Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Universiti Teknologi MARA, Kuala Lumpur, Malaysia.
Metabolism. 2018 Jun;83:92-101. doi: 10.1016/j.metabol.2018.01.012. Epub 2018 Feb 2.
The plasma membrane protein caveolin-1 (CAV-1) has been shown to be involved in modulating glucose homeostasis and the actions of the renin-angiotensin-aldosterone system (RAAS). Caloric restriction (CR) is widely accepted as an effective therapeutic approach to improve insulin sensitivity and reduce the severity of diabetes. Recent data indicate that polymorphisms of the CAV-1 gene are strongly associated with insulin resistance, hypertension and metabolic abnormalities in non-obese individuals. Therefore, we sought to determine whether CR improves the metabolic and cardiovascular (CV) risk factors in the lean CAV-1 KO mice.
MATERIALS/METHODS: Twelve- to fourteen-week-old CAV-1 knockout (KO) and genetically matched wild-type (WT) male mice were randomized by genotype to one of two dietary regimens: ad libitum (ad lib) food intake or 40% CR for 4 weeks. Three weeks following the onset of dietary restriction, all groups were assessed for insulin sensitivity. At the end of the study, all groups were assessed for fasting glucose, insulin, HOMA-IR, lipids, corticosterone levels and blood pressure (BP). Aldosterone secretion was determined from acutely isolated Zona Glomerulosa cells.
We confirmed that the CAV-1 KO mice on the ad lib diet display a phenotype consistent with the cardiometabolic syndrome, as shown by higher systolic BP (SBP), plasma glucose, HOMA-IR and aldosterone levels despite lower body weight compared with WT mice on the ad lib diet. CAV-1 KO mice maintained their body weight on the ad lib diet, but had substantially greater weight loss with CR, as compared to caloric restricted WT mice. CR-mediated changes in weight were associated with dramatic improvements in glucose and insulin tolerance in both genotypes. These responses to CR, however, were more robust in CAV-1KO vs. WT mice and were accompanied by reductions in plasma glucose, insulin and HOMA-IR in CAV-1KO but not WT mice. Surprisingly, in the CAV-1 KO, but not in WT mice, CR was associated with increased SBP and aldosterone levels, suggesting that in CAV-1 KO mice CR induced an increase in some CV risk factors.
CR improved the metabolic phenotype in CAV-1 KO mice by increasing insulin sensitivity; nevertheless, this intervention also increased CV risk by inappropriate adaptive responses in the RAAS and BP.
已有研究表明，质膜蛋白 caveolin-1（CAV-1）在调节葡萄糖稳态和肾素-血管紧张素-醛固酮系统（RAAS）的作用中发挥重要作用。热量限制（CR）被广泛认为是改善胰岛素敏感性和降低糖尿病严重程度的有效治疗方法。最近的数据表明，CAV-1 基因的多态性与非肥胖个体的胰岛素抵抗、高血压和代谢异常密切相关。因此，我们试图确定 CR 是否能改善瘦鼠 CAV-1 KO 模型的代谢和心血管（CV）危险因素。
材料/方法： 将 12-14 周龄的 CAV-1 敲除（KO）和基因匹配的野生型（WT）雄性小鼠按基因型随机分为两种饮食方案之一：自由饮食（ad lib）或 40% CR 限制 4 周。限制饮食 3 周后，所有组均进行胰岛素敏感性评估。研究结束时，所有组均进行空腹血糖、胰岛素、HOMA-IR、血脂、皮质酮水平和血压（BP）评估。醛固酮分泌通过急性分离的肾小球带细胞确定。
我们证实，与自由饮食的 WT 小鼠相比，CAV-1 KO 小鼠即使体重较低，但其自由饮食时的收缩压（SBP）、血糖、HOMA-IR 和醛固酮水平更高，表现出代谢综合征的表型。CAV-1 KO 小鼠在自由饮食时保持体重，但与 CR 限制的 WT 小鼠相比，它们的体重减轻更多。CR 介导的体重变化与两种基因型的葡萄糖和胰岛素耐量的显著改善相关。然而，与 WT 小鼠相比，CAV-1 KO 小鼠对 CR 的反应更为强烈，并且在 CAV-1 KO 小鼠中观察到血糖、胰岛素和 HOMA-IR 的降低，但在 WT 小鼠中没有观察到。令人惊讶的是，在 CAV-1 KO 小鼠中，而不是在 WT 小鼠中，CR 与 SBP 和醛固酮水平的升高相关，这表明在 CAV-1 KO 小鼠中，CR 诱导了 RAAS 和 BP 中一些 CV 危险因素的增加。
CR 通过增加胰岛素敏感性改善了 CAV-1 KO 小鼠的代谢表型；然而，这种干预也通过 RAAS 和 BP 中的不当适应性反应增加了 CV 风险。
