TLR4 and overnutrition: As shown in the literature, hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding [36], while overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain can be significantly prevented in mice with brain-specific inhibition of TLR4 signaling [37].