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Research Paper|Volume 13, Issue 8|pp 10891—10919

Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis

Stefanie Schreyer1, Nikolaus Berndt2, Johannes Eckstein3, Michael Mülleder4, Shabnam Hemmati-Sadeghi1, Charlotte Klein1, Basim Abuelnor1, Alina Panzel1, David Meierhofer5, Joachim Spranger6,7, Barbara Steiner1, Sebastian Brachs6,7
  • 1Department of Neurology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
  • 2Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 13353, Germany
  • 3Institute of Biochemistry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
  • 4Core Facility High Throughput Mass Spectrometry, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
  • 5Max Planck Institute for Molecular Genetics, Berlin 14195, Germany
  • 6Department of Endocrinology and Metabolism, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
  • 7DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
* Equal contribution
Received: February 17, 2021Accepted: March 27, 2021Published: April 16, 2021
https://doi.org/10.18632/aging.202978

Copyright: © 2021 Schreyer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alzheimer’s disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by 1H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.