Impaired Satiation and Increased Feeding Behaviour in the Triple-Transgenic Alzheimer's Disease Mouse Model

Abstract

Alzheimer's disease (AD) is associated with non-cognitive symptoms such as changes in feeding behaviour that are often characterised by an increase in appetite. Increased food intake is observed in several mouse models of AD including the triple transgenic (3×TgAD) mouse, but the mechanisms underlying this hyperphagia are unknown. We therefore examined feeding behaviour in 3×TgAD mice and tested their sensitivity to exogenous and endogenous satiety factors by assessing food intake and activation of key brain regions. In the behavioural satiety sequence (BSS), 3×TgAD mice consumed more food after a fast compared to Non-Tg controls. Feeding and drinking behaviours were increased and rest decreased in 3×TgAD mice, but the overall sequence of behaviours in the BSS was maintained. Exogenous administration of the satiety factor cholecystokinin (CCK; 8–30 µg/kg, i.p.) dose-dependently reduced food intake in Non-Tg controls and increased inactive behaviour, but had no effect on food intake or behaviour in 3×TgAD mice. CCK (15 µg/kg, i.p.) increased c-Fos protein expression in the supraoptic nucleus of the hypothalamus, and the nucleus tractus solitarius (NTS) and area postrema of the brainstem to the same extent in Non-Tg and 3×TgAD mice, but less c-Fos positive cells were detected in the paraventricular hypothalamic nucleus of CCK-treated 3×TgAD compared to Non-Tg mice. In response to a fast or a period of re-feeding, there was no difference in the number of c-Fos-positive cells detected in the arcuate nucleus of the hypothalamus, NTS and area postrema of 3×TgAD compared to Non-Tg mice. The degree of c-Fos expression in the NTS was positively correlated to food intake in Non-Tg mice, however, this relationship was absent in 3×TgAD mice. These data demonstrate that 3×TgAD mice show increased feeding behaviour and insensitivity to satiation, which is possibly due to defective gut-brain signalling in response to endogenous satiety factors released by food ingestion.

Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

“…Deregulated hypothalamic functions were reported in AD patients [18]. Consistently, impaired hypothalamic functions such as alternate feeding behaviors and excess food intake are reported in two AD transgenic mice models, 3xTgAD and Tg2576 mice [19,20]. 3xTgAD mice consume more food and are insensitive to cholecystokinin, a potent satiety factor [19].…”

“…Consistently, impaired hypothalamic functions such as alternate feeding behaviors and excess food intake are reported in two AD transgenic mice models, 3xTgAD and Tg2576 mice [19,20]. 3xTgAD mice consume more food and are insensitive to cholecystokinin, a potent satiety factor [19]. Prior to the presence of the amyloid pathology in the hypothalamus, increased food intake and decreased proopiomelanocortin and neuropeptide Y neurons of 3xTgAD mice are observed [21].…”

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…Additionally, genetic deletion of Tau resulted in increased body weight [152]. Impaired satiation and increased feeding behavior [153], as well as changes in body temperature [154] were also observed in a mouse model combining amyloid plaques and Tau pathology (3xTgAD). In Tg4510 mice, weight loss was specific to fat mass and co-occurred with deregulation of metabolic rate [151] as well as disturbances in circadian rhythm [98].…”

Hypermetabolic State in the 7-Month-Old Triple Transgenic Mouse Model of Alzheimer'S Disease and the Effect of Lipoic Acid: A 13C-NMR Study

“…There are also reports showing physiologic changes in the 3xTg-AD mice evidenced by increased food consumption, changes in weight, increased oxygen consumption, carbon dioxide production, defective gutbrain signaling, changes in core body temperature; thus, showing physiologic hyperactivity. [37][38][39] In addition to the association of hypermetabolism with plaques, a metabolic study in the tau transgenic mouse model of AD showed hypermetabolism in cerebral cortex. 19 Concluding Remarks The major finding of this study is the hypermetabolic state in the 7-month-old 3xTg-AD mice as compared with age-matched nonTg mice and these results are in contrast to the hypometabolism observed in 13-month-old 3xTg-AD mice.…”