The obesity caused by long-term HFD consumption had (1) low-grade inflammation found in both local (gut) and systemic (serum) sites, leading to low-grade systemic inflammation and the development of peripheral insulin resistance; (2) hippocampal dysplasticity; (3) brain mitochondrial dysfunction; and (4) cognitive decline. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.