Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice.
Impact of leptin-mediated sympatho-activation on cardiovascular function in obese mice.
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瘦素介导的交感激活对肥胖小鼠心血管功能的影响。
DOI：
10.1161/hypertensionaha.110.168427
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发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Stepp DW
中科院分区：
文献类型：
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作者：
Belin de Chantemèle EJ;Mintz JD;Rainey WE;Stepp DW
尽管瘦素的厌食作用在肥胖中消失，但瘦素介导的交感神经激活却得以保留。肥胖中瘦素介导的交感神经激活对心血管的影响尚不清楚。我们测试了这样的假设：32 周的高脂肪饮食 (HFD) 会诱导代谢性瘦素抵抗，但会保留瘦素介导的心血管系统交感神经激活。小鼠的 HFD 显着增加了体重和血浆瘦素浓度，但显着降低了瘦素的厌食作用。 HFD 会增加心率 (HR)、每搏输出量、心输出量和血浆醛固酮水平，但不会增加血压 (BP)。正如体内和离体测量的对去氧肾上腺素的收缩反应所反映的，HFD 降低了血管肾上腺素能反应性，这表明外周血管系统交感神经紧张的减少可能会减轻心脏和肾素血管紧张素醛固酮系统 (RAAS) 的交感神经激活。尽管肥胖，但交感神经抑制可部分恢复快速反应，并且在 ob/ob 和 db/db 小鼠中不存在，认为这是交感神经介导和瘦素特异性机制。虽然在 HFD 小鼠中输注瘦素对心率或血压没有影响，但在体重没有减轻的情况下，它进一步增加了醛固酮水平并进一步降低了血管肾上腺素能张力，表明瘦素介导的肥胖心血管系统持续刺激。总之，这些数据表明，尽管代谢性瘦素抵抗，瘦素介导的心脏刺激、脉管系统和醛固酮的产生在肥胖症中持续存在。瘦素对血压的影响可能受到循环中快速过敏反应的限制，这表明肾上腺素能脱敏失败可能是肥胖背景下高血压的必要步骤。
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 (HR), stroke volume, cardiac output and plasma aldosterone levels but not blood pressure (BP). 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 (RAAS). Tachyphlyaxis 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. While infusion of leptin in HFD mice had no effect on HR or BP, 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. BP 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.