4.7 Article

Taste receptor type 1 member 3 mediates diet-induced cognitive impairment in mice

Journal

LIFE SCIENCES
Volume 334, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2023.122194

Keywords

Taste receptor; Western diet; Cognitive impairment; AMP -activated protein kinase (AMPK); Sirtuin 3; Oxidative stress

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This study investigates the role of TAS1R3 in regulating cognitive impairment induced by long-term consumption of a western diet (WD) in mice. The results show that only wild-type mice fed WD exhibit cognitive impairment, while mice lacking TAS1R3 are not affected even under long-term WD feeding.
Aims: Long-term consumption of a western diet (WD), which is characterized by high intake of saturated fats and sugary drinks, causes cognitive impairment. However, the molecular mechanism by which WD induces cognitive impairment remains unclear. Taste receptor type 1 member 3 (TAS1R3), activated by ligands of WD, is expressed in extra-oral tissues, including the brain, and particularly in the hippocampus. This study investigated whether TAS1R3 regulates WD-induced cognitive impairment in mice.Main methods: Male C57BL/6J wild-type (WT) and Tas1r3 knock-out (KO) mice were fed either a normal diet (ND) or WD for 18 weeks. Cognitive functions were assessed using novel object recognition and Barnes maze tests. The mechanisms underlying WD-induced cognitive impairment were assessed using RNA-sequencing and bioinformatics analysis.Key findings: Cognitive impairment was observed in WT mice fed WD (WT-WD) compared with WT-ND mice. Conversely, mice lacking TAS1R3 were not cognitively impaired even under long-term WD feeding. Hippocampal transcriptome analysis revealed upregulated AMP-activated protein kinase (AMPK) signaling and increased AMPK-targeted sirtuin 3 expression in KO-WD mice. Pathway enrichment analysis showed that response to oxidative stress was downregulated, whereas neurogenesis was upregulated in dentate gyrus of KO-WD mice. In vitro studies validated the findings, indicating that Tas1r3 knockdown directly upregulated decreased sirtuin 3 expression, its downstream genes-related to oxidative stress, and apoptosis induced by WD condition in hippocampal neuron cells. Significance: TAS1R3 acts as a critical mediator of WD-induced cognitive impairment in mice, thereby offering potential as a novel therapeutic target to prevent WD-induced cognitive impairment.

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