TY - JOUR
T1 - Impaired brain fractalkine-CX3CR1 signaling is implicated in cognitive dysfunction in diet-induced obese mice
AU - Kawamura, Namiko
AU - Katsuura, Goro
AU - Yamada-Goto, Nobuko
AU - Novianti, Ela
AU - Inui, Akio
AU - Asakawa, Akihiro
N1 - Funding Information:
Acknowledgements We wish to thank the Joint Research Laboratory, Kagoshima University Graduate School of Medical and Dental Sciences, for use of their facilities. This work was supported by the Institute of Laboratory Animal Science Research Support Center, Kagoshima University. Contributors NK, GK, and NY-G performed the experiments, contributed to discussions, and wrote the manuscript. EN performed the experiments. AI and AA contributed to discussions and reviewed and edited the manuscript. NK is the guarantor of this work and as such had full access to all the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Funding Information:
Funding This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (16H06404 to AI).
Publisher Copyright:
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/2/10
Y1 - 2021/2/10
N2 - Introduction A diet high in saturated fat is well known to affect neuronal function and contribute to cognitive decline in experimental animals and humans. Fractalkine released from neurons acts on its receptor, CX3C chemokine receptor 1 (CX3CR1), in the microglia to regulate several brain functions. The present study addressed whether fractalkine-CX3CR1 signaling in the brain, especially the hippocampus, contributes to the cognitive deficits observed in diet-induced obese (DIO) mice. Research design and methods Mice were given 60% high-fat diet for 16 weeks. The expression of fractalkine and CX3CR1 in the hippocampus, amygdala and prefrontal cortex of DIO mice was analyzed. Cognitive ability in the Y-maze test and hippocampal glutamate receptors and synaptic markers were observed in DIO and CX3CR1 antagonist-treated mice. Regulation of fractalkine and CX3CR1 expression in the hippocampus was examined following administration of a selective insulin-like growth factor-1 (IGF-1) receptor inhibitor and a tyrosine receptor kinase B (TrkB) antagonist in normal mice. Results DIO mice exhibited significant cognitive deficits in the Y-maze test and decrease in fractalkine and CX3CR1 in the hippocampus and amygdala compared with mice fed a control diet (CD mice). Administration of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. DIO mice and CX3CR1 antagonist-treated mice exhibited significant decreases in protein levels of NMDA (N-methyl-D-aspartate) receptor subunit (NR2A), AMPA (α-amino-5-methyl-3-hydroxy-4-isoxazole propionate) receptor subunit (GluR1) and postsynaptic density protein 95 in the hippocampus compared with their respective controls. Furthermore, plasma IGF-1 and hippocampal brain-derived neurotrophic factor were significantly decreased in DIO mice compared with CD mice. Administration of a selective IGF-1 receptor inhibitor and a TrkB antagonist in normal mice significantly decreased fractalkine and CX3CR1 in the hippocampus. Conclusions These findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.
AB - Introduction A diet high in saturated fat is well known to affect neuronal function and contribute to cognitive decline in experimental animals and humans. Fractalkine released from neurons acts on its receptor, CX3C chemokine receptor 1 (CX3CR1), in the microglia to regulate several brain functions. The present study addressed whether fractalkine-CX3CR1 signaling in the brain, especially the hippocampus, contributes to the cognitive deficits observed in diet-induced obese (DIO) mice. Research design and methods Mice were given 60% high-fat diet for 16 weeks. The expression of fractalkine and CX3CR1 in the hippocampus, amygdala and prefrontal cortex of DIO mice was analyzed. Cognitive ability in the Y-maze test and hippocampal glutamate receptors and synaptic markers were observed in DIO and CX3CR1 antagonist-treated mice. Regulation of fractalkine and CX3CR1 expression in the hippocampus was examined following administration of a selective insulin-like growth factor-1 (IGF-1) receptor inhibitor and a tyrosine receptor kinase B (TrkB) antagonist in normal mice. Results DIO mice exhibited significant cognitive deficits in the Y-maze test and decrease in fractalkine and CX3CR1 in the hippocampus and amygdala compared with mice fed a control diet (CD mice). Administration of the CX3CR1 antagonist 18a in normal mice induced significant cognitive deficits in the Y-maze test. DIO mice and CX3CR1 antagonist-treated mice exhibited significant decreases in protein levels of NMDA (N-methyl-D-aspartate) receptor subunit (NR2A), AMPA (α-amino-5-methyl-3-hydroxy-4-isoxazole propionate) receptor subunit (GluR1) and postsynaptic density protein 95 in the hippocampus compared with their respective controls. Furthermore, plasma IGF-1 and hippocampal brain-derived neurotrophic factor were significantly decreased in DIO mice compared with CD mice. Administration of a selective IGF-1 receptor inhibitor and a TrkB antagonist in normal mice significantly decreased fractalkine and CX3CR1 in the hippocampus. Conclusions These findings indicate that the cognitive decline observed in DIO mice is due, in part, to reduced fractalkine-CX3CR1 signaling in the corticolimbic system.
KW - chemokines
KW - cognitive neuroscience
KW - mice
KW - obesity
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U2 - 10.1136/bmjdrc-2020-001492
DO - 10.1136/bmjdrc-2020-001492
M3 - Article
C2 - 33568358
AN - SCOPUS:85100985149
SN - 2052-4897
VL - 9
JO - BMJ Open Diabetes Research and Care
JF - BMJ Open Diabetes Research and Care
IS - 1
M1 - 001492
ER -