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

摘要

Abstract 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 JNK 2 on the IR , as well as study the effect of a high‐fat diet ( HFD ) in the brain. Our observations determined how JNK 2 ablation did not induce compensatory responses in the expression of the other isoforms but led to an increase in JNK s total activity. HFD ‐fed animals also showed an increased activity profile of the JNK s. These animals also displayed endoplasmic reticulum stress and up‐regulation of the protein tyrosine phosphatase 1B ( PTP 1B) 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 JNK 2 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 PTP 1B and suppressor of cytokine signalling 3 protein . Cover Image for this issue: doi: 10.1111/jnc.14502 .