Overall, our results align with the presented partial model and support the notion that unless intervened, HFD/obesity‐associated neuroinflammation may persist because of compromised antioxidant defense and inefficient suppression of proinflammatory cytokines due to the downregulated Sirt‐1‐BDNF‐Nrf2 axis. This evidence concerns the gene SIRT1 and obesity due to melanocortin 4 receptor deficiency.