Physiology and Behavior Laboratory, Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
Institute of Anatomy, University of Zurich, Zurich, Switzerland.
JCI Insight. 2018 Jul 26;3(14). doi: 10.1172/jci.insight.99015.
Aldosterone synthase inhibitors (ASIs) should alleviate obesity-related cardiovascular and renal problems resulting partly from aldosterone excess, but their clinical use may have limitations. To improve knowledge for the use of ASIs, we investigated physiology in aldosterone synthase-knockout (ASKO) mice. On regular chow diet (CD), ASKO mice ate more and weighed less than WT mice, largely because they hyperventilated to eliminate acid as CO2. Replacing CD with high-fat diet (HFD) lessened the respiratory burden in ASKO mice, as did 12- to 15-hour fasting. The latter eliminated the genotype differences in respiratory workload and energy expenditure (EE). Thus, aldosterone deficiency burdened the organism more when the animals ate carbohydrate-rich chow than when they ate a HFD. Chronic HFD exposure further promoted hyperinsulinemia in ASKO mice that contributed to visceral fat accumulation accompanied by reduced lipolysis, thermogenic reprogramming, and the absence of weight-gain-related EE increases. Intracerebroventricular aldosterone supplementation in ASKO mice attenuated the HFD-induced hyperinsulinemia, but did not affect EE, suggesting that the presence of aldosterone increased the body's energetic efficiency, thus counteracting the EE-increasing effect of low insulin. ASIs may therefore cause acid-overload-induced respiratory burden and promote obesity. Their use in patients with preexisting renal and cardiopulmonary diseases might be contraindicated.
醛固酮合酶抑制剂（ASIs）可以减轻部分由于醛固酮过多引起的肥胖相关心血管和肾脏问题，但它们的临床应用可能存在局限性。为了提高 ASIs 使用的认识，我们研究了醛固酮合酶敲除（ASKO）小鼠的生理学。在普通饲料（CD）饮食中，ASKO 小鼠比 WT 小鼠吃得更多，体重更轻，主要是因为它们通过过度通气将酸以 CO2 的形式排出体外。用高脂肪饮食（HFD）代替 CD 减轻了 ASKO 小鼠的呼吸负担，12-15 小时禁食也是如此。后者消除了呼吸工作量和能量消耗（EE）基因型差异。因此，当动物食用富含碳水化合物的饲料时，醛固酮缺乏对机体的负担比食用 HFD 时更大。慢性 HFD 暴露进一步促进了 ASKO 小鼠的高胰岛素血症，导致内脏脂肪堆积，同时伴随着脂肪分解减少、产热重编程和与体重增加相关的 EE 增加减少。向 ASKO 小鼠的侧脑室中补充醛固酮可减轻 HFD 诱导的高胰岛素血症，但不会影响 EE，表明醛固酮的存在提高了身体的能量效率，从而抵消了低胰岛素对 EE 的增加作用。因此，ASIs 可能会引起酸超负荷引起的呼吸负担，并促进肥胖。它们在存在预先存在的肾脏和心肺疾病的患者中的使用可能是禁忌的。
