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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

Impact of HFSTZ on glycemic control.WT or AD transgenic mice were treated with NCD or HFSTZ. (A) Fasting glucose levels by week. (B) Oral glucose tolerance testing was performed 6 weeks after dietary manipulation, and AUC values (right panel) were calculated. (C) Fasting insulin, (D) HOMA-IR, and (E) HbA1c% were determined at the end of the experiment. 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.g001: Impact of HFSTZ on glycemic control.WT or AD transgenic mice were treated with NCD or HFSTZ. (A) Fasting glucose levels by week. (B) Oral glucose tolerance testing was performed 6 weeks after dietary manipulation, and AUC values (right panel) were calculated. (C) Fasting insulin, (D) HOMA-IR, and (E) HbA1c% were determined at the end of the experiment. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).

Mentions: That employing a combination of a high fat diet and low-dose streptozotocin injections produced synergistic effects on metabolic disorders was first confirmed by two-way ANOVA analysis (S1 Table). HFSTZ resulted in significantly increased fasting blood glucose levels in both WT and APPswe/PS1dE9 transgenic (AD) mice 3 weeks after STZ injection (Fig 1A). In contrast, no differences in blood glucose were observed among NCD WT and AD mice. At the end of the experiment, the fasting blood glucose of HFSTZ AD mice was significantly higher than that of HFSTZ WT mice. When comparing glucose tolerance among the groups after 6 weeks, HFSTZ-induced glucose intolerance was worse in AD mice (higher area under the curve [AUC]) compared with that of WT mice (Fig 1B). For serum insulin concentration, we observed a stepwise increment of serum insulin levels in the following order: NCD WT, NCD AD, HFSTZ WT, and HFSTZ AD (Fig 1C). Although the mean HOMA-IR score of HFSTZ AD mice was consistently higher than that of HFSTZ WT mice, there was no difference in HOMA-IR between the NCD WT and NCD AD groups (Fig 1D). Interestingly, the glycated hemoglobin (HbA1c) percentage among the four groups was all approximately 4% and remained unchanged throughout the experiment (Fig 1E). Two-way ANOVA analysis indicated that the interaction of genetic type difference (APPswe/PS1dE9 vs. WT) and induced metabolic disorder (NCD vs. HFSTZ) was associated with increased fasting blood glucose (F interaction (1, 75) = 6.641, p < 0.05) and glucose intolerance (F interaction (1, 41) = 7.966, p < 0.01).


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)

Impact of HFSTZ on glycemic control.WT or AD transgenic mice were treated with NCD or HFSTZ. (A) Fasting glucose levels by week. (B) Oral glucose tolerance testing was performed 6 weeks after dietary manipulation, and AUC values (right panel) were calculated. (C) Fasting insulin, (D) HOMA-IR, and (E) HbA1c% were determined at the end of the experiment. 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.g001: Impact of HFSTZ on glycemic control.WT or AD transgenic mice were treated with NCD or HFSTZ. (A) Fasting glucose levels by week. (B) Oral glucose tolerance testing was performed 6 weeks after dietary manipulation, and AUC values (right panel) were calculated. (C) Fasting insulin, (D) HOMA-IR, and (E) HbA1c% were determined at the end of the experiment. Bars represent the mean ± SEM. Experimental groups labeled with different letters are significantly different from each other (p < 0.05).
Mentions: That employing a combination of a high fat diet and low-dose streptozotocin injections produced synergistic effects on metabolic disorders was first confirmed by two-way ANOVA analysis (S1 Table). HFSTZ resulted in significantly increased fasting blood glucose levels in both WT and APPswe/PS1dE9 transgenic (AD) mice 3 weeks after STZ injection (Fig 1A). In contrast, no differences in blood glucose were observed among NCD WT and AD mice. At the end of the experiment, the fasting blood glucose of HFSTZ AD mice was significantly higher than that of HFSTZ WT mice. When comparing glucose tolerance among the groups after 6 weeks, HFSTZ-induced glucose intolerance was worse in AD mice (higher area under the curve [AUC]) compared with that of WT mice (Fig 1B). For serum insulin concentration, we observed a stepwise increment of serum insulin levels in the following order: NCD WT, NCD AD, HFSTZ WT, and HFSTZ AD (Fig 1C). Although the mean HOMA-IR score of HFSTZ AD mice was consistently higher than that of HFSTZ WT mice, there was no difference in HOMA-IR between the NCD WT and NCD AD groups (Fig 1D). Interestingly, the glycated hemoglobin (HbA1c) percentage among the four groups was all approximately 4% and remained unchanged throughout the experiment (Fig 1E). Two-way ANOVA analysis indicated that the interaction of genetic type difference (APPswe/PS1dE9 vs. WT) and induced metabolic disorder (NCD vs. HFSTZ) was associated with increased fasting blood glucose (F interaction (1, 75) = 6.641, p < 0.05) and glucose intolerance (F interaction (1, 41) = 7.966, p < 0.01).

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