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Hypertension greatly increases the risk for major causes of disability and death including heart disease, target-organ damage, and stroke.1 The risk for cardiovascular disease is compounded by the high incidence of obesity and insulin resistance in patients with hypertension. While there is a well-established clinical association, the precise sites of action and molecular mechanisms linking obesity and hypertension are not fully understood.
Multiple mechanisms may provide a link between excess adiposity and development of hypertension including renal and vascular abnormalities, oxidative stress and inflammation, sympathetic activation, and the renin-angiotensin system (RAS).2 More recently, the adipocyte-derived hormone leptin has been implicated in obesity-induced hypertension. Leptin is secreted in direct proportion to adiposity and acts at hypothalamic receptors to promote satiety and energy expenditure as a compensatory mechanism to obesity. Leptin also activates hypothalamic and brainstem pathways to produce sympathetic-mediated pressor responses (Figure).2 The importance of brain leptin actions in sympathetic activation and hypertension is illustrated by the finding that central leptin receptor antagonism decreases blood pressure and renal sympathetic nerve activity in rabbits exposed to short-term high fat feeding.3 Resistance develops to the positive metabolic effects of leptin, whereas sensitivity to its cardiovascular effects is maintained. This selective resistance may involve differential intracellular signaling pathways and brain-specific sites of action for cardiovascular versus metabolic effects of leptin.4
An emerging concept is that the cardiovascular actions of leptin involve a facilitatory relationship with the RAS. In the periphery, angiotensin (Ang) II promotes leptin secretion from adipocytes.5 Furthermore, global deletion or pharmacologic inhibition of RAS components results in a lean phenotype with maintenance of low endogenous leptin levels.6 On the other hand, chronic systemic leptin infusion increases plasma RAS components, and plasma and lung Ang converting enzyme (ACE) activity is decreased in leptin-deficient ob/ob mice.7 In the central nervous system, leptin and Ang II type-1 receptors (AT1R) are co-localized in forebrain and hindbrain regions involved in cardiometabolic control (Figure). Central administration of an AT1 antagonist or knockout of the AT1a receptor prevents leptin-mediated sympathetic activation in mice, with preservation of effects of on feeding behavior.8 Conversely, acute central leptin infusion increases AT1a receptor gene expression in the subfornical organ and arcuate nucleus.8 These findings implicate brain leptin-RAS interactions in regulation of sympathetic activity.
In this issue of Hypertension, Xue et al.9 build upon this concept by showing that brain leptin-RAS interactions contribute to sensitization of the hypertensive response. In this study, short-term high fat feeding in rats elicited upregulation of central angiotensinergic and proinflammatory pathways in the hypothalamus (Figure), and subsequent sensitization to Ang II-mediated hypertension. This high fat diet (HFD)-induced sensitization was prevented by intracerebroventricular administration of a leptin receptor antagonist, suggesting effects due to endogenous actions of leptin within the brain. Central leptin infusion mimicked HFD-induced hypertension sensitization. Mechanistically, leptin effects were prevented by central pharmacologic inhibition of AT1 receptors, TNF-α synthesis, or microglial activation.
The induction-delay-expression experimental design has been used for decades to examine adaptive neural mechanisms involved in conditions including pain, drug addiction, and stress. The study by Xue et al.9 uniquely employed this design to examine leptin-mediated neuroplasticity and its role in sensitization to hypertension. The authors provide convincing evidence that leptin produces sustained upregulation in neural RAS and proinflammatory pathways controlling blood pressure (Figure), to induce hypertension sensitization. This study furthers evidence for the importance of cross talk between leptin, the RAS, and inflammation for cardiovascular control. Importantly, changes in these neural pathways were observed in an early phase of obesity development preceding the onset of hypertension, which may have implications in understanding etiology and prevention of hypertension. It is possible, however, that changes in these central pathways and the functional sensitization responses would differ with prolonged feeding and the subsequent development of leptin resistance.
In this study, leptin was infused centrally at pharmacologic doses that likely exceed levels produced by HFD. Peripheral infusion of leptin at doses matching endogenous levels achieved with high fat feeding would perhaps be a more relevant model. The authors did show, however, that central leptin antagonism prevented hypertension sensitization in HFD rats with physiologic elevations in plasma and brain leptin levels. It is not clear which specific brain regions participated in leptin-mediated hypertension sensitization as all drugs were administered by intracerebroventricular infusion. In addition, gene expression for RAS components and proinflammatory cytokines were only measured in lamina terminalis structures and in the paraventricular nucleus. Given the evidence for an extended network for leptin cardiovascular actions, it is important to determine which lamina terminalis structures participate in hypertension sensitization, and if other forebrain (e.g. arcuate nucleus) and hindbrain (e.g. solitary tract nucleus) nuclei are involved. Future studies in this regard could include measurement of protein and activity levels for RAS and inflammation components in these pathways, as well as the effect of brain region-specific blockade on these signaling mechanisms.
The findings from this study have raised some interesting questions. First, since the HFD elevated both plasma and brain leptin levels, do these effects result from local actions of brain-derived leptin or from circulating leptin acting at receptors localized to blood-brain barrier deficient circumventricular organs? Second, the HFD-induced sensitization to Ang II hypertension in rats was prevented by intraperitoneal administration of the ganglionic blocker hexamethonium in a previous study.10 Is this enhancement in central sympathetic activity attributed to leptin, and if so which afferent and efferent autonomic pathways are involved? Finally, what is the persistence of the neural RAS and inflammatory pathway changes in this model? It is also of interest to examine the sequence of these changes, their interdependence, and the precise intracellular signaling pathways involved.
Overall, the study by Xue et al.9 shows an important role for elevated leptin in sensitization to Ang II-induced hypertension, and provides new insight into potential brain sites of action for leptin-RAS interactions. This study expands upon previous work showing the impact of prior exposure to stimuli in eliciting persistent changes in the central nervous system, to contribute to sensitization of the hypertensive response. These findings may offer a causal link between obesity and the development of hypertension, as well as have important implications for understanding the pathogenesis of cardiometabolic disease.
Source of Funding: Dr. Arnold is funded by NIH grant HL122507.
Disclosures: There are no relationships to disclose.