Dietary-challenged mice with Alzheimer-like pathology show increased energy expenditure and reduced adipocyte hypertrophy and steatosis.
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.
['Schreyer|Stefanie|S|', 'Berndt|Nikolaus|N|', 'Eckstein|Johannes|J|', 'Mülleder|Michael|M|', 'Hemmati-Sadeghi|Shabnam|S|', 'Klein|Charlotte|C|', 'Abuelnor|Basim|B|', 'Panzel|Alina|A|', 'Meierhofer|David|D|', 'Spranger|Joachim|J|', 'Steiner|Barbara|B|', 'Brachs|Sebastian|S|']
D017667:Adipocytes D000544:Alzheimer Disease D016564:Amyloid beta-Protein Precursor D000818:Animals D001921:Brain D059305:Diet, High-Fat D019422:Dietary Sucrose D004195:Disease Models, Animal D004734:Energy Metabolism D005234:Fatty Liver D005260:Female D018149:Glucose Intolerance D006801:Humans D006984:Hypertrophy D008099:Liver D051379:Mice D008822:Mice, Transgenic D012720:Severity of Illness Index
energy expenditure hypertrophy steatosis Alzheimer's disease diet-induced obesity