Pharmacologic inhibition of TLR4, TLR4 knockout, TLR4-interactor knockdown, or hypothalamic ARC-restricted TLR4 knockdown reduces food intake, increases whole-body energy expenditure, reduces hypothalamic inflammation, and protects rodents from HFD-induced obesity (Milanski et al., 2009; Camandola and Mattson, 2017; Zhao et al., 2017; de Vicente et al., 2021). The gene discussed is TLR4; the disease is obesity due to melanocortin 4 receptor deficiency.