Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas.
Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
Endocrinology. 2019 Oct 1;160(10):2485-2494. doi: 10.1210/en.2019-00349.
27-Hydroxycholesterol (27HC) is an abundant cholesterol metabolite and has detrimental effects on the cardiovascular system, whereas its impact on adiposity is not well known. In this study, we found that elevations in 27HC cause increased body weight gain in mice fed a high-fat/high-cholesterol diet in an estrogen receptor α-dependent manner. Regardless of diet type, body fat mass was increased by 27HC without changes in food intake or fat absorption. 27HC did not alter energy expenditure in mice fed a normal chow diet and increased visceral white adipose mass by inducing hyperplasia but not hypertrophy. Although 27HC did not augment adipocyte terminal differentiation, it increased the adipose cell population that differentiates to mature adipocytes. RNA sequencing analysis revealed that 27HC treatment of mice fed a normal chow diet induces inflammatory gene sets similar to those seen after high-fat/high-cholesterol diet feeding, whereas there was no overlap in inflammatory gene expression among any other 27HC administration/diet change combination. Histological analysis showed that 27HC treatment increased the number of total and M1-type macrophages in white adipose tissues. Thus, 27HC promotes adiposity by directly affecting white adipose tissues and by increasing adipose inflammatory responses. Lowering serum 27HC levels may lead to an approach targeting cholesterol to prevent diet-induced obesity.
27-羟胆固醇（27HC）是一种丰富的胆固醇代谢物，对心血管系统有不良影响，但其对肥胖的影响尚不清楚。在这项研究中，我们发现，27HC 的升高以雌激素受体 α 依赖的方式导致高脂肪/高胆固醇饮食喂养的小鼠体重增加。无论饮食类型如何，27HC 都会增加体脂肪量，而不改变食物摄入量或脂肪吸收。27HC 不会改变正常饮食喂养小鼠的能量消耗，而是通过诱导增生而不是肥大来增加内脏白色脂肪质量。虽然 27HC 不会增强脂肪细胞的终末分化，但它增加了分化为成熟脂肪细胞的脂肪细胞群体。RNA 测序分析显示，27HC 处理正常饮食喂养的小鼠会诱导类似于高脂肪/高胆固醇饮食喂养后观察到的炎症基因集，而在任何其他 27HC 给药/饮食变化组合中都没有重叠的炎症基因表达。组织学分析表明，27HC 处理增加了白色脂肪组织中总巨噬细胞和 M1 型巨噬细胞的数量。因此，27HC 通过直接影响白色脂肪组织和增加脂肪炎症反应来促进肥胖。降低血清 27HC 水平可能会导致一种针对胆固醇的方法来预防饮食诱导的肥胖。
