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The incidence of neurodegenerative diseases is increasing globally in a sporadic fashion, possibly due to increased longevity and unhealthy life>
.
In particular, obesity is strongly associated with comorbidities such as cardiovascular disease, metabolic syndrome and type 2 diabetes (T2D), which affect the brain and are associated with mild cognitive impairment, Alzheimer's disease or vascular dementia
This may be due to increased longevity and an unhealthy life>
Magnetic resonance spectroscopy (MRS) enables non-invasive analysis of regional metabolic profiles
.
Diabetes and related comorbidities have been shown to cause changes in the concentrations of n-acetylaspartate, creatine, choline, inositol, glutamate, and glutamine in the brain
Magnetic resonance spectroscopy (MRS) enables non-invasive analysis of regional metabolic profiles
This study examined reversible changes in hippocampal and cortical metabolism and behavioral changes induced by an obese diet (high-fat and high-sucrose diet; HFHSD)
.
Mice were exposed to HFHSD for 24 or 16 weeks, followed by normalization of diet for 8 weeks
Mice in the experimental group were randomly assigned to 3 groups, one receiving a control diet (CD, n = 12 males + 15 females), a group receiving a high-fat and high-sucrose diet (HFHSD) for 6 months (n = 13 males + 13 females) females), the other group was fed HHFSD for 4 months (n=9 males + 10 females) followed by CD for 2 months (Fig.
Food intake and metabolic phenotype
Mice fed HFHSD consumed higher caloric intake compared to controls (Fig.
1B) due to higher intake of fat and sucrose, rather than carbohydrates or protein (Fig.
1C)
.
Consequently, mice fed HFHSD became overweight but returned to normal levels after transitioning to the control diet (Fig.
Mice fed HFHSD consumed higher caloric intake compared to controls (Fig.
Consistent with previous studies in mice fed an obesogenic diet, HFHSD caused a sex-dependent imbalance in glucose homeostasis that was fully restored after dietary reversal ( Figure 2 )
Fasting blood glucose ( diet P<0.
001; sex P<0.
001; interaction P=0.
292; Figure 2D) and plasma insulin levels ( diet P<0.
001; sex P=0.
011; interaction P=0.
007; Figure 2E )
in mice fed HFHSD ) slightly increased .
This translated into an increase in HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), indicating insulin resistance ( P<0.
Fasting blood glucose ( diet P < 0.
After establishing the reversible effects of diet on glycemic control, we next investigated whether metabolic syndrome was associated with behavioral changes
.
Spatial working memory was assessed by measuring spontaneous switching of the y-maze during phenotypic development (Fig.
3a)
.
Diet versus spontaneous change (at 24 weeks: diet P=0.
353; sex P=0.
034; interaction P=0.
334), or exploratory behavior described by the number of arm items (at 24 weeks: diet P=0.
638; sex P=0.
116; interaction P = 0.
988) had no effect
.
Next, perceptions of novelty were tested 24 weeks after the introduction of these diets
.
After becoming familiar with both objects, mice generally tended to spend more time exploring a new object, or an object that was replaced in the arena
.
When testing novel location recognition (diet P<0.
001; sex P=0.
341; interaction P=0.
867 ; Figure 3C) or novel object recognition (diet P<0.
001; sex P=0.
059; interaction P=0.
308; Figure 3D ), the reversal diet group fully recovered memory performance in the novel place recognition task (Fig.
3C) and improved memory performance in the novel object recognition task (Fig.
3D) compared with HFHSD
.
.
After becoming familiar with both objects, mice generally tended to spend more time exploring a new object, or an object that was replaced in the arena
.
When testing novel location recognition (diet P<0.
001; sex P=0.
341; interaction P=0.
867 ; Figure 3C) or novel object recognition (diet P<0.
001; sex P=0.
059; interaction P=0.
308; Figure 3D ), the reversal diet group fully recovered memory performance in the novel place recognition task (Fig.
3C) and improved memory performance in the novel object recognition task (Fig.
3D) compared with HFHSD
.
Next, perceptions of novelty were tested 24 weeks after the introduction of these diets
.
After becoming familiar with both objects, mice generally tended to spend more time exploring a new object, or an object that was replaced in the arena
.
When testing novel location recognition (diet P<0.
001; sex P=0.
341; interaction P=0.
867 ; Figure 3C) or novel object recognition (diet P<0.
001; sex P=0.
059; interaction P=0.
308; Figure 3D ), the reversal diet group fully recovered memory performance in the novel place recognition task (Fig.
3C) and improved memory performance in the novel object recognition task (Fig.
3D) compared with HFHSD
.
Check out the 8 minute open air exploration
.
HFHSD exposure decreased the total distance traveled within the arena (P=0.
006 for diet; P=0.
004 for sex; P=0.
224 for interaction; Figure 3E )
.
In addition, HFHSD-fed male mice exhibited fewer crossovers in quadrants of the arena compared to controls (diet P = 0.
008; sex P = 0.
047; interaction P = 0.
234) and increased immobility time (P = 0.
006 for diet; P = 0.
030 for sex; P = 0.
121 for interaction)
.
Taken together, these results suggest that novel environmental exploration is reduced after HFHSD exposure and normalized after dietary reversal .
Generally, rodents spent more time exploring the outer periphery of the arena, near the walls, than the unprotected central area
.
HFHSD-fed mice spent less time (diet P<0.
001; sex P=0.
375; interaction P=0.
716; Figure 3F ) and walked shorter distances in the center of the arena (diet P<0.
001; sex P=0.
071 ; interaction P = 0.
256)
.
Decreased exploration of the center versus the periphery indicated increased anxiety-like behaviors in HFHSD-fed mice, which recovered after normalization of the diet
.
Metabolite profile
Behavioral changes were similar in male and female mice (Figure 3)
.
Furthermore, it has been previously shown that the metabolite profiles measured by MRS in the hippocampus and cortex are similar in male and female mice
.
Therefore, to increase statistical power, we grouped male and female mice and analyzed their metabolite profiles
.
Figure 4 depicts the location of the VOI in the hippocampus and cortex, along with the respective spectra
.
.
Furthermore, it has been previously shown that the metabolite profiles measured by MRS in the hippocampus and cortex are similar in male and female mice
.
The metabolite profiles measured by MRS in the hippocampus and cortex were similar in male and female mice
.
Metabolite profiles measured by MRS in the hippocampus and cortex were similar in male and female mice.
Therefore, to increase statistical power, we grouped male and female mice and analyzed their metabolite profiles
.
Figure 4 depicts the location of the VOI in the hippocampus and cortex, along with the respective spectra
.
In the hippocampus ( Figure 5 ), the earliest metabolic alteration triggered by HFHSD was a reduction in lactate levels (P<0.
05, compared with controls on a 4-week diet ) , which persisted until the end of treatment
.
Glutamate (P<0.
01), N -acetylcarbamate (NAA; P<0.
05), taurine (P<0.
001) and creatine (P<0.
001) were increased at 8 weeks relative to the control group , and remained high throughout the intervention
.
At 16 weeks, GABA (P<0.
001), inositol (P<0.
01), phosphocreatine (P<0.
001), and glutathione (P<0.
001) in HFHSD-fed mice compared with controls concentration increased
.
HFHSD feeding also resulted in transient changes in alanine levels at 8 weeks of treatment (P < 0.
01) and in N -acetylformylglutamate (NAAG) levels at 16 weeks of treatment (P < 0.
05)
.
All of these metabolic alterations in the hippocampus disappeared 8 weeks after dietary reversal ( Figure 5)
.
.
Overall, the metabolite distribution within the cortex (Figure 6) was less affected by HFHSD feeding compared to the hippocampus, and the changes were generally in the opposite direction
.
Although cortical lactate levels remained unchanged, HFHSD-fed mice had increased alanine concentrations from 8 weeks of treatment compared with controls (P < 0.
01)
.
Compared with the control group, HFHSD-induced cortical N-acetylaspartate (P<0.
05) was further observed from 8 weeks, glutamine (P<0.
01) and glutathione (P<0.
01) from 16 weeks start to descend
.
There was a transient increase in cortical glycine concentration at 1 and 8 weeks of HFHSD feeding (P<0.
05, compared with controls )
.
Although glycine levels were similar in HFHSD-fed mice and controls at 24 weeks of treatment, they were increased by dietary reversal (P<0.
05 versus controls and HFHSD)
.
.
Although cortical lactate levels remained unchanged, HFHSD-fed mice had increased alanine concentrations from 8 weeks of treatment compared with controls (P < 0.
01)
.
Compared with the control group, HFHSD-induced cortical N-acetylaspartate (P<0.
05) was further observed from 8 weeks, glutamine (P<0.
01) and glutathione (P<0.
01) from 16 weeks start to descend
.
There was a transient increase in cortical glycine concentration at 1 and 8 weeks of HFHSD feeding (P<0.
05, compared with controls )
.
Although glycine levels were similar in HFHSD-fed mice and controls at 24 weeks of treatment, they were increased by dietary reversal compared to controls (P<0.
05 versus controls and HFHSD)
.
Brain glucose levels depend on blood glucose and the rate of brain glucose uptake and consumption
.
Consistent with the increase in blood glucose, a trend of increased brain glucose levels was observed in mice fed HHFSD compared to mice fed a control diet ( Figure 5 — Figure 6 )
.
Principal component analysis (PCA) was used to provide a global description of brain metabolism
.
This analysis revealed that brain metabolic shifts in the hippocampus (relative to controls) began at 8 weeks of HFHSD feeding ( Figure 7A )
.
PCA was performed on MRS data collected during the first 16 weeks of treatment and then used to calculate PCA scores for metabolite profiles obtained at 24 weeks
.
This analysis showed normalization of hippocampal metabolite profiles following dietary reversal (Figure 7A)
.
Results in the cortex were less pronounced, consistent with the less pronounced metabolic alterations observed in this region during the first 16 weeks of dietary intervention (Fig.
7A)
.
PCA described taurine and NAA as the most influential metabolites in the effect of HHFSD on brain metabolic profiles (Fig.
7B)
.
.
This analysis showed normalization of hippocampal metabolite profiles following dietary reversal (Figure 7A)
.
Results in the cortex were less pronounced, consistent with the less pronounced metabolic alterations observed in this region during the first 16 weeks of dietary intervention (Fig.
7A)
.
PCA described taurine and NAA as the most influential metabolites in the effect of HHFSD on brain metabolic profiles (Fig.
7B)
.
Analysis of neuroinflammation and neurodegeneration in HFHSD
neurodegenerationNeuroinflammation has been reported with exposure to an obesogenic diet
.
Therefore, fluorescence microscopy was used to observe Iba1, CD11b, GFAP, and glutamine synthase to explore whether there was neuroinflammation and gliosis after 24 weeks of HFHSD exposure (Fig.
8A)
.
HFHSD had no effect on the area or number of cortical or hippocampal microglia (Iba1 and CD11b positive cells) (Fig.
8B)
.
In turn, HFHSD induced a significant increase in the proportion of activated microglia (P<0.
001 for diet; P=0.
221 for brain region; P=0.
737 for interaction ), which was normalized by dietary reversal
.
HFHSD had no effect on cortical or hippocampal astrocyte numbers as observed by GFAP and glutamine synthase (astrocyte-specific enzyme) immunolabeling (Fig.
8C)
.
.
Therefore, fluorescence microscopy was used to observe Iba1, CD11b, GFAP, and glutamine synthase to explore whether there was neuroinflammation and gliosis after 24 weeks of HFHSD exposure (Fig.
8A)
.
HFHSD had no effect on the area or number of cortical or hippocampal microglia (Iba1 and CD11b positive cells) (Fig.
8B)
.
In turn, HFHSD induced a significant increase in the proportion of activated microglia (P<0.
001 for diet; P=0.
221 for brain region; P=0.
737 for interaction ), which was normalized by dietary reversal
.
HFHSD had no effect on cortical or hippocampal astrocyte numbers as observed by GFAP and glutamine synthase (astrocyte-specific enzyme) immunolabeling (Fig.
8C)
.
Notably, glutamine synthase was used as a marker for astrocytes, as cortical astrocytes showed GFAP staining only on the cortical surface and around some blood vessels
.
The regions occupied by glutamine synthase in the hippocampus and cortex (Fig.
8C) or the regions occupied by GFAP in the hippocampus (not shown) were also similar in the regions analyzed
.
Immunoblots for Iba1 and GFAP in cortical and hippocampal protein extracts were similar in the 3 groups, confirming no change in the total area of microglia and astrocytes (Fig.
8D)
.
Furthermore, no changes in the expression levels of the inflammatory regulator NF-κβ or cytokines in the hippocampus were observed (Fig.
8E)
.
.
The regions occupied by glutamine synthase in the hippocampus and cortex (Fig.
8C) or the regions occupied by GFAP in the hippocampus (not shown) were also similar in the regions analyzed
.
Immunoblots for Iba1 and GFAP in cortical and hippocampal protein extracts were similar in the 3 groups, confirming no change in the total area of microglia and astrocytes (Fig.
8D)
.
Furthermore, no changes in the expression levels of the inflammatory regulator NF-κβ or cytokines in the hippocampus were observed (Fig.
8E)
.
NeuN immunolabeling showed that HFHSD had no effect on the number of mature neurons in the granulosa cell layer of the cortex or hippocampus (Fig.
8F)
.
Furthermore, no HFHSD-induced changes in neuronal counts were observed in the molecular layer of the hippocampus or within the hippocampal hilum
.
Furthermore, the number of doublecortin-positive cells (immature neurons) in the hippocampal dentate gyrus did not vary between experimental groups (Fig.
8G)
.
Taken together, these results demonstrate that phenotypic microglia are altered upon chronic HFHSD feeding in the absence of a pro-inflammatory phenotype, astrogliosis, or neuronal loss
.
8F)
.
Furthermore, no HFHSD-induced changes in neuronal counts were observed in the molecular layer of the hippocampus or within the hippocampal hilum
.
Furthermore, the number of doublecortin-positive cells (immature neurons) in the hippocampal dentate gyrus did not vary between experimental groups (Fig.
8G)
.
Taken together, these results demonstrate that phenotypic microglia are altered upon chronic HFHSD feeding in the absence of a pro-inflammatory phenotype, astrogliosis, or neuronal loss
.
Taken together, mice fed HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in males than in females
.
Relative to controls, both male and female HFHSD-fed mice exhibited increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working-spatial memory as assessed by spontaneous alternation in the Y-maze
.
Altered metabolite profiles were observed in both the hippocampus and cortex, but were more pronounced in the hippocampus
.
HFHSD-induced metabolic changes included changes in lactate, glutamate, GABA, glutathione, taurine, N -acetyldiaphragmatic acid, total creatine, and total choline levels
.
Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered after 8 weeks of dietary normalization
.
In conclusion, cortical and hippocampal disturbances induced by long-term HFHSDy diet are reversible and not the result of permanent tissue damage
.
Overall, the present study revealed distinct systemic alterations in the metabolite profile of cortical and hippocampal mice fed on HFHSD
.
Changes in the metabolic profile indicate alterations in energy metabolism, adaptations against osmotic imbalance and mitochondrial stress, and cortical neurodegeneration
.
Importantly, although these changes occurred within a few weeks of the initiation of the obesogenic diet, the observed phenotypes were almost completely reversed upon resumption of the healthy diet
.
Thus, the cortical and hippocampal disturbances induced by long-term HFHSDy diet are reversible, suggesting that the response to an unhealthy diet is adaptation rather than permanent structural damage to the brain
.
.
Changes in the metabolic profile indicate alterations in energy metabolism, adaptations against osmotic imbalance and mitochondrial stress, and cortical neurodegeneration
.
Importantly, although these changes occurred within a few weeks of the initiation of the obesogenic diet, the observed phenotypes were almost completely reversed upon resumption of the healthy diet
.
This suggests that the response to an unhealthy diet is adaptation rather than permanent structural damage to the brain tissue
.
Original source:
Alba M Garcia-Serrano Aging Dis.Aging Dis.
Published online 2022 Feb 1.
doi: 10.
14336/AD.
2021.
0720.
10.
14336/AD.
2021.
0720.
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