Leptin Mediates High-Fat Diet Sensitization of Angiotensin II–Elicited Hypertension by Upregulating the Brain Renin–Angiotensin System and Inflammation

Abstract

Obesity is characterized by increased circulating levels of the adipocyte-derived hormone leptin, which can increase sympathetic nerve activity and raise blood pressure. A previous study revealed that rats fed a high fat diet (HFD) have an enhanced hypertensive response to subsequent angiotensin (Ang) II administration that is mediated at least in part by increased activity of brain renin-angiotensin system (RAS) and proinflammatory cytokines (PICs). The present study tested whether leptin mediates this HFD-induced sensitization of Ang II-elicited hypertension by interacting with brain RAS and PICs mechanisms. Rats fed a HFD for 3 weeks had significant increases in white adipose tissue mass, plasma leptin levels and mRNA expression of leptin and its receptors in the lamina terminalis (LT) and hypothalamic paraventricular nucleus (PVN). Central infusion of a leptin receptor antagonist during HFD feeding abolished HFD sensitization of Ang II-elicited hypertension. Furthermore, central infusion of leptin mimicked the sensitizing action of HFD. Concomitant central infusions of the AT1-R antagonist irbesartan, the TNF-α synthesis inhibitor pentoxifylline, or the inhibitor of microglial activation minocycline prevented the sensitization produced by central infusion of leptin. RT-PCR analysis indicated that either HFD or leptin administration upregulated mRNA expression of several components of the RAS and PICs in the LT and PVN. The leptin antagonist and the inhibitors of AT1-R, TNF-α synthesis and microglial activation all reversed the expression of these genes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by leptin through upregulation of central RAS and PICs.

Recent advances in the pathophysiology of arterial hypertension - potential implications for clinical practice

“…41 Another study found that high -fat diet elicits augmented hypertensive response to subsequent angiotensin II administration, which is mediated by leptin through upregulation of the central RAAS and proinflammatory cytokines. 42 These findings indicate that sensitization stems from permanent alterations in the brain RAAS and potentiated activation of markers associated with central plasticity which influence the long -term regulation of BP. Understanding the underlying mechanisms may have important implications for preventing and treating hypertension; however, this requires further investigation.…”

To Sensitize or Not to Sensitize

“…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.…”

“…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.…”

“…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.…”

Metabolic Vascular Syndrome: New Insights into a Multidimensional Network of Risk Factors and Diseases

“…These observations contradict the results of a recent 3.5-year prospective observational study which showed that high plasma omentin concentrations might serve as a biomarker for an enhanced risk of cardiovascular mortality in patients with established or suspected stable coronary artery disease [47]. Leptin, about 20 years after its discovery as the key marker of the amount of energy stores with serum concentrations proportional to body fat mass but also regulated by short-and long-term food deprivation [48,49], is known as an appetite-suppressing hormone with many other regulatory roles and fortunate effects in leptin-deficient humans (for short review see [50] able to enhance the sympathetic nerve activity but also to upregulate the brain renin-angiotensin system during high-fat diet [51].…”