Publications (2)4.28 Total impact
Article: Fasting induces an anti-inflammatory effect on the neuroimmune system which a high-fat diet prevents.[show abstract] [hide abstract]
ABSTRACT: The neuroimmunological and behavioral consequences of a high-fat diet (HFD) are not well delineated. This is especially true when short term (24 h) fasting is used as a physiologic stressor. In this study, we examined the impact of a HFD on learning and memory and depressive-like behaviors to understand how fasting impacts neuroimmunity and whether obesity modulates the response. Mice were fed diets containing either 10% (low-fat diet (LFD) mice) or 60% (HFD mice) calories from fat for 10-12 weeks. Gene transcripts for 26 pro-/anti-inflammatory cytokines and markers of macrophage activation were examined in adipose tissue and whole brain. Mouse learning and memory (spontaneous alternation, novel object) and depressive-like behaviors (saccharin preference, burrowing, forced swim) were studied in the fed and fasted state as were gene transcripts for F4/80, CD11b, interleukin-1α (IL-1α), IL-1β, IL-1R1, IL-1R2, IL-1RA, IL-6 and tumor necrosis factor-α in cortex, hippocampus and hypothalamus. In the fed state, HFD mice compared to LFD mice had reduced locomotor activity, and were adverse to saccharin and burrowed less. After fasting, LFD mice vs. HFD mice lost 18 vs. 5% of their body weight, respectively. In addition, HFD mice failed to downregulate gene transcripts for the myeloid-cell associated proteins F4/80, CD11b and IL-1α in the brain, failed to appropriately explore a novel object, failed to reduce locomotor activity and had increased saccharin consumption and burrowing. These data indicate that fasting induces an anti-inflammatory effect on the neuroimmune system which a HFD prevents. This breakdown appears linked to the IL-1 system because of the association of this cytokine with memory and learning.Obesity 04/2011; 19(8):1586-94. · 4.28 Impact Factor
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ABSTRACT: Obesity is a harmful and costly condition which continues to increase in prevalence. Co-morbidities accompanying this disease include brain-based disorders that impact cognition and mood. Anhedonia is a biobehavior associated with depression that manifests in mice as a loss of interest in consuming a highly palatable sucrose or saccharin solution. Here we show that obese mice fed a high-fat diet (HFD), fail to exhibit an interest in saccharin (27% vs 74%) compared to mice fed a low-fat diet (LFD) (p < 0.007). When HFD mice undergo a fasting period of 24 hours, saccharin preferences equilibrate to water consumption (51% saccharin vs 49% water). Other behaviors such as immobility during the forced swim test (FST) and burrowing behavior are improved by fasting in HFD mice. We have previously shown and demonstrate here that basal serum leptin and IL-1RA concentrations are increased in mice fed HFD for 12 weeks compared to mice fed LFD. Leptin has been associated with modulation of motivation to obtain reward and anti-depressant activity, and IL-1RA has been implicated in the mediation of central leptin resistance. To examine if these cytokines contributed to the increased saccharin consumption and other behaviors observed in fasted HFD mice, we measured serum concentrations during the fed and fasted states. Leptin decreased, although not significantly, in mice fed a HFD (43,844 vs 42,791 pg/mL) and LFD (8,118 vs 3,104 pg/mL) after a 24-hour fast. IL-1RA did not significantly change in either group fed LFD or HFD when fasted, and IL-1β was not detectable in any group. We further investigated differences in leptin, leptin receptor (LepR), IL-1RA, IL-1R1, IL-1R2, IL1α and IL-1β brain expression in fed and fasted HFD and LFD mice utilizing real-time PCR (RT PCR) gene expression analysis. A 2-fold increase in leptin expression was seen in both LFD (1 vs 2) and HFD (2 vs 4) after a 24 hour fast (p < 0.05). IL-1RA expression was increased 2.3-fold in HFD compared to LFD in the fed state (1 ± 0.31 vs 2.26 ± 0.66) (p < 0.05) and trended toward increasing in the HFD fed vs fasted (1.89 vs 4.16) but this was not significant. IL-1R1 expression was decreased in fed (0.79 ± 0.09 vs 1 ± 0.08) and fasted (0.68 ± 0.14 vs 0.88 ± 0.07; p < 0.05) HFD mice compared to LFD mice. IL-1R2 expression was decreased during fasting in mice fed HFD compared to mice fed LFD (1.013 ± 0.12 vs. 1.40 ± 0.08; p < 0.005). IL-1α expression was increased 1.5-fold after fasting in mice fed HFD compared to mice fed LFD (0.923 ± 0.14 vs. 0.59 ± 0.15; p < 0.05) and decreased by 1.6-fold during fasting within the LFD group compared to its fed state (0.6 ± 0.15 vs 1 ± 0.19; p < 0.05). Taken together, these data show that changes in brain gene expression of leptin, IL-1α, IL-1R2, IL-1R1 and IL-1RA occur during fasting, and that these changes may be affected by nutritional status and contribute to differences in saccharin preference in mice fed a HFD. In order to determine if IL-1RA played a role in saccharin consumption, IL-1RA knockout mice were given a saccharin preference test. Similar to mice fed HFD, IL-1RA KO mice had an aversion to saccharin compared to control WT mice. IL-1RA KO mice consumed 12% saccharin solution compared to control WT mice that consumed 65% of their total daily fluid intake from saccharin solution (p < 0.005). Taken together, these data indicate that a deviation in normal levels of brain IL-1RA may contribute to saccharin aversion, and that fasting has a behavioral benefit in mice fed HFD that may be reliant on increased leptin expression in the brain.