severe and repair was less evident. Insulin levels progressively diminished with 9-day exposure to a HFD; after returning to a regular diet, insulin levels rebounded toward, but did not reach, normal values. Increase in β cell mass was 4-fold after 9 days and 3-fold after 18 days, and there was no increase after 28 days of a HFD. Increases in β cell mass during a HFD were not different when comparing values before and after a return to regular diet within the 9-, 18-, or 28-day studies. No changes were observed in apoptosis or β cell replication. Formation of intracellular markers of oxidative stress, intranuclear translocation of Nrf2, and formation of intracellular antioxidant proteins indicated the participation of HFD/oxidative stress induction of the Nrf2/antioxidant pathway. Flow cytometry-based assessment of β cell volume, morphology, and insulin-specific immunoreactivity, as well as ultrastructural analysis by transmission electron microscopy, revealed that short-term exposure to a HFD produced significant changes in β cell morphology and function that are reversible after returning to regular chow. These results suggest that a possible mechanism mediating the ability of β cells to self-repair after a short-term exposure to a HFD is the activation of the Nrf2/antioxidant pathway.

Dataset Information

High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.

Publications

High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.

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