Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice
| Autor: | Shalini Dogra, Boda Arun Kumar, Ajeet Kumar, Chandan Sona, Deepmala Umrao, Prem N. Yadav |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Agonist MAPK/ERK pathway Male cognition medicine.medical_specialty endocrine system Docosahexaenoic Acids medicine.drug_class Central nervous system Hippocampus Diet High-Fat Brain-derived neurotrophic factor Receptors G-Protein-Coupled lcsh:RC321-571 03 medical and health sciences Mice 0302 clinical medicine Neurotrophic factors Internal medicine Free fatty acid receptor 1 medicine Diabetes Mellitus Animals Obesity lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cells Cultured GPR40 Memory Disorders business.industry Association Learning Brain Mice Inbred C57BL DHA 030104 developmental biology medicine.anatomical_structure Endocrinology Neurology Docosahexaenoic acid diabesity business 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 118, Iss, Pp 94-107 (2018) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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