Obesity and Metabolism Laboratory, U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
Endocrinology. 2012 Sep;153(9):4266-77. doi: 10.1210/en.2011-2006. Epub 2012 Jul 9.
Menopause promotes central obesity, adipose tissue (AT) inflammation, and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages, T cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation and IR are poorly understood. Here we determined the temporal kinetics of fat accretion, AT inflammation, and IR over a 26-wk time course in ovariectomized (OVX) mice, a model of menopause. OVX and sham-operated (SHM) C57BL6 mice were fed a normal chow diet. Weight, body composition (magnetic resonance imaging), total and regional adiposity, activity, food intake, AT crown-like structures, biohumoral measures, and insulin sensitivity (insulin tolerance testing and homeostatic model assessment) were determined at wk 12, 20, and 26. Macrophages and T cells from perigonadal AT were immunophenotyped by fluorescence-associated cell sorting, and perigonadal adipose tissue (PGAT) gene expression was quantified by quantitative PCR. OVX mice (≈ 31 g) became fatter than SHM mice (≈ 26 g) by wk 12, but mice were equally insulin sensitive. PGAT of OVX mice contained more T cells but expressed higher levels of M2-MΦ (arginase-1) and T cell-regulatory (cytotoxic T-lymphocyte antigen 4) genes. At wk 20, both OVX and SHM mice weighed approximately 35 g and were equally insulin sensitive with comparable amounts of PGAT and total body fat. OVX mice became less insulin sensitive than SHM mice by wk 26, coincident with the down-regulation of PGAT arginase-1 (-20-fold) and cytotoxic T-lymphocyte antigen 4 (2-fold) and up-regulation of M1/Th1 genes CD11c (+2-fold), IL12p40 (+2-fold), and interferon-γ (+78-fold). Ovarian hormone loss in mice induces PGAT inflammation and IR by mechanisms that can be uncoupled from OVX-induced obesity.
绝经会促进中心性肥胖、脂肪组织（AT）炎症和胰岛素抵抗（IR）。肥胖和雌激素的丧失都会激活先天和适应性免疫细胞（巨噬细胞、T 细胞）。体重增加和卵巢激素丧失对 AT 炎症和 IR 的各自影响尚不清楚。在这里，我们在去卵巢（OVX）小鼠 26 周的时间过程中确定了脂肪堆积、AT 炎症和 IR 的时间动力学，OVX 是绝经的模型。OVX 和假手术（SHM）C57BL6 小鼠喂食正常的 Chow 饮食。在第 12、20 和 26 周时，测定体重、身体成分（磁共振成像）、总脂肪和局部脂肪、活动、食物摄入、PGAT 冠层结构、生物体液测量和胰岛素敏感性（胰岛素耐量试验和稳态模型评估）。通过荧光相关细胞分选对 PGAT 中的巨噬细胞和 T 细胞进行免疫表型分析，并通过定量 PCR 定量 PGAT 基因表达。OVX 小鼠（≈31g）在第 12 周时比 SHM 小鼠（≈26g）胖，但小鼠的胰岛素敏感性相同。OVX 小鼠的 PGAT 含有更多的 T 细胞，但表达更高水平的 M2-MΦ（精氨酸酶-1）和 T 细胞调节（细胞毒性 T 淋巴细胞抗原 4）基因。在第 20 周时，OVX 和 SHM 小鼠的体重均约为 35g，胰岛素敏感性相同，PGAT 和全身脂肪量相当。OVX 小鼠在第 26 周时比 SHM 小鼠的胰岛素敏感性下降，同时 PGAT 精氨酸酶-1（-20 倍）和细胞毒性 T 淋巴细胞抗原 4（2 倍）下调，M1/Th1 基因 CD11c（+2 倍）、IL12p40（+2 倍）和干扰素-γ（+78 倍）上调。小鼠卵巢激素丧失通过与 OVX 诱导的肥胖无关的机制诱导 PGAT 炎症和 IR。
