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Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice.

Shie FS, Shiao YJ, Yeh CW, Lin CH, Tzeng TT, Hsu HC, Huang FL, Tsay HJ, Liu HK - PLoS ONE (2015)

Bottom Line: For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity.In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis.Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, ROC.

ABSTRACT
Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

No MeSH data available.


Related in: MedlinePlus

Analysis for serum lipid and hepatic steatosis.The levels of (A) serum TG, (B) total cholesterol, and cholesterol in (C) VLDL and LDL, as well as (D) HDL measured after 11-week dietary manipulations. (E) Representative histological microphotographs of liver sections stained with Oil Red O (scale bar, 50 μm) and hepatic TG contents of mice were quantified. (F) Serum GOT and (G) Serum GPT were also measured. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).
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pone.0134531.g003: Analysis for serum lipid and hepatic steatosis.The levels of (A) serum TG, (B) total cholesterol, and cholesterol in (C) VLDL and LDL, as well as (D) HDL measured after 11-week dietary manipulations. (E) Representative histological microphotographs of liver sections stained with Oil Red O (scale bar, 50 μm) and hepatic TG contents of mice were quantified. (F) Serum GOT and (G) Serum GPT were also measured. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).

Mentions: Dyslipidemia and hepatic steatosis was exacerbated in HFSTZ AD mice.HFD consumption has been shown to lead to obesity and dyslipidemia [22]. Therefore, we continued to analyze serum lipid profiles at the end of our experiment. The serum level of TG significantly increased in HFSTZ AD mice, but not HFSTZ WT mice, as compared with NCD WT and AD mice (Fig 3A). In addition, the serum total cholesterol of HFSTZ-treated mice was significantly higher than that of NCD-fed mice, and HFSTZ AD mice had higher total cholesterol concentrations than HFSTZ WT mice (Fig 3B). HFSTZ treatment significantly increased the serum concentrations of VLDL and LDL as compared with the NCD groups; but there was no difference between AD and WT mice (Fig 3C). Interestingly, the pattern of changes in serum HDL was similar to that in the total cholesterol (Fig 3D). Two-way ANOVA revealed that AD genetic background interacted with HFSTZ to increase serum cholesterol levels (F interaction (1, 28) = 6.598, p < 0.05). HFSTZ condition is known to cause dyslipidemia and increase hepatic TG levels in rodents [19]. Therefore, we performed histological and tissue TG assays to examine the extent of TG accumulation. There was severe hepatic TG staining in HFSTZ AD mice as shown by Oil Red O staining (Fig 3E, left panel). Consistently, liver TG content in HFSTZ AD mice was significantly higher than those measured in the other three groups (Fig 3E, right panel). In contrast, there were no differences in TG content in skeletal muscle among the four groups (data not shown). Two-way ANOVA analysis confirmed an interaction between APPswe/PS1dE9 genotype and HFSTZ on hepatic TG levels (F interaction (1, 61) = 8.648, p < 0.05). In terms of liver function, serum GOT was significantly increased in HFSTZ AD and WT mice (Fig 3F). However, there was no significant difference in serum GPT among the groups (Fig 3G).


Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice.

Shie FS, Shiao YJ, Yeh CW, Lin CH, Tzeng TT, Hsu HC, Huang FL, Tsay HJ, Liu HK - PLoS ONE (2015)

Analysis for serum lipid and hepatic steatosis.The levels of (A) serum TG, (B) total cholesterol, and cholesterol in (C) VLDL and LDL, as well as (D) HDL measured after 11-week dietary manipulations. (E) Representative histological microphotographs of liver sections stained with Oil Red O (scale bar, 50 μm) and hepatic TG contents of mice were quantified. (F) Serum GOT and (G) Serum GPT were also measured. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526466&req=5

pone.0134531.g003: Analysis for serum lipid and hepatic steatosis.The levels of (A) serum TG, (B) total cholesterol, and cholesterol in (C) VLDL and LDL, as well as (D) HDL measured after 11-week dietary manipulations. (E) Representative histological microphotographs of liver sections stained with Oil Red O (scale bar, 50 μm) and hepatic TG contents of mice were quantified. (F) Serum GOT and (G) Serum GPT were also measured. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).
Mentions: Dyslipidemia and hepatic steatosis was exacerbated in HFSTZ AD mice.HFD consumption has been shown to lead to obesity and dyslipidemia [22]. Therefore, we continued to analyze serum lipid profiles at the end of our experiment. The serum level of TG significantly increased in HFSTZ AD mice, but not HFSTZ WT mice, as compared with NCD WT and AD mice (Fig 3A). In addition, the serum total cholesterol of HFSTZ-treated mice was significantly higher than that of NCD-fed mice, and HFSTZ AD mice had higher total cholesterol concentrations than HFSTZ WT mice (Fig 3B). HFSTZ treatment significantly increased the serum concentrations of VLDL and LDL as compared with the NCD groups; but there was no difference between AD and WT mice (Fig 3C). Interestingly, the pattern of changes in serum HDL was similar to that in the total cholesterol (Fig 3D). Two-way ANOVA revealed that AD genetic background interacted with HFSTZ to increase serum cholesterol levels (F interaction (1, 28) = 6.598, p < 0.05). HFSTZ condition is known to cause dyslipidemia and increase hepatic TG levels in rodents [19]. Therefore, we performed histological and tissue TG assays to examine the extent of TG accumulation. There was severe hepatic TG staining in HFSTZ AD mice as shown by Oil Red O staining (Fig 3E, left panel). Consistently, liver TG content in HFSTZ AD mice was significantly higher than those measured in the other three groups (Fig 3E, right panel). In contrast, there were no differences in TG content in skeletal muscle among the four groups (data not shown). Two-way ANOVA analysis confirmed an interaction between APPswe/PS1dE9 genotype and HFSTZ on hepatic TG levels (F interaction (1, 61) = 8.648, p < 0.05). In terms of liver function, serum GOT was significantly increased in HFSTZ AD and WT mice (Fig 3F). However, there was no significant difference in serum GPT among the groups (Fig 3G).

Bottom Line: For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity.In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis.Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis.

View Article: PubMed Central - PubMed

Affiliation: Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, ROC.

ABSTRACT
Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD). For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ) in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

No MeSH data available.


Related in: MedlinePlus