MAPK8 and obesity due to melanocortin 4 receptor deficiency: Aggregated AGEs can activate the JNK, Iκ-B kinase (IKK), NF-κB, and TNF-α pathways to trigger hypothalamic insulin and leptin resistance, resulting in hypothalamic dysfunction, imbalanced energy control, and subsequently elevated food consumption and body weight with obesity and metabolic syndromes78.