Neural program in BP regulation vs obesity-related hypertension. Central control of BP in normal physiology involves neural actions of leptin and TNFα; whereas previous work revealed how the connection between leptin and TNFα affects BP, the current study further elucidates that leptin and TNFα also use the melanocortinergic pathway and glutamatergic pathway, respectively, to mediate the physiological control of BP. Crosstalk between these two processes at the level of the downstream neuronal circuitry was identified. In the obesity condition, increased leptin release activates glutamatergic neurons, which contributes to hypertension mainly independently of melanocortinergic neurons, whereas an obesity-associated increase in TNFα (partially due to high leptin level) activates melanocortinergic and glutamatergic neurons, both sequentially and in parallel, to mediate the induction of hypertension. Dotted lines indicate the weakened pathway in obesity compared with normal physiology. Bold lines indicate the pathways that become predominantly important steps in this complex mechanism in obesity. In general, glutamatergic activation is poised at the crossroad of translating obesity-related signals to hypertension and thus represents a critical target for combating obesity-related hypertension.