Leptin, Obesity, and Hypertension: A Review of Pathogenetic Mechanisms

The adipokine leptin is expressed at higher concentrations in obese subjects, who also incidentally have a higher prevalence of hypertension. The pathogenesis of this obesity-related hypertension is controversial and is believed to be related to many factors including increased sympathetic activity, abnormalities of the renin-angiotensin system, sodium retention, and an endotheliopathy acting independently or in concert with increased circulating leptin. This review discusses the potential mechanisms through which changes in leptin signal transduction pathways in tissues with the leptin receptor, especially the hypothalamus, mediate the pathogenetic relationships between obesity and hypertension. The hypothesis is explored that leptin effects on blood pressure (BP) are meditated by the downstream effects of hypothalamic leptin signaling and ultimately result in activation of specific melanocortin receptors located on sympathetic neurons in the spinal cord. The physiological consequences of this sympathetic activation of the heart and kidney are activation of the renin-angiotensin system, sodium retention and circulatory expansion and finally, elevated BP. This sequence of events has been elegantly demonstrated with leptin infusion and gene knockout studies in animal models but has not been convincingly reproducibly confirmed in humans. Further studies in human subjects on the specific roles of hypothalamic leptin in essential hypertension are indicated as elucidation of the signaling pathways should provide better understanding of the role of weight loss in BP control and afford an additional mechanism for pharmacologic control of BP in adults and children at risk of cardiovascular disease.