Neural Programmatic Role of Leptin, TNFα, Melanocortin, and Glutamate in Blood Pressure Regulation vs Obesity-Related Hypertension in Male C57BL/6 Mice

Continuous nutritional surplus sets the stage for hypertension development. Whereas moderate dietary obesity in mice is normotensive, the homeostatic balance is disrupted concurrent with an increased risk of hypertension. However, it remains unclear how the obesity-associated prehypertensive state is converted into overt hypertension. Here, using mice with high-fat-diet (HFD)-induced moderate obesity vs control diet (CD)-fed lean mice, we comparatively studied the effects of central leptin and tumor necrosis factor-α (TNFα) as well as the involvement of the neuropeptide melanocortin pathway vs the neurotransmitter glutamate pathway. Compared with CD-fed lean mice, the pressor effect of central excess leptin and TNFα, but not melanocortin, was sensitized in HFD-fed mice. The pressor effect of central leptin in HFD-fed mice was strongly suppressed by glutamatergic inhibition but not by melanocortinergic inhibition. The pressor effect of central TNFα was substantially reversed by melanocortinergic inhibition in HFD-fed mice but barely in CD-fed mice. Regardless of diet, the hypertensive effects of central TNFα and melanocortin were both partially reversed by glutamatergic suppression. Hence, neural control of blood pressure is mediated by a signaling network between leptin, TNFα, melanocortin, and glutamate and changes in dynamics due to central excess leptin and TNFα mediate the switch from normal physiology to obesity-related hypertension.