Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri.
Genome Technology Access Center, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
Endocrinology. 2020 Feb 1;161(2). doi: 10.1210/endocr/bqz010.
Increased visceral adiposity and hyperglycemia, 2 characteristics of metabolic syndrome, are also present in conditions of excess glucocorticoids (GCs). GCs are hormones thought to act primarily via the glucocorticoid receptor (GR). GCs are commonly prescribed for inflammatory disorders, yet their use is limited due to many adverse metabolic side effects. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies about the exact role of MR in metabolic disease. Using MR knockout mice (MRKO), we find that both white and brown adipose depots form normally when compared with wild-type mice at P5. We created mice with adipocyte-specific deletion of MR (FMRKO) to better understand the role of MR in metabolic dysfunction. Treatment of mice with excess GCs for 4 weeks, via corticosterone in drinking water, induced increased fat mass and glucose intolerance to similar levels in FMRKO and floxed control mice. Separately, when fed a high-fat diet for 16 weeks, FMRKO mice had reduced body weight, fat mass, and hepatic steatosis, relative to floxed control mice. Decreased adiposity likely resulted from increased energy expenditure since food intake was not different. RNA sequencing analysis revealed decreased enrichment of genes associated with adipogenesis in inguinal white adipose of FMRKO mice. Differentiation of mouse embryonic fibroblasts (MEFs) showed modestly impaired adipogenesis in MRKO MEFs compared with wild type, but this was rescued upon the addition of peroxisome proliferator-activated receptor gamma (PPARγ) agonist or PPARγ overexpression. Collectively, these studies provide further evidence supporting the potential value of MR as a therapeutic target for conditions associated with metabolic syndrome.
内脏脂肪增加和高血糖是代谢综合征的两个特征，也存在于糖皮质激素（GCs）过量的情况下。GCs 被认为主要通过糖皮质激素受体（GR）发挥作用。GCs 常用于治疗炎症性疾病，但由于许多不良代谢副作用，其应用受到限制。除了 GR，GCs 还与盐皮质激素受体（MR）结合，但关于 MR 在代谢疾病中的确切作用有许多相互矛盾的研究。使用 MR 敲除小鼠（MRKO），我们发现与野生型小鼠相比，P5 时白色和棕色脂肪组织都正常形成。我们创建了脂肪细胞特异性 MR 缺失的小鼠（FMRKO），以更好地理解 MR 在代谢功能障碍中的作用。通过在饮用水中添加皮质酮，用过量 GCs 处理小鼠 4 周，诱导脂肪量增加和葡萄糖耐量异常，在 FMRKO 和 floxed 对照小鼠中达到相似水平。另外，当用高脂肪饮食喂养 16 周时，FMRKO 小鼠的体重、脂肪量和肝脂肪变性比 floxed 对照小鼠减少。脂肪量减少可能是由于能量消耗增加所致，因为食物摄入量没有差异。RNA 测序分析显示，腹股沟白色脂肪中的与脂肪生成相关的基因富集减少。与野生型相比，MRKO MEFs 的脂肪生成能力略有受损，但在添加过氧化物酶体增殖物激活受体γ（PPARγ）激动剂或过表达 PPARγ 后得到挽救。总之，这些研究为 MR 作为代谢综合征相关疾病的治疗靶点提供了进一步的证据。
