Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice
GPR40 (Free fatty acid receptor 1) has emerged as an important therapeutic target for diabetes. Several studies have demonstrated the association of comorbid psychiatric conditions with decreased n-3 polyunsaturated fatty acids, which may act as an agonist for GPR40. In this study, we for the first...
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doaj-9a2ebfb655ce44b1ab8a26dcad9eb9fb2021-03-22T12:46:47ZengElsevierNeurobiology of Disease1095-953X2018-10-0111894107Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in miceChandan Sona0Ajeet Kumar1Shalini Dogra2Boda Arun Kumar3Deepmala Umrao4Prem N. Yadav5Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India; Academy of Scientific and Innovative Research (AcSIR), India; Corresponding author at: Pharmacology Division, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, UP, India.GPR40 (Free fatty acid receptor 1) has emerged as an important therapeutic target for diabetes. Several studies have demonstrated the association of comorbid psychiatric conditions with decreased n-3 polyunsaturated fatty acids, which may act as an agonist for GPR40. In this study, we for the first time provide evidence of reduced GPR40 signaling in the hippocampus and cortex which may be a critical underlying mechanism mediating cognitive deficits in diabesity (diabetes and obesity together). Specifically, we showed decreased GPR40 and brain-derived neurotrophic factor (BDNF) expression in the brain regions of high-fat-diet-induced obese and db/db mice. Next, we demonstrated that chronic treatment with docosahexaenoic acid (DHA) or the synthetic GPR40 agonist, GW9508, significantly alleviates cognitive functions in mice, which correlates with increased BDNF expression in the hippocampus. This supports the hypothesis that DHA improves cognitive function in diabesity via GPR40 agonism. We also showed that DHA specifically activates GPR40 and modulates BDNF expression in primary cortical neurons mediated by the extracellular receptor kinase (ERK) and P38-mitogen-activated protein kinase (MAPK) pathways. Finally, the central nervous system (CNS)-specific blockade of GPR40 signaling abrogated the memory potentiating effects of DHA, and induction of BDNF expression in the hippocampus. Thus, we provided evidence that DHA stimulation of GPR40 mediate some of DHA's beneficial effects in metabolic syndrome and identify GPR40 as a viable therapeutic target for the treatment of CNS-related comorbidities associated with diabesity.http://www.sciencedirect.com/science/article/pii/S0969996118302080GPR40Brain-derived neurotrophic factorcognitionDHAdiabesity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chandan Sona Ajeet Kumar Shalini Dogra Boda Arun Kumar Deepmala Umrao Prem N. Yadav |
spellingShingle |
Chandan Sona Ajeet Kumar Shalini Dogra Boda Arun Kumar Deepmala Umrao Prem N. Yadav Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice Neurobiology of Disease GPR40 Brain-derived neurotrophic factor cognition DHA diabesity |
author_facet |
Chandan Sona Ajeet Kumar Shalini Dogra Boda Arun Kumar Deepmala Umrao Prem N. Yadav |
author_sort |
Chandan Sona |
title |
Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
title_short |
Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
title_full |
Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
title_fullStr |
Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
title_full_unstemmed |
Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
title_sort |
docosahexaenoic acid modulates brain-derived neurotrophic factor via gpr40 in the brain and alleviates diabesity-associated learning and memory deficits in mice |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2018-10-01 |
description |
GPR40 (Free fatty acid receptor 1) has emerged as an important therapeutic target for diabetes. Several studies have demonstrated the association of comorbid psychiatric conditions with decreased n-3 polyunsaturated fatty acids, which may act as an agonist for GPR40. In this study, we for the first time provide evidence of reduced GPR40 signaling in the hippocampus and cortex which may be a critical underlying mechanism mediating cognitive deficits in diabesity (diabetes and obesity together). Specifically, we showed decreased GPR40 and brain-derived neurotrophic factor (BDNF) expression in the brain regions of high-fat-diet-induced obese and db/db mice. Next, we demonstrated that chronic treatment with docosahexaenoic acid (DHA) or the synthetic GPR40 agonist, GW9508, significantly alleviates cognitive functions in mice, which correlates with increased BDNF expression in the hippocampus. This supports the hypothesis that DHA improves cognitive function in diabesity via GPR40 agonism. We also showed that DHA specifically activates GPR40 and modulates BDNF expression in primary cortical neurons mediated by the extracellular receptor kinase (ERK) and P38-mitogen-activated protein kinase (MAPK) pathways. Finally, the central nervous system (CNS)-specific blockade of GPR40 signaling abrogated the memory potentiating effects of DHA, and induction of BDNF expression in the hippocampus. Thus, we provided evidence that DHA stimulation of GPR40 mediate some of DHA's beneficial effects in metabolic syndrome and identify GPR40 as a viable therapeutic target for the treatment of CNS-related comorbidities associated with diabesity. |
topic |
GPR40 Brain-derived neurotrophic factor cognition DHA diabesity |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118302080 |
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