Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 560 RRB, Nashville, TN 37232-6602, USA.
Diabetologia. 2013 Apr;56(4):901-10. doi: 10.1007/s00125-012-2814-8. Epub 2013 Jan 12.
AIMS/HYPOTHESIS: Obesity is associated with aldosterone excess, hypertension and the metabolic syndrome, but the relative contribution of aldosterone to obesity-related complications is debated. We previously demonstrated that aldosterone impairs insulin secretion, and that genetic aldosterone deficiency increases glucose-stimulated insulin secretion in vivo. We hypothesised that elimination of endogenous aldosterone would prevent obesity-induced insulin resistance and hyperglycaemia.
Wild-type and aldosterone synthase-deficient (As (-/-)) mice were fed a high-fat (HF) or normal chow diet for 12 weeks. We assessed insulin sensitivity and insulin secretion using clamp methodology and circulating plasma adipokines, and examined adipose tissue via histology.
HF diet induced weight gain similarly in the two groups, but As (-/-) mice were protected from blood glucose elevation. HF diet impaired insulin sensitivity similarly in As (-/-) and wild-type mice, assessed by hyperinsulinaemic-euglycaemic clamps. Fasting and glucose-stimulated insulin were higher in HF-fed As (-/-) mice than in wild-type controls. Although there was no difference in insulin sensitivity during HF feeding in As (-/-) mice compared with wild-type controls, fat mass, adipocyte size and adiponectin increased, while adipose macrophage infiltration decreased. HF feeding significantly increased hepatic steatosis and triacylglycerol content in wild-type mice, which was attenuated in aldosterone-deficient mice.
CONCLUSIONS/INTERPRETATION: These studies demonstrate that obesity induces insulin resistance independently of aldosterone and adipose tissue inflammation, and suggest a novel role for aldosterone in promoting obesity-induced beta cell dysfunction, hepatic steatosis and adipose tissue inflammation.
目的/假设：肥胖与醛固酮过多、高血压和代谢综合征有关，但醛固酮对肥胖相关并发症的相对贡献仍存在争议。我们之前的研究表明，醛固酮会损害胰岛素分泌，而醛固酮基因缺失会增加体内葡萄糖刺激的胰岛素分泌。我们假设消除内源性醛固酮将预防肥胖引起的胰岛素抵抗和高血糖。
野生型和醛固酮合酶缺陷型（As（-/-））小鼠分别用高脂肪（HF）或正常饲料喂养 12 周。我们使用钳夹技术评估胰岛素敏感性和胰岛素分泌，以及循环血浆脂肪因子，并通过组织学检查观察脂肪组织。
HF 饮食在两组中引起相似的体重增加，但 As（-/-）小鼠免受血糖升高的影响。HF 饮食对 As（-/-）和野生型小鼠的胰岛素敏感性产生相似的损害，通过高胰岛素正葡萄糖钳夹进行评估。HF 喂养的 As（-/-）小鼠的空腹和葡萄糖刺激胰岛素均高于野生型对照组。尽管在 HF 喂养期间，As（-/-）小鼠与野生型对照组相比，胰岛素敏感性没有差异，但脂肪量、脂肪细胞大小和脂联素增加，而脂肪组织巨噬细胞浸润减少。HF 喂养显著增加了野生型小鼠的肝脂肪变性和三酰甘油含量，而在醛固酮缺乏的小鼠中则减弱。
结论/解释：这些研究表明，肥胖诱导的胰岛素抵抗独立于醛固酮和脂肪组织炎症，提示醛固酮在促进肥胖诱导的β细胞功能障碍、肝脂肪变性和脂肪组织炎症方面具有新的作用。
