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

• Published in: Journal of neurochemistry 2019-04, Vol.149 (2), p.255-268
• Main Authors: Busquets, Oriol, Eritja, Àuria, López, Blanca M., Ettcheto, Miren, Manzine, Patricia R., Castro‐Torres, Rubén D., Verdaguer, Ester, Olloquequi, Jordi, Vázquez‐Carrera, Manuel, Auladell, Carme, Folch, Jaume, Camins, Antoni
• Format: Article
• Language: English
• Subjects: Ablation; Alzheimer's disease; Animals; Brain; Brain - metabolism; Cognition - physiology; Cognitive ability; Cytokines; Diabetes mellitus; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; ER stress; Genotypes; High fat diet; Inflammation; Insulin; Insulin resistance; Insulin Resistance - physiology; Isoforms; JNK; JNK protein; Kinases; Male; metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 9 - metabolism; Nervous system; Neurodegenerative diseases; neuroinflammation; Protein-tyrosine-phosphatase; Proteins; PTP1B; Receptor, Insulin - metabolism; Signaling; SOCS-3 protein; Substrates; Tyrosine
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14682

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. Cover Image for this issue: doi: 10.1111/jnc.14502. Type 3 diabetes, a previous step to the appearance of sporadic or late‐onset Alzheimer's disease, is characterized for a decrease in the sensitivity of the insulin receptor (IR) in the brain. The c‐JUN N‐terminal kinases (JNK) are regulators of the signalling of the IR. For this study a model of JNK2 knock‐out transgenic mice, coupled with a high‐fat diet (HFD) treatment, was used to describe a reduction in insulin sensitivity and increased cognitive impairment related to stress in the endoplasmic reticulum and the up‐regulation of the protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signalling 3 (SOCS3) proteins. Cover Image for this issue: doi: 10.1111/jnc.14502.