Georgia Health Sciences University, Vascular Biology Center, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.
Hypertension. 2011 Aug;58(2):271-9. doi: 10.1161/HYPERTENSIONAHA.110.168427. Epub 2011 Jun 20.
Although the anorexic effects of leptin are lost in obesity, leptin-mediated sympatho-activation is preserved. The cardiovascular consequences of leptin-mediated sympatho-activation in obesity are poorly understood. We tested the hypothesis that 32 weeks of high-fat diet (HFD) induces metabolic leptin resistance but preserves leptin-mediated sympatho-activation of the cardiovascular system. HFD in mice significantly increased body weight and plasma leptin concentrations but significantly reduced the anorexic effects of leptin. HFD increased heart rate, stroke volume, cardiac output, and plasma aldosterone levels but not blood pressure. As reflected by the contractile response to phenylephrine measured both in vivo and ex vivo, vascular adrenergic reactivity was reduced by HFD, suggesting that reductions in sympathetic tone to the periphery vasculature may mitigate sympatho-activation of the heart and the renin-angiotensin-aldosterone system. Tachyphylaxis was partially restored by symptho-inhibition and not present in ob/ob and db/db mice, despite obesity, arguing for a sympatho-mediated and leptin-specific mechanism. Although infusion of leptin in HFD mice had no effect on heart rate or blood pressure, it further increased aldosterone levels and further reduced vascular adrenergic tone in the absence of weight loss, indicating persistent leptin-mediated stimulation of the cardiovascular system in obesity. In conclusion, these data indicate that, despite metabolic leptin resistance, leptin-mediated stimulation of the heart, the vasculature, and aldosterone production persists in obesity. Blood pressure effects in response to leptin may be limited by a tachyphylactic response in the circulation, suggesting that failure of adrenergic desensitization may be a requisite step for hypertension in the context of obesity.
尽管肥胖症患者的瘦素产生厌食作用丧失，但瘦素介导的交感神经激活仍然存在。肥胖症患者中瘦素介导的交感神经激活对心血管的影响知之甚少。我们检验了这样一个假设，即高脂饮食（HFD）会导致代谢性瘦素抵抗，但仍能保留瘦素对心血管系统的介导性兴奋作用。HFD 喂养的小鼠体重和血浆瘦素浓度显著增加，但瘦素的厌食作用显著降低。HFD 增加了心率、每搏量、心输出量和血浆醛固酮水平，但不影响血压。HFD 降低了血管对苯肾上腺素的反应性，这从体内和体外测量的收缩反应都可以反映出来，这表明外周血管的交感神经张力降低可能减轻了心脏和肾素-血管紧张素-醛固酮系统的兴奋。尽管肥胖，交感神经抑制部分恢复了对苯肾上腺素的反应性，而在 ob/ob 和 db/db 肥胖小鼠中并不存在这种情况，这表明存在一种交感神经介导的和瘦素特异性的机制。尽管 HFD 小鼠中瘦素的输注对心率或血压没有影响，但它进一步增加了醛固酮水平，并进一步降低了血管对苯肾上腺素的反应性，而没有体重减轻，这表明肥胖症患者中瘦素对心血管系统的持续介导性兴奋。总之，这些数据表明，尽管存在代谢性瘦素抵抗，但肥胖症患者的心脏、血管和醛固酮生成仍受到瘦素介导的刺激。对瘦素的血压反应可能受到循环中的脱敏反应限制，这表明在肥胖症的情况下，肾上腺素能失敏失败可能是高血压的必要步骤。
