Dataset Information

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid ? Clearance.

ABSTRACT: Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid ? (A?) in overweight mice because its systemic elimination may impact brain A? load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain A? clearance and is increased in the serum of overweight mice. Overweight mice showed increased A? accumulation by the liver, the major site of elimination of systemic A?, but unaltered brain A? levels. We also found that A? accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver A? accumulation-ameliorated by IGF-I administration, and unchanged brain A? levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the A? precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPP?/sAPP? ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of A? without affecting brain A? load. Increased serum IGF-I likely contributes to enhanced peripheral A? clearance in overweight mice, without affecting brain A? load probably because its brain entrance is reduced.

SUBMITTER: Herrero-Labrador R

PROVIDER: S-EPMC7766006 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.

Herrero-Labrador Raquel R Trueba-Saiz Angel A Martinez-Rachadell Laura L Fernandez de Sevilla Mᵃ Estrella ME Zegarra-Valdivia Jonathan A JA Pignatelli Jaime J Diaz-Pacheco Sonia S Fernandez Ana M AM Torres Aleman Ignacio I

International journal of molecular sciences 20201218 24

Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed inc ...[more]

PMID: 33352990

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Project description:Recent discovery reveals HFD insult can cause insulin resistance very rapidly, but the underlying mechanism is still not well understood. We performed a short term experiment in a Diet Induced Insulin resistance mouse model. Objective: Insulin resistance (IR) is one of the earliest predictors of type 2 diabetes. However, diagnosis of IR is limited. High fat fed mouse models provide key insights into IR. We hypothesized that early features of IR are associated with persistent changes in gene expression (GE) and endeavoured to (a) develop novel methods for improving signal:noise in analysis of human GE using mouse models; (b) identify a GE motif that accurately diagnoses IR in humans; and (c) identify novel biology associated with IR in humans. Methods: We integrated human muscle GE data with longitudinal mouse GE data and developed an unbiased three-level cross-species analysis platform (single-gene, gene-set and networks) to generate a gene expression motif (GEM) indicative of IR. A logistic regression classification model validated GEM in 3 independent human datasets (n =115). Results: This GEM of 93 genes substantially improved diagnosis of IR compared to routine clinical measures across multiple independent datasets. Individuals misclassified by GEM possessed other metabolic features raising the possibility that they represent a separate metabolic subclass. The GEM was enriched in pathways previously implicated in insulin action and revealed novel associations between Î²-catenin and Jak1 and IR. Functional analyses using small molecule inhibitors showed an important role for these proteins in insulin action. Conclusions: This study shows that systems approaches for identifying molecular signatures provides a powerful way to stratify individuals into discrete metabolic groups. Moreover, we speculate that the Î²-catenin pathway may represent a novel biomarker for IR in humans that warrant future investigation. Comparison of gene expression in muscle tissue during High Fat Diet (HFD) time course (day 5 and day 42). Chow diet will serve as control for HFD. 4 samples per group serve as experimental replicates.

Dataset Information

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid ? Clearance.

Publications

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance.

Similar Datasets

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