Role of brain c-Jun N-terminal kinase 2 in the control of the insulin receptor and its relationship with cognitive performance in a high-fat diet pre-clinical model
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Insulin resistance has negative consequences on the physiological functioning of the nervous system. The appearance of type 3 diabetes in the brain leads to the development of the sporadic form of Alzheimer's disease. The c-Jun N-terminal kinases (JNK), a subfamily of the Mitogen Activated Protein Kinases, are enzymes composed by three different isoforms with differential modulatory activity against the insulin receptor (IR) and its substrate. This research focused on understanding the regulatory role of JNK2 on the IR, as well as study the effect of a high-fat diet (HFD) in the brain. Our observations determined how JNK2 ablation did not induce compensatory responses in the expression of the other isoforms but led to an increase in JNKs total activity. HFD-fed animals also showed an increased activity profile of the JNKs. These animals also displayed endoplasmic reticulum stress and up-regulation of the protein tyrosine phosphatase 1B (PTP1B) and the suppressor of cytokine signalling 3 protein. Consequently, a reduction in insulin sensitivity was detected and it is correlated with a decrease on the signalling of the IR. Moreover, cognitive impairment was observed in all groups but only wild-type genotype animals fed with HFD showed neuroinflammatory responses. In conclusion, HFD and JNK2 absence cause alterations in normal cognitive activity by altering the signalling of the IR. These affectations are related to the appearance of endoplasmic reticulum stress and an increase in the levels of inhibitory proteins like PTP1B and suppressor of cytokine signalling 3 protein. (Figure presented.). Cover Image for this issue: doi: 10.1111/jnc.14502. © 2019 International Society for Neurochemistry
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